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Kim JM, Minh TH, Jeon EJ, Park JM, Kim S, Choi JS. Effect of short-term gravitational changes on the human minor salivary gland stem cell characteristics. J Oral Biosci 2025; 67:100625. [PMID: 39914647 DOI: 10.1016/j.job.2025.100625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 02/03/2025] [Accepted: 02/04/2025] [Indexed: 03/18/2025]
Abstract
OBJECTIVES Human minor salivary gland stem cells (huMSGSCs) are promising in regenerative medicine. Their multipotent capabilities enable tissue regeneration and offer treatment potential for various diseases. The effects of hypergravity (HyperG) and microgravity (MicroG) on stemness and therapeutic potential are not well explored. Therefore, this study investigated the effects of short-term HyperG and MicroG exposure on huMSGSC stemness and differentiation potential for treating salivary gland dysfunction. METHODS huMSGSCs were exposed to 1G, MicroG, and HyperG. Cell morphology, proliferation, sphere formation, and differentiation potential were analyzed. Stem cell and tight junction markers were evaluated using flow cytometry, real-time PCR, Western blot, and immunofluorescence analysis. RESULTS huMSGSCs showed fibroblast-like morphology and robust proliferation up to passage 10. Differentiation into adipocytes, chondrocytes, and osteocytes was successful, despite enhanced lineage-specific marker expression. HyperG significantly increased proliferation at 48 and 72 h, MicroG-exposed cells formed more numerous and smaller spheres, and HyperG-exposed cells produced larger spheres. HyperG elevated stem cell marker (CD90, LGR5, SOX2) expression levels, and the expression of tight junction protein expressions (ZO-1, ZO-2) was higher under HyperG treatment. CONCLUSIONS Short-term HyperG and MicroG exposure differentially influenced huMSGSC stemness and differentiation potential. HyperG enhanced proliferation, stem cell marker expression, and differentiation capacity. These findings suggest the potential of optimizing huMSGSCs for regenerative therapies that target salivary gland dysfunction and other tissue regeneration applications.
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Affiliation(s)
- Jeong Mi Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Inha University, College of Medicine, 27 Inhang-ro, Jung-gu, Incheon, 22332, Republic of Korea; Research center for controlling Intercellular Communication (RCIC), College of Medicine, Inha University, 100 Inha-ro, Michuholgu, Incheon, 22212, Republic of Korea
| | - Tri Ho Minh
- Department of Otorhinolaryngology-Head and Neck Surgery, Inha University, College of Medicine, 27 Inhang-ro, Jung-gu, Incheon, 22332, Republic of Korea
| | - Eun Jeong Jeon
- Department of Otorhinolaryngology-Head and Neck Surgery, Inha University, College of Medicine, 27 Inhang-ro, Jung-gu, Incheon, 22332, Republic of Korea; Research center for controlling Intercellular Communication (RCIC), College of Medicine, Inha University, 100 Inha-ro, Michuholgu, Incheon, 22212, Republic of Korea; Department of Biomedical Science, Program in Biomedical Science & Engineering, Inha University, 100 Inha-ro, Michuholgu, Incheon, 22212, Republic of Korea
| | - Jin Mi Park
- Department of Otorhinolaryngology-Head and Neck Surgery, Inha University, College of Medicine, 27 Inhang-ro, Jung-gu, Incheon, 22332, Republic of Korea; Research center for controlling Intercellular Communication (RCIC), College of Medicine, Inha University, 100 Inha-ro, Michuholgu, Incheon, 22212, Republic of Korea
| | - Sungryeal Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Inha University, College of Medicine, 27 Inhang-ro, Jung-gu, Incheon, 22332, Republic of Korea; Inha Institute of Aerospace Medicine, Inha University College of Medicine, Incheon, 22332, Republic of Korea
| | - Jeong-Seok Choi
- Department of Otorhinolaryngology-Head and Neck Surgery, Inha University, College of Medicine, 27 Inhang-ro, Jung-gu, Incheon, 22332, Republic of Korea; Research center for controlling Intercellular Communication (RCIC), College of Medicine, Inha University, 100 Inha-ro, Michuholgu, Incheon, 22212, Republic of Korea; Department of Biomedical Science, Program in Biomedical Science & Engineering, Inha University, 100 Inha-ro, Michuholgu, Incheon, 22212, Republic of Korea; Inha Institute of Aerospace Medicine, Inha University College of Medicine, Incheon, 22332, Republic of Korea.
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Liang J, Zhao J, Yang L, Wang Q, Liao J, Li J, Zhuang W, Li F, He J, Tang Y, Chen H, Huang C. MSC-exosomes pretreated by Danshensu extracts pretreating to target the hsa-miR-27a-5p and STAT3-SHANK2 to enhanced antifibrotic therapy. Stem Cell Res Ther 2025; 16:40. [PMID: 39901236 PMCID: PMC11792327 DOI: 10.1186/s13287-025-04181-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 01/23/2025] [Indexed: 02/05/2025] Open
Abstract
BACKGROUND Peritoneal fibrosis (PF) is a serious complication commonly associated with prolonged peritoneal dialysis. Mesenchymal stem cells (MSCs) and their exosomes (Exo) have shown significant therapeutic promise in treating fibrotic conditions. Danshensu (DSS), a bioactive compound from the traditional Chinese herb Danshen reverses fibrosis. This study aims to investigate a novel strategy to enhance the therapeutic efficacy against PF by DSS preconditioning MSCs-derived exosomes (DSS-Exo). METHODS The in vitro studies included the effects of DSS duration on MSCs, and the characterization of DSS-Exo and Exo, followed by the assessment of RNA and protein expression levels of peritoneal fibrosis markers and inflammatory cytokines levels after treating human peritoneal mesothelial (HMrSV5) cells. In vivo experiments were conducted on a PF mouse model to observe cell morphology, collagen deposition, fibrosis localization, and to evaluate peritoneal functions such as filtration rate, urea nitrogen clearance, peritoneal thickness, and protein leakage. Mechanistic insights were gained through the analysis of the STAT3/HIF-1α/VEGF signaling pathway, tissue dual-fluorescence localization,chromatin immunoprecipitation sequencing (ChIP-seq), and dual-luciferase reporter (DLR) assays. Additionally, the differential expression of miRNAs between DSS-Exo and Exo was explored and validation of key miRNA. RESULTS DSS-Exo significantly upregulated E-cadherin, downregulated VEGFA, α-SMA, CTGF and Fibronectin expression in HMrSV5 cells compared to untreated Exo. In vivo studies revealed that DSS-Exo enhanced the ability of Exo to improve peritoneal function,such as the peritoneal filtration rate and urea nitrogen, glucose clearance, while reducing peritoneal thickness and protein leakage, and cell morphology, reduce collagen deposition, and decrease the degree of fibrosis. Mechanistically, these exosomes inhibited the STAT3/HIF-1α/VEGF signaling pathway within peritoneal mesothelial tissues. Furthermore, ChIP-seq and DLR demonstrated that DSS-Exo affected STAT3 directly binds to SHANK2 promoter regions, forming hydrogen bonds between 5 key amino acids such as GLN-344, HIS-332 and 6 key bases such as DG-258, DG-261. miRNA profiling identified DSS-Exo increased hsa-miR-27a-5p_R-1 to regulated STAT3-SHANK2 and modulating the EMT. CONCLUSION This study highlighted the innovative use of Danshensu in enhancing MSC-derived exosome therapy for PF. The identification of the hsa-miR-27a-5p_R-1-STAT3-SHANK2 axis may reveal new molecular mechanisms underlying fibrosis, further research is needed to fully elucidate its impact on PF. The integration of Danshensu from traditional Chinese medicine into modern MSC exosome therapy represents a promising frontier in the development of novel treatments for fibrotic diseases.
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Affiliation(s)
- Jiabin Liang
- The Affiliated Panyu Central Hospital of Guangzhou Medical University, Guangzhou, China
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jingxiu Zhao
- Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Laboratory Science, ShunDe Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lin Yang
- The Affiliated Panyu Central Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qian Wang
- The Affiliated Panyu Central Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jing Liao
- Panyu Hospital of Traditional Chinese Medicine, Guangzhou, China
| | - Jianhao Li
- The Affiliated Panyu Central Hospital of Guangzhou Medical University, Guangzhou, China
| | - Weizhao Zhuang
- The Affiliated Panyu Central Hospital of Guangzhou Medical University, Guangzhou, China
| | - Fanghong Li
- The Affiliated Panyu Central Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jinxian He
- The Affiliated Panyu Central Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yukuan Tang
- The Affiliated Panyu Central Hospital of Guangzhou Medical University, Guangzhou, China
| | - Hanwei Chen
- The Affiliated Panyu Central Hospital of Guangzhou Medical University, Guangzhou, China.
- Panyu Health Management Center, Guangzhou, 511400, China.
| | - Chen Huang
- The Affiliated Panyu Central Hospital of Guangzhou Medical University, Guangzhou, China.
- Medical Imaging Institute of Panyu, Guangzhou, 511400, China.
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Hodgson-Garms M, Moore MJ, Martino MM, Kelly K, Frith JE. Proteomic profiling of iPSC and tissue-derived MSC secretomes reveal a global signature of inflammatory licensing. NPJ Regen Med 2025; 10:7. [PMID: 39905050 PMCID: PMC11794695 DOI: 10.1038/s41536-024-00382-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 12/03/2024] [Indexed: 02/06/2025] Open
Abstract
Much of the therapeutic potential of mesenchymal stromal cells (MSCs) is underpinned by their secretome which varies significantly with source, donor and microenvironmental cues. Understanding these differences is essential to define the mechanisms of MSC-based tissue repair and optimise cell therapies. This study analysed the secretomes of bone-marrow (BM.MSCs), umbilical-cord (UC.MSCs), adipose-tissue (AT.MSCs) and clinical/commercial-grade induced pluripotent stem cell-derived MSCs (iMSCs), under resting and inflammatory licenced conditions. iMSCs recapitulated the inflammatory licensing process, validating their comparability to tissue-derived MSCs. Overall, resting secretomes were defined by extracellular matrix (ECM) and pro-regenerative proteins, while licensed secretomes were enriched in chemotactic and immunomodulatory proteins. iMSC and UC.MSC secretomes contained proteins indicating proliferative potential and telomere maintenance, whereas adult tissue-derived secretomes contained fibrotic and ECM-related proteins. The data and findings from this study will inform the optimum MSC source for particular applications and underpin further development of MSC therapies.
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Affiliation(s)
- Margeaux Hodgson-Garms
- Department of Materials Science and Engineering, Monash University, Melbourne, VIC, Australia.
- Cynata Therapeutics, Melbourne, VIC, Australia.
| | - Matthew J Moore
- Department of Materials Science and Engineering, Monash University, Melbourne, VIC, Australia
| | - Mikaël M Martino
- Australian Regenerative Medicine Institute, Melbourne, VIC, Australia
- Victorian Heart Institute, Monash University, Melbourne, VIC, Australia
| | | | - Jessica E Frith
- Department of Materials Science and Engineering, Monash University, Melbourne, VIC, Australia.
- Australian Regenerative Medicine Institute, Melbourne, VIC, Australia.
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Chen L, He D, Li Z, Cui S, Yu M, Zhao Z, Chen Y, Song J, Jiang N, Yu H, Liu Y. Endo 180 participates in collagen remodeling of the periodontal ligament during orthodontic tooth movement. BMC Oral Health 2024; 24:1576. [PMID: 39741253 DOI: 10.1186/s12903-024-05362-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 12/18/2024] [Indexed: 01/02/2025] Open
Abstract
BACKGROUND Orthodontic tooth movement (OTM) relies on the remodeling of periodontal tissues, including the periodontal ligament (PDL) and alveolar bone. Collagen remodeling plays a crucial role during this process, allowing for the necessary changes in the PDL's structure and function. Endo180, an urokinase plasminogen activator receptor-associated protein, is a transmembrane receptor regulated collagen remodeling. This study aims to investigate whether and how Endo180 participates in collagen remodeling within the PDL during OTM. MATERIALS AND METHODS A mechanical force-induced OTM rat model was established using a closed coiled spring to mesially move the right maxillary first molar. The distance of OTM was examined by micro-computed tomography (micro-CT). The collagen remodeling within the PDL was assessed using atomic force microscope (AFM), Hematoxylin-Eosin (HE) staining and Masson staining. Protein expressions of Endo180, collagen I (COL I) and collagen III (COL III) were analyzed via immunofluorescence staining. Additionally, the mRNA expressions of Endo180, COL I, and COL III in force-induced PDL cells were examined by RT-qPCR in vitro. To further illustrate the role of Endo180 in regulating COL I and COL III expressions, Endo180 siRNA (siEndo) was applied to force-stimulated PDL cells. RESULTS Force application increased OTM distance and disrupted collagen fiber organization, with a greater decrease in collagen elastic modulus on the mesial side than on the distal side of the PDL. After 7 days of force application, Endo180 and COL III expressions significantly increased in PDL tissues, while COL I expression decreased in PDL tissues. Compressive force loading in vitro upregulated the mRNA expressions of Endo180 and COL III, but downregulated COL I mRNA expression. Notably, Endo180 knockdown using siRNA suppressed force-induced COL III expression while restoring the downregulated COL I expression under compressive force stimuli. CONCLUSION Force-induced Endo180 expression modulates collagen remodeling in PDL during OTM by upregulating COL III and downregulating COL I. This collagen reorganization facilitates efficient tooth movement, highlighting Endo180 as a potential therapeutic target to optimize orthodontic treatment outcomes.
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Affiliation(s)
- Liyuan Chen
- Department of Orthodontics, Central Laboratory, Hospital for Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health & NMPA Key Laboratory for Dental Materials & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Peking University School, 22th Zhongguancun South Ave, Beijing, 100081, China
| | - Danqing He
- Department of Orthodontics, Central Laboratory, Hospital for Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health & NMPA Key Laboratory for Dental Materials & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Peking University School, 22th Zhongguancun South Ave, Beijing, 100081, China
| | - Zixin Li
- Department of Stomatology, Peking University People's Hospital, Beijing, China
| | - Shengjie Cui
- Department of General Dentistry, Peking University School and Hospital of Stomatology, Beijing, China
| | - Min Yu
- Department of Orthodontics, Central Laboratory, Hospital for Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health & NMPA Key Laboratory for Dental Materials & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Peking University School, 22th Zhongguancun South Ave, Beijing, 100081, China
| | - Zimo Zhao
- Department of Orthodontics, Central Laboratory, Hospital for Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health & NMPA Key Laboratory for Dental Materials & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Peking University School, 22th Zhongguancun South Ave, Beijing, 100081, China
| | - Yuetong Chen
- Department of Orthodontics, Central Laboratory, Hospital for Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health & NMPA Key Laboratory for Dental Materials & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Peking University School, 22th Zhongguancun South Ave, Beijing, 100081, China
| | - Jiayi Song
- Department of Orthodontics, Central Laboratory, Hospital for Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health & NMPA Key Laboratory for Dental Materials & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Peking University School, 22th Zhongguancun South Ave, Beijing, 100081, China
| | - Nan Jiang
- Central Laboratory, Peking University School and Hospital of Stomatology & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Huajie Yu
- Peking University Hospital of Stomatology Fourth Division, No.41 Dongsihuan Zhong Road, Beijing, China.
| | - Yan Liu
- Department of Orthodontics, Central Laboratory, Hospital for Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health & NMPA Key Laboratory for Dental Materials & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Peking University School, 22th Zhongguancun South Ave, Beijing, 100081, China.
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Rojas-Rivera D, Beltrán S, Muñoz-Carvajal F, Ahumada-Montalva P, Abarzúa L, Gomez L, Hernandez F, Bergmann CA, Labrador L, Calegaro-Nassif M, Bertrand MJ, Manque PA, Woehlbier U. The autophagy protein RUBCNL/PACER represses RIPK1 kinase-dependent apoptosis and necroptosis. Autophagy 2024; 20:2444-2459. [PMID: 38873940 PMCID: PMC11572279 DOI: 10.1080/15548627.2024.2367923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 06/01/2024] [Accepted: 06/10/2024] [Indexed: 06/15/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are used in cell therapy; nonetheless, their application is limited by their poor survival after transplantation in a proinflammatory microenvironment. Macroautophagy/autophagy activation in MSCs constitutes a stress adaptation pathway, promoting cellular homeostasis. Our proteomics data indicate that RUBCNL/PACER (RUN and cysteine rich domain containing beclin 1 interacting protein like), a positive regulator of autophagy, is also involved in cell death. Hence, we screened MSC survival upon various cell death stimuli under loss or gain of function of RUBCNL. MSCs were protected from TNF (tumor necrosis factor)-induced regulated cell death when RUBCNL was expressed. TNF promotes inflammation by inducing RIPK1 kinase-dependent apoptosis or necroptosis. We determine that MSCs succumb to RIPK1 kinase-dependent apoptosis upon TNF sensing and necroptosis when caspases are inactivated. We show that RUBCNL is a negative regulator of both RIPK1-dependent apoptosis and necroptosis. Furthermore, RUBCNL mutants that lose the ability to regulate autophagy, retain their function in negatively regulating cell death. We also found that RUBCNL forms a complex with RIPK1, which disassembles in response to TNF. In line with this finding, RUBCNL expression limits assembly of RIPK1-TNFRSF1A/TNFR1 complex I, suggesting that complex formation between RUBCNL and RIPK1 represses TNF signaling. These results provide new insights into the crosstalk between the RIPK1-mediated cell death and autophagy machineries and suggest that RUBCNL, due to its functional duality in autophagy and apoptosis/necroptosis, could be targeted to improve the therapeutic efficacy of MSCs. Abbreviations: BAF: bafilomycin A1; CASP3: caspase 3; Caspases: cysteine-aspartic proteases; cCASP3: cleaved CASP3; CQ: chloroquine; CHX: cycloheximide; cPARP: cleaved poly (ADP-ribose) polymerase; DEPs: differential expressed proteins; ETO: etoposide; MEF: mouse embryonic fibroblast; MLKL: mixed lineage kinase domain-like; MSC: mesenchymal stem cell; MTORC1: mechanistic target of rapamycin kinase complex 1; Nec1s: necrostatin 1s; NFKB/NF-kB: nuclear factor of kappa light polypeptide gene enhancer in B cells; PLA: proximity ligation assay; RCD: regulated cell death; RIPK1: receptor (TNFRSF)-interacting serine-threonine kinase 1; RIPK3: receptor-interacting serine-threonine kinase 3; RUBCNL/PACER: RUN and cysteine rich domain containing beclin 1 interacting protein like; siCtrl: small interfering RNA nonsense; siRNA: small interfering RNA; TdT: terminal deoxynucleotidyl transferase; Tm: tunicamycin; TNF: tumor necrosis factor; TNFRSF1A/TNFR1: tumor necrosis factor receptor superfamily, member 1a.
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Affiliation(s)
- Diego Rojas-Rivera
- Cell Death & Biomedicine Laboratory, Centro de Biomedicina, Universidad Mayor, Santiago, Chile
- VIB Center for Inflammation Research, Universidad Mayor, Ghent, Belgium
| | - Sebastián Beltrán
- Center for Integrative Biology, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
- Programa de Doctorado en Genómica Integrativa, VRI, Facultad de Ciencia, Universidad Mayor, Santiago, Chile
- Escuela de Tecnología Médica, Facultad de Medicina y Ciencias de la Salud, Universidad Mayor, Santiago, Chile
| | | | - Pablo Ahumada-Montalva
- Cell Death & Biomedicine Laboratory, Centro de Biomedicina, Universidad Mayor, Santiago, Chile
- Programa de Doctorado en Neurobiología, VRI, Facultad de Ciencia, Universidad Mayor, Santiago, Chile
| | - Lorena Abarzúa
- Cell Death & Biomedicine Laboratory, Centro de Biomedicina, Universidad Mayor, Santiago, Chile
| | - Laura Gomez
- Center for Integrative Biology, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
| | - Fernanda Hernandez
- Center for Integrative Biology, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
| | - Cristian A. Bergmann
- Center for Integrative Biology, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
- Programa de Doctorado en Genómica Integrativa, VRI, Facultad de Ciencia, Universidad Mayor, Santiago, Chile
| | - Luis Labrador
- Center for Integrative Biology, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
- Programa de Doctorado en Genómica Integrativa, VRI, Facultad de Ciencia, Universidad Mayor, Santiago, Chile
| | - Melissa Calegaro-Nassif
- Laboratorio de Autofagia y Neuroprotección, Centro de Biomedicina, Universidad Mayor, Santiago, Chile
| | - Mathieu J.M. Bertrand
- VIB Center for Inflammation Research, Universidad Mayor, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Patricio A. Manque
- Center for Integrative Biology, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
- Centro de Oncologia de Precision (COP), Escuela de Medicina, Universidad Mayor, Santiago, Chile
| | - Ute Woehlbier
- Center for Integrative Biology, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
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Yuan Y, Liu T. Influence of mesenchymal stem cells from different origins on the therapeutic effectiveness of systemic lupus erythematosus. Exp Cell Res 2024; 442:114263. [PMID: 39307406 DOI: 10.1016/j.yexcr.2024.114263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 08/09/2024] [Accepted: 09/19/2024] [Indexed: 11/01/2024]
Abstract
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune inflammatory disorder characterized by alterations in the balance between inflammatory and regulatory cytokines. Mesenchymal stem cells (MSCs), which are non-hematopoietic stem cells with multipotent differentiation potential, due to their immunomodulatory, tissue repair, low immunogenicity, and chemotactic properties, have garnered increasing interest in SLE treatment. Studies increasingly reveal the heterogeneous nature of MSC populations. With sources including dental pulp, adipose tissue, bone marrow, and umbilical cord, the therapeutic effects of MSCs on SLE vary depending on their origin. This review consolidates clinical research on MSCs from different sources in treating SLE and analyzes the possible causes underlying these variable outcomes. Additionally, it elucidates five potential factors impacting the outcomes of MSC therapy in SLE: the influence of the microenvironment on MSCs, the complexity and paradoxical aspects of MSC mechanisms in SLE treatment, the heterogeneity of MSCs, the in vivo differentiation potential and post-transplant survival rates of MSCs, and disparities in MSC preparation conditions.
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Affiliation(s)
- Yuan Yuan
- Hengyang Medical College, University of South China, Hengyang, 421001, Hunan Province, China.
| | - Tong Liu
- Hengyang Medical College, University of South China, Hengyang, 421001, Hunan Province, China
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Yu C, Liu J, Sakurai R, Wang Y, Afrose L, Gour A, Sharma A, Chandan G, Rehan VK. Perinatal nicotine vaping exposure induces pro-myofibroblastic phenotype in rat bone marrow-derived mesenchymal stem cells. Reprod Toxicol 2024; 129:108673. [PMID: 39059775 PMCID: PMC11377149 DOI: 10.1016/j.reprotox.2024.108673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/18/2024] [Accepted: 07/21/2024] [Indexed: 07/28/2024]
Abstract
Perinatal nicotine exposure via tobacco smoking results in increased proclivity to chronic lung disease (CLD); however, the underlying molecular mechanisms remain incompletely understood. We previously demonstrated that in addition to nicotine's direct effects on the developing lung, there are also adverse molecular alterations in bone marrow-derived mesenchymal stem cells (BMSCs), which are vital to lung injury repair. Whether perinatal nicotine exposure via electronic-cigarette (e-cig) vaping also adversely affects BMSCs is unknown. This is highly relevant due to marked increase in e-cig vaping including by pregnant women. Hypothesizing that perinatal nicotine exposure via e-cig vaping predisposes BMSCs to a pro-myofibroblastic phenotype, pregnant rat dams were exposed to fresh air (control), vehicle (e-cig without nicotine), or e-cig (e-cig with nicotine) daily during pregnancy and lactation. At postnatal day 21, offspring BMSCs were isolated and studied for cell proliferation, migration, wound healing response, and expression of key Wnt and PPARγ signaling intermediates (β-catenin, LEF-1, PPARγ, ADRP and C/EBPα) and myogenic markers (fibronectin, αSMA, calponin) proteins using immunoblotting. Compared to controls, perinatal e-cig exposure resulted in significant decrease in BMSC proliferation, migration, and wound healing response. The expression of key Wnt signaling intermediates (β-catenin, LEF-1) and myogenic markers (fibronectin, αSMA, calponin) increased significantly, while PPARγ signaling intermediates (PPARγ, ADRP, and C/EBPα) decreased significantly. Based on these data, we conclude that perinatally e-cig exposed BMSCs demonstrate pro-myofibroblastic phenotype and impaired injury-repair potential, indicating a potentially similar susceptibility to CLD following perinatal nicotine exposure via vaping as seen following parenteral perinatal nicotine exposure.
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Affiliation(s)
- Celia Yu
- Department of Pediatrics, The Lundquist Institute of Biomedical Innovation at Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502, USA
| | - Jie Liu
- Department of Pediatrics, The Lundquist Institute of Biomedical Innovation at Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502, USA
| | - Reiko Sakurai
- Department of Pediatrics, The Lundquist Institute of Biomedical Innovation at Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502, USA
| | - Ying Wang
- Department of Pediatrics, The Lundquist Institute of Biomedical Innovation at Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502, USA
| | - Leela Afrose
- Department of Pediatrics, The Lundquist Institute of Biomedical Innovation at Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502, USA
| | - Abhishek Gour
- Department of Pharmaceutics, University of Florida, 1345 Center Drive, Gainesville, FL 32610, USA
| | - Abhisheak Sharma
- Department of Pharmaceutics, University of Florida, 1345 Center Drive, Gainesville, FL 32610, USA
| | - Gourav Chandan
- Department of Pediatrics, The Lundquist Institute of Biomedical Innovation at Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502, USA
| | - Virender K Rehan
- Department of Pediatrics, The Lundquist Institute of Biomedical Innovation at Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502, USA.
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Zheng L, Chen W, Yao K, Xie Y, Liao C, Zhou T. Clinical and preclinical studies of mesenchymal stem cells to alleviate peritoneal fibrosis. Stem Cell Res Ther 2024; 15:237. [PMID: 39080683 PMCID: PMC11290310 DOI: 10.1186/s13287-024-03849-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 07/15/2024] [Indexed: 08/02/2024] Open
Abstract
Peritoneal dialysis is an important part of end-stage kidney disease replacement therapy. However, prolonged peritoneal dialysis can result in peritoneal fibrosis and ultrafiltration failure, forcing patients to withdraw from peritoneal dialysis treatment. Therefore, there is an urgent need for some effective measures to alleviate the occurrence and progression of peritoneal fibrosis. Mesenchymal stem cells play a crucial role in immunomodulation and antifibrosis. Numerous studies have investigated the fact that mesenchymal stem cells can ameliorate peritoneal fibrosis mainly through the paracrine pathway. It has been discovered that mesenchymal stem cells participate in the improvement of peritoneal fibrosis involving the following signaling pathways: TGF-β/Smad signaling pathway, AKT/FOXO signaling pathway, Wnt/β-catenin signaling pathway, TLR/NF-κB signaling pathway. Additionally, in vitro experiments, mesenchymal stem cells have been shown to decrease mesothelial cell death and promote proliferation. In animal models, mesenchymal stem cells can enhance peritoneal function by reducing inflammation, neovascularization, and peritoneal thickness. Mesenchymal stem cell therapy has been demonstrated in clinical trials to improve peritoneal function and reduce peritoneal fibrosis, thus improving the life quality of peritoneal dialysis patients.
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Affiliation(s)
- Lingqian Zheng
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Wenmin Chen
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Kaijin Yao
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Yina Xie
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Chunling Liao
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Tianbiao Zhou
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China.
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9
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Taherian M, Bayati P, Mojtabavi N. Stem cell-based therapy for fibrotic diseases: mechanisms and pathways. Stem Cell Res Ther 2024; 15:170. [PMID: 38886859 PMCID: PMC11184790 DOI: 10.1186/s13287-024-03782-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 06/04/2024] [Indexed: 06/20/2024] Open
Abstract
Fibrosis is a pathological process, that could result in permanent scarring and impairment of the physiological function of the affected organ; this condition which is categorized under the term organ failure could affect various organs in different situations. The involvement of the major organs, such as the lungs, liver, kidney, heart, and skin, is associated with a high rate of morbidity and mortality across the world. Fibrotic disorders encompass a broad range of complications and could be traced to various illnesses and impairments; these could range from simple skin scars with beauty issues to severe rheumatologic or inflammatory disorders such as systemic sclerosis as well as idiopathic pulmonary fibrosis. Besides, the overactivation of immune responses during any inflammatory condition causing tissue damage could contribute to the pathogenic fibrotic events accompanying the healing response; for instance, the inflammation resulting from tissue engraftment could cause the formation of fibrotic scars in the grafted tissue, even in cases where the immune system deals with hard to clear infections, fibrotic scars could follow and cause severe adverse effects. A good example of such a complication is post-Covid19 lung fibrosis which could impair the life of the affected individuals with extensive lung involvement. However, effective therapies that halt or slow down the progression of fibrosis are missing in the current clinical settings. Considering the immunomodulatory and regenerative potential of distinct stem cell types, their application as an anti-fibrotic agent, capable of attenuating tissue fibrosis has been investigated by many researchers. Although the majority of the studies addressing the anti-fibrotic effects of stem cells indicated their potent capabilities, the underlying mechanisms, and pathways by which these cells could impact fibrotic processes remain poorly understood. Here, we first, review the properties of various stem cell types utilized so far as anti-fibrotic treatments and discuss the challenges and limitations associated with their applications in clinical settings; then, we will summarize the general and organ-specific mechanisms and pathways contributing to tissue fibrosis; finally, we will describe the mechanisms and pathways considered to be employed by distinct stem cell types for exerting anti-fibrotic events.
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Affiliation(s)
- Marjan Taherian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Paria Bayati
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Nazanin Mojtabavi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
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10
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Shao Z, Wang B, Gao H, Zhang S. Microenvironmental interference with intra-articular stem cell regeneration influences the onset and progression of arthritis. Front Genet 2024; 15:1380696. [PMID: 38841721 PMCID: PMC11150611 DOI: 10.3389/fgene.2024.1380696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 04/30/2024] [Indexed: 06/07/2024] Open
Abstract
Studies have indicated that the preservation of joint health and the facilitation of damage recovery are predominantly contingent upon the joint's microenvironment, including cell-cell interactions, the extracellular matrix's composition, and the existence of local growth factors. Mesenchymal stem cells (MSCs), which possess the capacity to self-renew and specialize in many directions, respond to cues from the microenvironment, and aid in the regeneration of bone and cartilage, are crucial to this process. Changes in the microenvironment (such as an increase in inflammatory mediators or the breakdown of the extracellular matrix) in the pathological context of arthritis might interfere with stem cell activation and reduce their ability to regenerate. This paper investigates the potential role of joint microenvironmental variables in promoting or inhibiting the development of arthritis by influencing stem cells' ability to regenerate. The present status of research on stem cell activity in the joint microenvironment is also outlined, and potential directions for developing new treatments for arthritis that make use of these intervention techniques to boost stem cell regenerative potential through altering the intra-articular environment are also investigated. This review's objectives are to investigate these processes, offer fresh perspectives, and offer a solid scientific foundation for the creation of arthritic treatment plans in the future.
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Affiliation(s)
| | | | | | - Shenqi Zhang
- Department of Joint and Sports Medicine, Zaozhuang Municipal Hospital Affiliated to Jining Medical University, Zaozhuang, Shandong, China
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11
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Tang S, Zhang R, Bai H, Shu R, Chen D, He L, Zhou L, Liao Z, Chen M, Pei F, Mao JJ, Shi X. Endogenus chondrocytes immobilized by G-CSF in nanoporous gels enable repair of critical-size osteochondral defects. Mater Today Bio 2024; 24:100933. [PMID: 38283982 PMCID: PMC10819721 DOI: 10.1016/j.mtbio.2023.100933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 12/19/2023] [Accepted: 12/26/2023] [Indexed: 01/30/2024] Open
Abstract
Injured articular cartilage is a leading cause for osteoarthritis. We recently discovered that endogenous stem/progenitor cells not only reside in the superficial zone of mouse articular cartilage, but also regenerated heterotopic bone and cartilage in vivo. However, whether critical-size osteochondral defects can be repaired by pure induced chemotatic cell homing of these endogenous stem/progenitor cells remains elusive. Here, we first found that cells in the superficial zone of articular cartilage surrounding surgically created 3 × 1 mm defects in explant culture of adult goat and rabbit knee joints migrated into defect-filled fibrin/hylaro1nate gel, and this migration was significantly more robust upon delivery of exogenous granulocyte-colony stimulating factor (G-CSF). Remarkably, G-CSF-recruited chondrogenic progenitor cells (CPCs) showed significantly stronger migration ability than donor-matched chondrocytes and osteoblasts. G-CSF-recruited CPCs robustly differentiated into chondrocytes, modestly into osteoblasts, and barely into adipocytes. In vivo, critical-size osteochondral defects were repaired by G-CSF-recruited endogenous cells postoperatively at 6 and 12 weeks in comparison to poor healing by gel-only group or defect-only group. ICRS and O'Driscoll scores of articular cartilage were significantly higher for both 6- and 12-week G-CSF samples than corresponding gel-only and defect-only groups. Thus, endogenous stem/progenitor cells may be activated by G-CSF, a Food and Drug Administration (FDA)-cleared bone-marrow stimulating factor, to repair osteochondral defects.
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Affiliation(s)
- Shangkun Tang
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ruinian Zhang
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hanying Bai
- Center for Craniofacial Regeneration, Columbia University, New York, NY, 10032, USA
| | - Rui Shu
- Center for Craniofacial Regeneration, Columbia University, New York, NY, 10032, USA
- West China School/Hospital of Stomatology, Sichuan University, Chengdu,610041, China
| | - Danying Chen
- Center for Craniofacial Regeneration, Columbia University, New York, NY, 10032, USA
| | - Ling He
- Center for Craniofacial Regeneration, Columbia University, New York, NY, 10032, USA
| | - Ling Zhou
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610041, China
| | - Zheting Liao
- Center for Craniofacial Regeneration, Columbia University, New York, NY, 10032, USA
| | - Mo Chen
- Center for Craniofacial Regeneration, Columbia University, New York, NY, 10032, USA
| | - Fuxing Pei
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jeremy J. Mao
- Center for Craniofacial Regeneration, Columbia University, New York, NY, 10032, USA
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
- Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
| | - Xiaojun Shi
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, 610041, China
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12
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Yang LF, He JD, Jiang WQ, Wang XD, Yang XC, Liang Z, Zhou YK. Interferon-gamma Treatment of Human Umbilical Cord Mesenchymal Stem Cells can Significantly Reduce Damage Associated with Diabetic Peripheral Neuropathy in Mice. Curr Stem Cell Res Ther 2024; 19:1129-1141. [PMID: 37644749 DOI: 10.2174/1574888x19666230829155046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 07/17/2023] [Accepted: 07/24/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND Diabetic peripheral neuropathy causes significant pain to patients. Umbilical cord mesenchymal stem cells have been shown to be useful in the treatment of diabetes and its complications. The aim of this study was to investigate whether human umbilical cord mesenchymal stem cells treated with interferon-gamma can ameliorate nerve injury associated with diabetes better than human umbilical cord mesenchymal stem cells without interferon-gamma treatment. METHODS Human umbilical cord mesenchymal stem cells were assessed for adipogenic differentiation, osteogenic differentiation, and proliferation ability. Vonfry and a hot disc pain tester were used to evaluate tactile sensation and thermal pain sensation in mice. Hematoxylin-eosin and TUNEL staining were performed to visualize sciatic nerve fiber lesions and Schwann cell apoptosis in diabetic mice. Western blotting was used to detect expression of the apoptosis-related proteins Bax, B-cell lymphoma-2, and caspase-3 in mouse sciatic nerve fibers and Schwann cells. Real-Time Quantitative PCR was used to detect mRNA levels of the C-X-C motif chemokine ligand 1, C-X-C motif chemokine ligand 2, C-X-C motif chemokine ligand 9, and C-X-C motif chemokine ligand 10 in mouse sciatic nerve fibers and Schwann cells. Enzyme-linked immunosorbent assay was used to detect levels of the inflammatory cytokines, interleukin- 1β, interleukin-6, and tumor necrosis factor-α in serum and Schwann cells. RESULTS The adipogenic differentiation capacity, osteogenic differentiation capacity, and proliferation ability of human umbilical cord mesenchymal stem cells were enhanced after interferon-gamma treatment. Real-Time Quantitative PCR revealed that interferon-gamma promoted expression of the adipogenic markers, PPAR-γ and CEBP-α, as well as of the osteogenic markers secreted phosphoprotein 1, bone gamma-carboxyglutamate protein, collagen type I alpha1 chain, and Runt-related transcription factor 2. The results of hematoxylin-eosin and TUNEL staining showed that pathological nerve fiber damage and Schwann cell apoptosis were reduced after the injection of interferon-gamma-treated human umbilical cord mesenchymal stem cells. Expression of the apoptosis-related proteins, caspase-3 and Bax, was significantly reduced, while expression of the anti-apoptotic protein B-cell lymphoma-2 was significantly increased. mRNA levels of the cell chemokines, C-X-C motif chemokine ligand 1, C-X-C motif chemokine ligand 2, C-X-C motif chemokine ligand 9, and C-X-C motif chemokine ligand 10, were significantly reduced, and levels of the inflammatory cytokines, interleukin-1β, interleukin-6, and tumor necrosis factor-α, were decreased. Tactile and thermal pain sensations were improved in diabetic mice. CONCLUSION Interferon-gamma treatment of umbilical cord mesenchymal stem cells enhanced osteogenic differentiation, adipogenic differentiation, and proliferative potential. It can enhance the ability of human umbilical cord mesenchymal stem cells to alleviate damage to diabetic nerve fibers and Schwann cells, in addition to improving the neurological function of diabetic mice.
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Affiliation(s)
- Li-Fen Yang
- Department of Endocrinology and Metabolism, First People's Hospital of Yunnan Province, China
| | - Jun-Dong He
- Department of Endocrinology and Metabolism, First People's Hospital of Yunnan Province, China
- Medical School, Kunming University of Science and Technology, Kunming, 650300, Yunnan Province, People's Republic of China
| | - Wei-Qi Jiang
- The First Clinical Medical College, Kunming Medical University, Kunming, 650050, People's Republic of China
| | - Xiao-Dan Wang
- Kunming Yan'an Hospital Kunming, 650051, People's Republic of China
| | - Xiao-Chun Yang
- Department of Ophthalmology First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, 650032, People's Republic of China
| | - Zhi Liang
- Department of Information Center, First People's Hospital of Yunnan Province, China
| | - Yi-Kun Zhou
- Department of Endocrinology and Metabolism, First People's Hospital of Yunnan Province, China
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13
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Kwon HY, Yoon Y, Hong JE, Rhee KJ, Sohn JH, Jung PY, Kim MY, Baik SK, Ryu H, Eom YW. Role of TGF-β and p38 MAPK in TSG-6 Expression in Adipose Tissue-Derived Stem Cells In Vitro and In Vivo. Int J Mol Sci 2023; 25:477. [PMID: 38203646 PMCID: PMC10778696 DOI: 10.3390/ijms25010477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 12/26/2023] [Accepted: 12/28/2023] [Indexed: 01/12/2024] Open
Abstract
Mesenchymal stem cells (MSCs) regulate immune cell activity by expressing tumor necrosis factor-α (TNF-α)-stimulated gene 6 (TSG-6) in inflammatory environments; however, whether anti-inflammatory responses affect TSG-6 expression in MSCs is not well understood. Therefore, we investigated whether transforming growth factor-β (TGF-β) regulates TSG-6 expression in adipose tissue-derived stem cells (ASCs) and whether effective immunosuppression can be achieved using ASCs and TGF-β signaling inhibitor A83-01. TGF-β significantly decreased TSG-6 expression in ASCs, but A83-01 and the p38 inhibitor SB202190 significantly increased it. However, in septic C57BL/6 mice, A83-01 further reduced the survival rate of the lipopolysaccharide (LPS)-treated group and ASC transplantation did not improve the severity induced by LPS. ASC transplantation alleviated the severity of sepsis induced by LPS+A83-01. In co-culture of macrophages and ASCs, A83-01 decreased TSG-6 expression whereas A83-01 and SB202190 reduced Cox-2 and IDO-2 expression in ASCs. These results suggest that TSG-6 expression in ASCs can be regulated by high concentrations of pro-inflammatory cytokines in vitro and in vivo, and that A83-01 and SB202190 can reduce the expression of immunomodulators in ASCs. Therefore, our data suggest that co-treatment of ASCs with TGF-β or p38 inhibitors is not adequate to modulate inflammation.
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Affiliation(s)
- Hye Youn Kwon
- Department of Surgery, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea; (H.Y.K.); (P.Y.J.)
| | - Yongdae Yoon
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea; (Y.Y.); (M.Y.K.); (S.K.B.)
| | - Ju-Eun Hong
- Department of Biomedical Laboratory Science, College of Software and Digital Healthcare Convergence, Yonsei University Mirae Campus, Wonju 26493, Republic of Korea; (J.-E.H.); (K.-J.R.)
| | - Ki-Jong Rhee
- Department of Biomedical Laboratory Science, College of Software and Digital Healthcare Convergence, Yonsei University Mirae Campus, Wonju 26493, Republic of Korea; (J.-E.H.); (K.-J.R.)
| | - Joon Hyung Sohn
- Department of Convergence Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea;
| | - Pil Young Jung
- Department of Surgery, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea; (H.Y.K.); (P.Y.J.)
| | - Moon Young Kim
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea; (Y.Y.); (M.Y.K.); (S.K.B.)
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
| | - Soon Koo Baik
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea; (Y.Y.); (M.Y.K.); (S.K.B.)
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
| | - Hoon Ryu
- Department of Surgery, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea; (H.Y.K.); (P.Y.J.)
| | - Young Woo Eom
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea; (Y.Y.); (M.Y.K.); (S.K.B.)
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14
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da Silva TB, Rendra E, David CAW, Bieback K, Cross MJ, Wilm B, Liptrott NJ, Murray P. Umbilical cord mesenchymal stromal cell-derived extracellular vesicles lack the potency to immunomodulate human monocyte-derived macrophages in vitro. Biomed Pharmacother 2023; 167:115624. [PMID: 37783151 DOI: 10.1016/j.biopha.2023.115624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 09/26/2023] [Accepted: 09/28/2023] [Indexed: 10/04/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) have been reported to display efficacy in a variety of preclinical models, but without long-term engraftment, suggesting a role for secreted factors, such as MSC-derived extracellular vesicles (EVs). MSCs are known to elicit immunomodulatory effects, an important aspect of which is their ability to affect macrophage phenotype. However, it is not clear if these effects are mediated by MSC-derived EVs, or other factors secreted by the MSCs. Here, we use flow cytometry to assess the effects of human umbilical cord (hUC) MSC-derived EVs on the expression of pro-inflammatory (CD80) and anti-inflammatory (CD163) surface markers in human monocyte-derived macrophages (hMDMs). hUC-MSC-derived EVs did not change the surface marker expression of the hMDMs. In contrast, when hMDMs were co-incubated with hUC-MSCs in indirect co-cultures, changes were observed in the expression of CD14, CD80 and CD163, particularly in M1 macrophages, suggesting that soluble factors are necessary to elicit a shift in phenotype. However, even though EVs did not alter the surface marker expression of macrophages, they promoted angiogenesis and phagocytic capacity increased proportionally to increases in EV concentration. Taken together, these results suggest that hUC-MSC-derived EVs are not sufficient to alter macrophage phenotype and that additional MSC-derived factors are needed.
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Affiliation(s)
- Tamiris Borges da Silva
- Department of Molecular Physiology and Cell Signalling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, UK
| | - Erika Rendra
- Institute of Transfusion Medicine and Immunology, Mannheim Institute of Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany
| | - Christopher A W David
- Immunocompatibility Group, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Karen Bieback
- Institute of Transfusion Medicine and Immunology, Mannheim Institute of Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany; Mannheim Institute for Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, Germany
| | - Michael J Cross
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GL, UK
| | - Bettina Wilm
- Department of Molecular Physiology and Cell Signalling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, UK
| | - Neill J Liptrott
- Immunocompatibility Group, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Patricia Murray
- Department of Molecular Physiology and Cell Signalling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, UK.
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15
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Zhuang X, Jiang Y, Yang X, Fu L, Luo L, Dong Z, Zhao J, Hei F. Advances of mesenchymal stem cells and their derived extracellular vesicles as a promising therapy for acute respiratory distress syndrome: from bench to clinic. Front Immunol 2023; 14:1244930. [PMID: 37711624 PMCID: PMC10497773 DOI: 10.3389/fimmu.2023.1244930] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 08/14/2023] [Indexed: 09/16/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung injury characterized by diffuse alveolar damage. The period prevalence of ARDS was 10.4% of ICU admissions in 50 countries. Although great progress has been made in supportive care, the hospital mortality rate of severe ARDS is still up to 46.1%. Moreover, up to now, there is no effective pharmacotherapy for ARDS and most clinical trials focusing on consistently effective drugs have met disappointing results. Mesenchymal stem cells (MSCs) and their derived extracellular vesicles (EVs) have spawned intense interest of a wide range of researchers and clinicians due to their robust anti-inflammatory, anti-apoptotic and tissue regeneration properties. A growing body of evidence from preclinical studies confirmed the promising therapeutic potential of MSCs and their EVs in the treatment of ARDS. Based on the inspiring experimental results, clinical trials have been designed to evaluate safety and efficacy of MSCs and their EVs in ARDS patients. Moreover, trials exploring their optimal time window and regimen of drug administration are ongoing. Therefore, this review aims to present an overview of the characteristics of mesenchymal stem cells and their derived EVs, therapeutic mechanisms for ARDS and research progress that has been made over the past 5 years.
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Affiliation(s)
| | | | | | | | | | | | | | - Feilong Hei
- Department of Cardiopulmonary Bypass, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
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16
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Ah-Pine F, Khettab M, Bedoui Y, Slama Y, Daniel M, Doray B, Gasque P. On the origin and development of glioblastoma: multifaceted role of perivascular mesenchymal stromal cells. Acta Neuropathol Commun 2023; 11:104. [PMID: 37355636 PMCID: PMC10290416 DOI: 10.1186/s40478-023-01605-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 06/18/2023] [Indexed: 06/26/2023] Open
Abstract
Glioblastoma, IDH wild-type is the most common and aggressive form of glial tumors. The exact mechanisms of glioblastoma oncogenesis, including the identification of the glioma-initiating cell, are yet to be discovered. Recent studies have led to the hypothesis that glioblastoma arises from neural stem cells and glial precursor cells and that cell lineage constitutes a key determinant of the glioblastoma molecular subtype. These findings brought significant advancement to the comprehension of gliomagenesis. However, the cellular origin of glioblastoma with mesenchymal molecular features remains elusive. Mesenchymal stromal cells emerge as potential glioblastoma-initiating cells, especially with regard to the mesenchymal molecular subtype. These fibroblast-like cells, which derive from the neural crest and reside in the perivascular niche, may underlie gliomagenesis and exert pro-tumoral effects within the tumor microenvironment. This review synthesizes the potential roles of mesenchymal stromal cells in the context of glioblastoma and provides novel research avenues to better understand this lethal disease.
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Affiliation(s)
- F. Ah-Pine
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France
- Service d’Anatomie et Cytologie Pathologiques, CHU de La Réunion sites SUD – Saint-Pierre, BP 350, 97448 Saint-Pierre Cedex, France
| | - M. Khettab
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France
- Service d’Oncologie Médicale, CHU de La Réunion sites SUD – Saint-Pierre, BP 350, 97448 Saint-Pierre Cedex, France
| | - Y. Bedoui
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France
- Service d’Anatomie et Cytologie Pathologiques, CHU de La Réunion sites SUD – Saint-Pierre, BP 350, 97448 Saint-Pierre Cedex, France
| | - Y. Slama
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France
| | - M. Daniel
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France
- Service de Médecine d’Urgences-SAMU-SMUR, CHU de La Réunion - Site Félix Guyon, Allée Des Topazes CS 11 021, 97400 Saint-Denis, France
| | - B. Doray
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France
- Service de Génétique, CHU de La Réunion - Site Félix Guyon, Allée Des Topazes CS 11 021, 97400 Saint-Denis, France
| | - P. Gasque
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France
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17
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Phan TV, Oo Y, Ahmed K, Rodboon T, Rosa V, Yodmuang S, Ferreira JN. Salivary gland regeneration: from salivary gland stem cells to three-dimensional bioprinting. SLAS Technol 2023; 28:199-209. [PMID: 37019217 DOI: 10.1016/j.slast.2023.03.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 03/13/2023] [Accepted: 03/28/2023] [Indexed: 04/05/2023]
Abstract
Hyposalivation and severe dry mouth syndrome are the most common complications in patients with head and neck cancer (HNC) after receiving radiation therapy. Conventional treatment for hyposalivation relies on the use of sialogogues such as pilocarpine; however, their efficacy is constrained by the limited number of remnant acinar cells after radiation. After radiotherapy, the salivary gland (SG) secretory parenchyma is largely destroyed, and due to the reduced stem cell niche, this gland has poor regenerative potential. To tackle this, researchers must be able to generate highly complex cellularized 3D constructs for clinical transplantation via technologies, including those that involve bioprinting of cells and biomaterials. A potential stem cell source with promising clinical outcomes to reserve dry mouth is adipose mesenchymal stem cells (AdMSC). MSC-like cells like human dental pulp stem cells (hDPSC) have been tested in novel magnetic bioprinting platforms using nanoparticles that can bind cell membranes by electrostatic interaction, as well as their paracrine signals arising from extracellular vesicles. Both magnetized cells and their secretome cues were found to increase epithelial and neuronal growth of in vitro and ex vivo irradiated SG models. Interestingly, these magnetic bioprinting platforms can be applied as a high-throughput drug screening system due to the consistency in structure and functions of their organoids. Recently, exogenous decellularized porcine ECM was added to this magnetic platform to stimulate an ideal environment for cell tethering, proliferation, and/or differentiation. The combination of these SG tissue biofabrication strategies will promptly allow for in vitro organoid formation and establishment of cellular senescent organoids for aging models, but challenges remain in terms of epithelial polarization and lumen formation for unidirectional fluid flow. Current magnetic bioprinting nanotechnologies can provide promising functional and aging features to in vitro craniofacial exocrine gland organoids, which can be utilized for novel drug discovery and/or clinical transplantation.
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Affiliation(s)
- Toan V Phan
- Avatar Biotechnologies for Oral Health and Healthy Longevity Research Unit, Department of Research Affairs, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand; International Graduate Program in Oral Biology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Yamin Oo
- Avatar Biotechnologies for Oral Health and Healthy Longevity Research Unit, Department of Research Affairs, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Khurshid Ahmed
- Avatar Biotechnologies for Oral Health and Healthy Longevity Research Unit, Department of Research Affairs, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand; Department of Industrial Biotechnology, Faculty of Agro-Industry, Prince of Songkla University, Songkhla, Thailand
| | - Teerapat Rodboon
- Avatar Biotechnologies for Oral Health and Healthy Longevity Research Unit, Department of Research Affairs, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand; Department of Clinical Pathology, Faculty of Medicine, Navamindradhiraj University, Bangkok, Thailand
| | - Vinicius Rosa
- Faculty of Dentistry, National University of Singapore, Singapore, Singapore; Centre for Advanced 2D Materials, National University of Singapore, Singapore, Singapore; Department of Materials Science and Engineering, College of Design and Engineering, National University of Singapore, Singapore, Singapore; ORCHIDS: Oral Care Health Innovations and Designs Singapore, National University of Singapore, Singapore, Singapore
| | - Supansa Yodmuang
- Avatar Biotechnologies for Oral Health and Healthy Longevity Research Unit, Department of Research Affairs, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand; Department of Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Joao N Ferreira
- Avatar Biotechnologies for Oral Health and Healthy Longevity Research Unit, Department of Research Affairs, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.
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Calcat-I-Cervera S, Rendra E, Scaccia E, Amadeo F, Hanson V, Wilm B, Murray P, O'Brien T, Taylor A, Bieback K. Harmonised culture procedures minimise but do not eliminate mesenchymal stromal cell donor and tissue variability in a decentralised multicentre manufacturing approach. Stem Cell Res Ther 2023; 14:120. [PMID: 37143116 PMCID: PMC10161493 DOI: 10.1186/s13287-023-03352-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 04/20/2023] [Indexed: 05/06/2023] Open
Abstract
BACKGROUND Mesenchymal stromal cells (MSCs), commonly sourced from adipose tissue, bone marrow and umbilical cord, have been widely used in many medical conditions due to their therapeutic potential. Yet, the still limited understanding of the underlying mechanisms of action hampers clinical translation. Clinical potency can vary considerably depending on tissue source, donor attributes, but importantly, also culture conditions. Lack of standard procedures hinders inter-study comparability and delays the progression of the field. The aim of this study was A- to assess the impact on MSC characteristics when different laboratories, performed analysis on the same MSC material using harmonised culture conditions and B- to understand source-specific differences. METHODS Three independent institutions performed a head-to-head comparison of human-derived adipose (A-), bone marrow (BM-), and umbilical cord (UC-) MSCs using harmonised culture conditions. In each centre, cells from one specific tissue source were isolated and later distributed across the network to assess their biological properties, including cell expansion, immune phenotype, and tri-lineage differentiation (part A). To assess tissue-specific function, angiogenic and immunomodulatory properties and the in vivo biodistribution were compared in one expert lab (part B). RESULTS By implementing a harmonised manufacturing workflow, we obtained largely reproducible results across three independent laboratories in part A of our study. Unique growth patterns and differentiation potential were observed for each tissue source, with similar trends observed between centres. Immune phenotyping verified expression of typical MSC surface markers and absence of contaminating surface markers. Depending on the established protocols in the different laboratories, quantitative data varied slightly. Functional experiments in part B concluded that conditioned media from BM-MSCs significantly enhanced tubulogenesis and endothelial migration in vitro. In contrast, immunomodulatory studies reported superior immunosuppressive abilities for A-MSCs. Biodistribution studies in healthy mice showed lung entrapment after administration of all three types of MSCs, with a significantly faster clearance of BM-MSCs. CONCLUSION These results show the heterogeneous behaviour and regenerative properties of MSCs as a reflection of intrinsic tissue-origin properties while providing evidence that the use of harmonised culture procedures can reduce but do not eliminate inter-lab and operator differences.
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Affiliation(s)
- Sandra Calcat-I-Cervera
- College of Medicine, Nursing and Health Science, School of Medicine, Regenerative Medicine Institute (REMEDI), University of Galway, Galway, Ireland
| | - Erika Rendra
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service, Baden-Württemberg-Hessen, Friedrich-Ebert Str. 107, 68167, Mannheim, Germany
| | - Eleonora Scaccia
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service, Baden-Württemberg-Hessen, Friedrich-Ebert Str. 107, 68167, Mannheim, Germany
| | - Francesco Amadeo
- Department of Molecular Physiology and Cell Signalling, University of Liverpool, Liverpool, UK
- Cellular Therapies Laboratory, NHS Blood and Transplant, Liverpool, UK
- Centre for Preclinical Imaging, University of Liverpool, Liverpool, UK
| | - Vivien Hanson
- Cellular Therapies Laboratory, NHS Blood and Transplant, Liverpool, UK
| | - Bettina Wilm
- Department of Molecular Physiology and Cell Signalling, University of Liverpool, Liverpool, UK
- Centre for Preclinical Imaging, University of Liverpool, Liverpool, UK
| | - Patricia Murray
- Department of Molecular Physiology and Cell Signalling, University of Liverpool, Liverpool, UK
- Centre for Preclinical Imaging, University of Liverpool, Liverpool, UK
| | - Timothy O'Brien
- College of Medicine, Nursing and Health Science, School of Medicine, Regenerative Medicine Institute (REMEDI), University of Galway, Galway, Ireland
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Galway, Ireland
| | - Arthur Taylor
- Department of Molecular Physiology and Cell Signalling, University of Liverpool, Liverpool, UK
- Centre for Preclinical Imaging, University of Liverpool, Liverpool, UK
| | - Karen Bieback
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service, Baden-Württemberg-Hessen, Friedrich-Ebert Str. 107, 68167, Mannheim, Germany.
- Mannheim Institute of Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
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19
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Rodriguez-Menocal L, Davis SC, Guzman W, Gil J, Valdes J, Solis M, Higa A, Natesan S, Schulman CI, Christy RJ, Badiavas EV. Model to Inhibit Contraction in Third-Degree Burns Employing Split-Thickness Skin Graft and Administered Bone Marrow-Derived Stem Cells. J Burn Care Res 2023; 44:302-310. [PMID: 36048023 DOI: 10.1093/jbcr/irac119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Indexed: 11/14/2022]
Abstract
Third-degree burns typically result in pronounced scarring and contraction in superficial and deep tissues. Established techniques such as debridement and grafting provide benefit in the acute phase of burn therapy, nevertheless, scar and contraction remain a challenge in deep burns management. Our ambition is to evaluate the effectiveness of novel cell-based therapies, which can be implemented into the standard of care debridement and grafting procedures. Twenty-seven third-degree burn wounds were created on the dorsal area of Red Duroc pig. After 72 h, burns are surgically debrided using a Weck knife. Split-thickness skin grafts (STSGs) were then taken after debridement and placed on burn scars combined with bone marrow stem cells (BM-MSCs). Biopsy samples were taken on days 17, 21, and 45 posttreatment for evaluation. Histological analysis revealed that untreated control scars at 17 days are more raised than burns treated with STSGs alone and/or STSGs with BM-MSCs. Wounds treated with skin grafts plus BM-MSCs appeared thinner and longer, indicative of reduced contraction. qPCR revealed some elevation of α-SMA expression at day 21 and Collagen Iα2 in cells derived from wounds treated with skin grafts alone compared to wounds treated with STSGs + BM-MSCs. We observed a reduction level of TGFβ-1 expression at days 17, 21, and 45 in cells derived from wounds treated compared to controls. These results, where the combined use of stem cells and skin grafts stimulate healing and reduce contraction following third-degree burn injury, have a potential as a novel therapy in the clinic.
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Affiliation(s)
- Luis Rodriguez-Menocal
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery/Interdisciplinary/Stem Cell Institute, University of Miami School of Medicine, Miami, Florida, USA
| | - Stephen C Davis
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, Miami, Florida, USA
| | - Wellington Guzman
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery/Interdisciplinary/Stem Cell Institute, University of Miami School of Medicine, Miami, Florida, USA
| | - Joel Gil
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, Miami, Florida, USA
| | - Jose Valdes
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, Miami, Florida, USA
| | - Michael Solis
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, Miami, Florida, USA
| | - Alexander Higa
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, Miami, Florida, USA
| | - Shanmugasundaram Natesan
- Extremity Trauma and Regenerative Medicine Program, US Army Institute of Surgical Research, Texas, USA
| | - Carl I Schulman
- Department of Surgery, Ryder Trauma Center, University of Miami School of Medicine, Miami, Florida, USA
| | - Robert J Christy
- Extremity Trauma and Regenerative Medicine Program, US Army Institute of Surgical Research, Texas, USA
| | - Evangelos V Badiavas
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery/Interdisciplinary/Stem Cell Institute, University of Miami School of Medicine, Miami, Florida, USA
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20
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Sheykhbahaei N, Bayramzadeh F, Koopaie M. Transdifferentiation of periodontal ligament stem cells into acinar cells using an indirect co-culture system. Cell Tissue Bank 2023; 24:241-251. [PMID: 35982342 DOI: 10.1007/s10561-022-10029-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 07/13/2022] [Indexed: 11/29/2022]
Abstract
Serous Acinar Cells (ACs) are mature and functional secretory epithelial cells that develop and complete through other stem cells at the end of the ductal system. So, the regeneration of the salivary gland damaged by radiation does not occur without cell therapy. Todays, an accessible tissue like the Periodontal Ligament (PDL) of the tooth was considered to easily extract the Mesenchymal Stem Cells (MSCs). In-vitro differentiation of stem cells before transplantation to damaged tissue reduces the risk of tumorigenesis. This study was conducted to evaluate the feasibility of differentiation of PDLSCs into salivary acinar cells by a co-culture system. PDLSCs were isolated from adult human PDL tissue and co-cultured with rat parotid ACs using an indirect co-culture system. The transdifferentiation of PDLSCs was evaluated by PCR of Aquaporin 5 (AQP5) and Carbonic anhydrase 6 (CA6) genes, then quantitative real-time PCR was used to measure the gene expression levels. The data were analyzed by ANOVA. Specific bond with the correct size on 6% acrylamide gel and TBE5X buffer showed the expression of AQP5 and CA6 in PDLSCs co-cultured with acinar cells. RT-PCR revealed co-cultured PDLSCs with or without KGF (Keratinocyte Growth Factor) showed significantly increased expression of AQP5 genes in compared to the initial PDLSCs. Expression of AQP5 and CA6, indicating successful transdifferentiation of PDLSCs into ACs, in co-culture system for 3 weeks.
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Affiliation(s)
- Nafiseh Sheykhbahaei
- Oral and Maxillofacial Medicine, School of Dentistry, Tehran University of Medical Science, North Kargar St, P.O. BOX: 14395-433, Tehran, 14399-55991, Iran
| | | | - Maryam Koopaie
- Oral and Maxillofacial Medicine, School of Dentistry, Tehran University of Medical Science, North Kargar St, P.O. BOX: 14395-433, Tehran, 14399-55991, Iran.
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21
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Dwivedi S, Choudhary P, Gupta A, Singh S. Therapeutical growth in oligodendroglial fate induction via transdifferentiation of stem cells for neuroregenerative therapy. Biochimie 2023; 211:35-56. [PMID: 36842627 DOI: 10.1016/j.biochi.2023.02.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 12/20/2022] [Accepted: 02/21/2023] [Indexed: 02/27/2023]
Abstract
The merits of stem cell therapy and research are undisputed due to their widespread usage in the treatment of neurodegenerative diseases and demyelinating disorders. Cell replacement therapy especially revolves around stem cells and their induction into different cell lineages both adult and progenitor - belonging to each germ layer, prior to transplantation or disease modeling studies. The nervous system is abundant in glial cells and among these are oligodendrocytes capable of myelinating new-born neurons and remyelination of axons with lost or damaged myelin sheath. But demyelinating diseases generate tremendous deficit between myelin loss and recovery. To compensate for this loss, analyze the defects in remyelination mechanisms as well as to trigger full recovery in such patients mesenchymal stem cells (MSCs) have been induced to transdifferentiate into oligodendrocytes. But such experiments are riddled with problems like prolonged, tenuous and complicated protocols that stretch longer than the time taken for the spread of demyelination-associated after-effects. This review delves into such protocols and the combinations of different molecules and factors that have been recruited to derive bona fide oligodendrocytes from in vitro differentiation of embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and MSCs with special focus on MSC-derived oligodendrocytes.
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Affiliation(s)
- Shrey Dwivedi
- Department of Applied Sciences, Indian Institute of Information Technology, Allahabad, U.P., India
| | - Princy Choudhary
- Department of Applied Sciences, Indian Institute of Information Technology, Allahabad, U.P., India
| | - Ayushi Gupta
- Department of Applied Sciences, Indian Institute of Information Technology, Allahabad, U.P., India
| | - Sangeeta Singh
- Department of Applied Sciences, Indian Institute of Information Technology, Allahabad, U.P., India.
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22
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Kagami H, Inoue M, Agata H, Asahina I, Nagamura-Inoue T, Taguri M, Tojo A. A Clinical Study of Alveolar Bone Tissue Engineering Using Autologous Bone Marrow Stromal Cells: Effect of Optimized Cell-Processing Protocol on Efficacy. J Clin Med 2022; 11:jcm11247328. [PMID: 36555944 PMCID: PMC9783548 DOI: 10.3390/jcm11247328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 12/01/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022] Open
Abstract
(1) Objectives: The effect of cell-processing protocols on the clinical efficacy of bone tissue engineering is not well-known. To maximize efficacy, we optimized the cell-processing protocol for bone-marrow-derived mesenchymal stromal cells for bone tissue engineering. In this study, the efficacy of bone tissue engineering using this modified protocol was compared to that of the original protocol. (2) Materials and Methods: This single-arm clinical study included 15 patients. Cells were obtained from bone marrow aspirates and expanded in culture flasks containing basic fibroblast growth factor. The cells were seeded onto β-tricalcium phosphate granules and induced into osteogenic cells for two weeks. Then, the cell-scaffold composites were transplanted into patients with severe atrophic alveolar bone. Radiographic evaluations and bone biopsies were performed. The results were compared with those of a previous clinical study that used the original protocol. (3) Results: Panoramic X-ray and computed tomography showed bone regeneration at the transplantation site in all cases. The average bone area in the biopsy samples at 4 months was 44.0%, which was comparable to that in a previous clinical study at 6 months (41.9%) but with much less deviation. No side effects related to cell transplantation were observed. In regenerated bone, 100% of the implants were integrated. (4) Conclusions: Compared to the original protocol, the non-inferiority of this protocol was proven. The introduction of an optimized cell-processing protocol resulted in a comparable quality of regenerated bone, with less fluctuation. Optimized cell-processing protocols may contribute to stable bone regeneration.
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Affiliation(s)
- Hideaki Kagami
- Division of Stem Cell Engineering, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
- Tissue Engineering Research Group, Division of Molecular Therapy, The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
- Department of Oral and Maxillofacial Surgery, Matsumoto Dental University, Shiojiri 399-0781, Japan
- Institute for Oral Science, Matsumoto Dental University, Shiojiri 399-0781, Japan
- Department of Dentistry and Oral Surgery, Aichi Medical University, Nagakute 480-1195, Japan
- Correspondence:
| | - Minoru Inoue
- Tissue Engineering Research Group, Division of Molecular Therapy, The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
- Department of Oral and Maxillofacial Surgery, Matsumoto Dental University, Shiojiri 399-0781, Japan
- Inoue Dental Clinic, Shizuoka 420-0866, Japan
| | - Hideki Agata
- Division of Stem Cell Engineering, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
- Tissue Engineering Research Group, Division of Molecular Therapy, The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
- Agata Dental Clinic, Hamamatsu 430-0929, Japan
| | - Izumi Asahina
- Division of Stem Cell Engineering, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
- Unit of Translational Medicine, Department of Regenerative Oral Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan
- Department of Oral and Maxillofacial Surgery, Juntendo University Hospital, Tokyo 113-8431, Japan
| | - Tokiko Nagamura-Inoue
- Department of Cell Processing and Transfusion, The Institute of Medical Science, Research Hospital, The University of Tokyo, Tokyo 108-8639, Japan
| | - Masataka Taguri
- Division of Medical Data Science, Tokyo Medical University, Tokyo 160-8402, Japan
| | - Arinobu Tojo
- Tissue Engineering Research Group, Division of Molecular Therapy, The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
- Institute of Innovation Advancement, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
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23
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Li X, Dai B, Guo J, Zhu Y, Xu J, Xu S, Yao Z, Chang L, Li Y, He X, Chow DHK, Zhang S, Yao H, Tong W, Ngai T, Qin L. Biosynthesized Bandages Carrying Magnesium Oxide Nanoparticles Induce Cortical Bone Formation by Modulating Endogenous Periosteal Cells. ACS NANO 2022; 16:18071-18089. [PMID: 36108267 DOI: 10.1021/acsnano.2c04747] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Bone grafting is frequently conducted to treat bone defects caused by trauma and tumor removal, yet with significant medical and socioeconomic burdens. Space-occupying bone substitutes remain challenging in the control of osteointegration, and meanwhile activation of endogenous periosteal cells by using non-space-occupying implants to promote new bone formation becomes another therapeutic strategy. Here, we fabricated a magnesium-based artificial bandage with optimal micropatterns for activating periosteum-associated biomineralization. Collagen was self-assembled on the surface of magnesium oxide nanoparticles embedded electrospun fibrous membranes as a hierarchical bandage structure to facilitate the integration with periosteum in situ. After the implantation on the surface of cortical bone in vivo, magnesium ions were released to generate a pro-osteogenic immune microenvironment by activating the endogenous periosteal macrophages into M2 phenotype and, meanwhile, promote blood vessel formation and neurite outgrowth. In a cortical bone defect model, magnesium-based artificial bandage guided the surrounding newly formed bone tissue to cover the defected area. Taken together, our study suggests that the strategy of stimulating bone formation can be achieved with magnesium delivery to periosteum in situ and the proposed periosteal bandages act as a bioactive media for accelerating bone healing.
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Affiliation(s)
- Xu Li
- Musculoskeletal Research Laboratory, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong999077, China
- Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong999077, China
| | - Bingyang Dai
- Musculoskeletal Research Laboratory, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong999077, China
- Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong999077, China
| | - Jiaxin Guo
- Musculoskeletal Research Laboratory, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong999077, China
- Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong999077, China
| | - Yuwei Zhu
- Department of Chemistry, The Chinese University of Hong Kong, Hong Kong999077, China
| | - Jiankun Xu
- Musculoskeletal Research Laboratory, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong999077, China
- Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong999077, China
| | - Shunxiang Xu
- Musculoskeletal Research Laboratory, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong999077, China
- Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong999077, China
| | - Zhi Yao
- Musculoskeletal Research Laboratory, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong999077, China
- Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong999077, China
| | - Liang Chang
- Musculoskeletal Research Laboratory, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong999077, China
- Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong999077, China
| | - Ye Li
- Musculoskeletal Research Laboratory, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong999077, China
- Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong999077, China
| | - Xuan He
- Musculoskeletal Research Laboratory, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong999077, China
- Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong999077, China
| | - Dick Ho Kiu Chow
- Musculoskeletal Research Laboratory, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong999077, China
- Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong999077, China
| | - Shian Zhang
- Musculoskeletal Research Laboratory, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong999077, China
- Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong999077, China
| | - Hao Yao
- Musculoskeletal Research Laboratory, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong999077, China
- Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong999077, China
| | - Wenxue Tong
- Musculoskeletal Research Laboratory, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong999077, China
- Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong999077, China
| | - To Ngai
- Department of Chemistry, The Chinese University of Hong Kong, Hong Kong999077, China
| | - Ling Qin
- Musculoskeletal Research Laboratory, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong999077, China
- Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong999077, China
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24
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Ho KKW, Lee WYW, Griffith JF, Ong MTY, Li G. Randomized control trial of mesenchymal stem cells versus hyaluronic acid in patients with knee osteoarthritis - A Hong Kong pilot study. J Orthop Translat 2022; 37:69-77. [PMID: 36262962 PMCID: PMC9550852 DOI: 10.1016/j.jot.2022.07.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 06/11/2022] [Accepted: 07/26/2022] [Indexed: 11/25/2022] Open
Abstract
Objective This pilot study evaluated the efficacy of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) versus hyaluronic acid (HA) in surgically naïve patients with knee osteoarthritis (OA). Methods Single-centre, single-blind randomized study of patients with knee OA. Twenty patients were randomized into groups of 10 each for intra-articular injection of cultured BM-MSCs (6 ml of BM-MSCs at 1 × 106 cells/mL) or HA (6 ml). Clinical assessments of pain, quality of life, radiographic imaging, and magnetic resonance imaging (MRI) compositional change were performed at baseline and 12 months follow-up. Results Compared with HA, BM-MSCs injection resulted in significant improvement in qualify of life and reduction in pain as reflected by visual analogue scale (VAS) pain score, Western Ontario and McMaster Universities Arthritis Index (WOMAC) score, and 36-Item Short Form Survey (SF-36) score collectively. T2-relaxation time tended to decrease more in the BM-MSCs group with a 38 ± 24.0% reduction in 6 out of 10 BM-MSC participants; while there was only a 12 ± 7.9% reduction in 4 out of 10 HA participants at the end of follow-up. The remaining participants showed either no response or had relaxation time increased on MRI assessment. Conclusions This pilot study found that autologous BM-MSCs significantly reduced pain, improved functional assessment score, and improved quality of life parameters comparing with HA at one year follow-up. Further clinical trial with larger sample size and longer follow up duration is warranted. The Translational Potential of this Article This pilot RCT demonstrated the feasibility and potential effectiveness of BM-MSCs advanced therapy for patients with knee OA compared to HA injection. Further multi-center clinical trial with a larger sample size and longer follow up duration in accordance with latest regulatory guidelines is warranted to ascertain the long term safety and effectiveness of MSCs therapy for cartilage regeneration in OA. Registration The study was registered in the Centre for Clinical Research Biostatistics - Clinical Trials Registry (CUHK_CCT00469).
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Affiliation(s)
- Kevin Ki-Wai Ho
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China
| | - Wayne Yuk-Wai Lee
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China
| | - James F Griffith
- Department of Imaging and Interventional Radiology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China
| | - Michael Tim-Yun Ong
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China
| | - Gang Li
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.,Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China
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Recent Patents Involving Stromal Vascular Fraction. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2022. [DOI: 10.1007/s40883-022-00283-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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Park KS, Bergqvist M, Lässer C, Lötvall J. Targeting Myd88 using peptide-loaded mesenchymal stem cell membrane-derived synthetic vesicles to treat systemic inflammation. J Nanobiotechnology 2022; 20:451. [PMID: 36243859 PMCID: PMC9571445 DOI: 10.1186/s12951-022-01660-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 10/07/2022] [Indexed: 11/10/2022] Open
Abstract
Mesenchymal stem cells (MSC) secrete extracellular vesicles (EV) with a regenerative profile, and an increasing number of studies have focused on the utilization of MSC-EV for therapeutic drug delivery. However, EV are usually produced by cells in low quantities and are packed with numerous cytoplasmic components, which may be unfavorable for further drug loading. In this study, we developed a simple process for generating membrane vesicles directly from the cells, which we refer to as synthetic eukaryotic vesicles (SyEV). We hypothesized that MSC-derived SyEV can be efficiently loaded with an anti-inflammatory drug and the loaded vesicles can strongly suppress the systemic inflammation induced by bacterial outer membrane vesicles (OMV). SyEV were generated from MSC membranes through serial extrusion of the cells, ionic stress, and subsequent vesiculation of the membrane sheets, leading to high yield and purity of the SyEV with few cytosolic components remaining. When these SyEV were given to macrophages or mice exposed to OMV, the release of pro-inflammatory cytokines was similarly attenuated comparable to treatment with natural EV. We then loaded the SyEV with large numbers of peptides targeting Myd88 and observed enhanced therapeutic potential of the loaded vesicles in OMV-induced macrophages. Further, in vivo experiments showed that the peptide-encapsulated MSC-SyEV suppressed cytokine production synergistically. Taken together, these findings suggest that SyEV-based therapeutics is a highly interesting platform for delivering an advanced therapeutic drug for the treatment of systemic inflammation without severe side effects.
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Affiliation(s)
- Kyong-Su Park
- Krefting Research Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
| | - Markus Bergqvist
- Krefting Research Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Cecilia Lässer
- Krefting Research Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Jan Lötvall
- Krefting Research Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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Watson-Levings RS, Palmer GD, Levings PP, Dacanay EA, Evans CH, Ghivizzani SC. Gene Therapy in Orthopaedics: Progress and Challenges in Pre-Clinical Development and Translation. Front Bioeng Biotechnol 2022; 10:901317. [PMID: 35837555 PMCID: PMC9274665 DOI: 10.3389/fbioe.2022.901317] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/27/2022] [Indexed: 11/25/2022] Open
Abstract
In orthopaedics, gene-based treatment approaches are being investigated for an array of common -yet medically challenging- pathologic conditions of the skeletal connective tissues and structures (bone, cartilage, ligament, tendon, joints, intervertebral discs etc.). As the skeletal system protects the vital organs and provides weight-bearing structural support, the various tissues are principally composed of dense extracellular matrix (ECM), often with minimal cellularity and vasculature. Due to their functional roles, composition, and distribution throughout the body the skeletal tissues are prone to traumatic injury, and/or structural failure from chronic inflammation and matrix degradation. Due to a mixture of environment and endogenous factors repair processes are often slow and fail to restore the native quality of the ECM and its function. In other cases, large-scale lesions from severe trauma or tumor surgery, exceed the body’s healing and regenerative capacity. Although a wide range of exogenous gene products (proteins and RNAs) have the potential to enhance tissue repair/regeneration and inhibit degenerative disease their clinical use is hindered by the absence of practical methods for safe, effective delivery. Cumulatively, a large body of evidence demonstrates the capacity to transfer coding sequences for biologic agents to cells in the skeletal tissues to achieve prolonged delivery at functional levels to augment local repair or inhibit pathologic processes. With an eye toward clinical translation, we discuss the research progress in the primary injury and disease targets in orthopaedic gene therapy. Technical considerations important to the exploration and pre-clinical development are presented, with an emphasis on vector technologies and delivery strategies whose capacity to generate and sustain functional transgene expression in vivo is well-established.
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Affiliation(s)
- Rachael S. Watson-Levings
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
| | - Glyn D. Palmer
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
| | - Padraic P. Levings
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
| | - E. Anthony Dacanay
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
| | - Christopher H. Evans
- Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MI, United States
| | - Steven C. Ghivizzani
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
- *Correspondence: Steven C. Ghivizzani,
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Kearney CM, Khatab S, van Buul GM, Plomp SGM, Korthagen NM, Labberté MC, Goodrich LR, Kisiday JD, Van Weeren PR, van Osch GJVM, Brama PAJ. Treatment Effects of Intra-Articular Allogenic Mesenchymal Stem Cell Secretome in an Equine Model of Joint Inflammation. Front Vet Sci 2022; 9:907616. [PMID: 35812845 PMCID: PMC9257274 DOI: 10.3389/fvets.2022.907616] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/20/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundAllogenic mesenchymal stem cell (MSC) secretome is a novel intra-articular therapeutic that has shown promise in in vitro and small animal models and warrants further investigation.ObjectivesTo investigate if intra-articular allogenic MSC-secretome has anti-inflammatory effects using an equine model of joint inflammation.Study DesignRandomized positively and negatively controlled experimental study.MethodIn phase 1, joint inflammation was induced bilaterally in radiocarpal joints of eight horses by injecting 0.25 ng lipopolysaccharide (LPS). After 2 h, the secretome of INFy and TNFα stimulated allogeneic equine MSCs was injected in one randomly assigned joint, while the contralateral joint was injected with medium (negative control). Clinical parameters (composite welfare scores, joint effusion, joint circumference) were recorded, and synovial fluid samples were analyzed for biomarkers (total protein, WBCC; eicosanoid mediators, CCL2; TNFα; MMP; GAGs; C2C; CPII) at fixed post-injection hours (PIH 0, 8, 24, 72, and 168 h). The effects of time and treatment on clinical and synovial fluid parameters and the presence of time-treatment interactions were evaluated. For phase 2, allogeneic MSC-secretome vs. allogeneic equine MSCs (positive control) was tested using a similar methodology.ResultsIn phase 1, the joint circumference was significantly (p < 0.05) lower in the MSC-secretome treated group compared to the medium control group at PIH 24, and significantly higher peak synovial GAG values were noted at PIH 24 (p < 0.001). In phase 2, no significant differences were noted between the treatment effects of MSC-secretome and MSCs.Main LimitationsThis study is a controlled experimental study and therefore cannot fully reflect natural joint disease. In phase 2, two therapeutics are directly compared and there is no negative control.ConclusionsIn this model of joint inflammation, intra-articular MSC-secretome injection had some clinical anti-inflammatory effects. An effect on cartilage metabolism, evident as a rise in GAG levels was also noted, although it is unclear whether this could be considered a beneficial or detrimental effect. When directly comparing MSC-secretome to MSCs in this model results were comparable, indicating that MSC-secretome could be a viable off-the-shelf alternative to MSC treatment.
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Affiliation(s)
- Clodagh M. Kearney
- School of Veterinary Medicine, University College Dublin, Dublin, Ireland
- *Correspondence: Clodagh M. Kearney
| | - Sohrab Khatab
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Gerben M. van Buul
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
- Beacon Hospital, Dublin, Ireland
| | - Saskia G. M. Plomp
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Nicoline M. Korthagen
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Margot C. Labberté
- School of Veterinary Medicine, University College Dublin, Dublin, Ireland
| | - Laurie R. Goodrich
- Equine Orthopaedic Research Center, Colorado State University, Fort Collins, CO, United States
| | - John D. Kisiday
- Equine Orthopaedic Research Center, Colorado State University, Fort Collins, CO, United States
| | - P. R. Van Weeren
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Gerjo J. V. M. van Osch
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
- Department of Otorhinolaryngology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Pieter A. J. Brama
- School of Veterinary Medicine, University College Dublin, Dublin, Ireland
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Bergmann CA, Beltran S, Vega-Letter AM, Murgas P, Hernandez MF, Gomez L, Labrador L, Cortés BI, Poblete C, Quijada C, Carrion F, Woehlbier U, Manque PA. The Autophagy Protein Pacer Positively Regulates the Therapeutic Potential of Mesenchymal Stem Cells in a Mouse Model of DSS-Induced Colitis. Cells 2022; 11:cells11091503. [PMID: 35563809 PMCID: PMC9101276 DOI: 10.3390/cells11091503] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 04/14/2022] [Accepted: 04/21/2022] [Indexed: 02/01/2023] Open
Abstract
Mesenchymal stem cells (MSC) have emerged as a promising tool to treat inflammatory diseases, such as inflammatory bowel disease (IBD), due to their immunoregulatory properties. Frequently, IBD is modeled in mice by using dextran sulfate sodium (DSS)-induced colitis. Recently, the modulation of autophagy in MSC has been suggested as a novel strategy to improve MSC-based immunotherapy. Hence, we investigated a possible role of Pacer, a novel autophagy enhancer, in regulating the immunosuppressive function of MSC in the context of DSS-induced colitis. We found that Pacer is upregulated upon stimulation with the pro-inflammatory cytokine TNFα, the main cytokine released in the inflammatory environment of IBD. By modulating Pacer expression in MSC, we found that Pacer plays an important role in regulating the autophagy pathway in this cell type in response to TNFα stimulation, as well as in regulating the immunosuppressive ability of MSC toward T-cell proliferation. Furthermore, increased expression of Pacer in MSC enhanced their ability to ameliorate the symptoms of DSS-induced colitis in mice. Our results support previous findings that autophagy regulates the therapeutic potential of MSC and suggest that the augmentation of autophagic capacity in MSC by increasing Pacer levels may have therapeutic implications for IBD.
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Affiliation(s)
- Cristian A. Bergmann
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
| | - Sebastian Beltran
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
- Escuela de Tecnología Médica, Universidad Mayor, Santiago 7500000, Chile
| | - Ana Maria Vega-Letter
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago 7620001, Chile;
- Centro de Investigación e Innovación Biomédica, Universidad de los Andes, Santiago 7620157, Chile
| | - Paola Murgas
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
- Escuela de Tecnología Médica, Universidad Mayor, Santiago 7500000, Chile
- Escuela de Biotecnología, Facultad de Ciencias, Universidad Mayor, Santiago 7500000, Chile
| | - Maria Fernanda Hernandez
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
| | - Laura Gomez
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
| | - Luis Labrador
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
| | - Bastián I. Cortés
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
| | - Cristian Poblete
- Laboratorio de Morfofisiopatología y Citodiagnóstico, Escuela de Tecnología Médica, Facultad de Ciencias, Universidad Mayor, Santiago 7500000, Chile;
| | - Cristobal Quijada
- Servicio de Anatomía Patológica, Hospital Clínico de la Universidad de Chile, Santiago 8380456, Chile;
| | - Flavio Carrion
- Programa de Inmunología Translacional, Facultad de Medicina, Universidad del Desarrollo Clínica Alemana, Santiago 7590943, Chile;
- Departamento de Investigación, Postgrado y Educación Contínua (DIPEC), Facultad de Ciencias de la Salud, Universidad del Alba, Santiago 8320000, Chile
| | - Ute Woehlbier
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
- Escuela de Biotecnología, Facultad de Ciencias, Universidad Mayor, Santiago 7500000, Chile
- Correspondence: (U.W.); (P.A.M.)
| | - Patricio A. Manque
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
- Center for Genomics and Bioinformatics (CGB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile
- Centro de Oncologia de Precision (COP), Escuela de Medicina, Universidad Mayor, Santiago 7500000, Chile
- Correspondence: (U.W.); (P.A.M.)
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Kulesza A, Zielniok K, Hawryluk J, Paczek L, Burdzinska A. Ibuprofen in Therapeutic Concentrations Affects the Secretion of Human Bone Marrow Mesenchymal Stromal Cells, but Not Their Proliferative and Migratory Capacity. Biomolecules 2022; 12:biom12020287. [PMID: 35204788 PMCID: PMC8961564 DOI: 10.3390/biom12020287] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 01/28/2022] [Accepted: 02/03/2022] [Indexed: 11/29/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are able to modulate the immune system activity and the regeneration processes mainly through the secretion of multiple soluble factors, including prostaglandin E2 (PGE2). PGE2 is produced as a result of cyclooxygenases (COX) activity. In the present study, we investigated how ibuprofen, a nonselective COX inhibitor, affects the proliferation, migration and secretion of human bone marrow MSCs (hBM-MSCs). For this purpose, six hBM-MSCs populations were treated with ibuprofen at doses which do not differ from maximum serum concentrations during standard pharmacotherapy. Ibuprofen treatment (25 or 50 µg/mL) substantially reduced the secretion of PGE2 in all tested populations. Following ibuprofen administration, MSCs were subjected to proliferation (BrdU), transwell migration, and scratch assays, while its effect on MSCs secretome was evaluated by Proteome Profiler and Luminex immunoassays. Ibuprofen did not cause statistically significant changes in the proliferation rate and migration ability of MSCs (p > 0.05). However, ibuprofen (25 µg/mL for 3 days) significantly decreased mean secretion of: CCL2 (by 44%), HGF (by 31%), IL-6 (by 22%), VEGF (by 20%) and IL-4 (by 8%) compared to secretion of control MSCs (p < 0.05). Our results indicate that ibuprofen at therapeutic concentrations may impair the pro-regenerative properties of hBM-MSCs.
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Affiliation(s)
- Agnieszka Kulesza
- Department of Immunology, Transplantology and Internal Diseases, Faculty of Medicine, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (A.K.); (J.H.); (L.P.)
| | - Katarzyna Zielniok
- Department of Clinical Immunology, Faculty of Medicine, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland;
| | - Jakub Hawryluk
- Department of Immunology, Transplantology and Internal Diseases, Faculty of Medicine, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (A.K.); (J.H.); (L.P.)
| | - Leszek Paczek
- Department of Immunology, Transplantology and Internal Diseases, Faculty of Medicine, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (A.K.); (J.H.); (L.P.)
- Department of Bioinformatics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5A, 02-106 Warsaw, Poland
| | - Anna Burdzinska
- Department of Immunology, Transplantology and Internal Diseases, Faculty of Medicine, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (A.K.); (J.H.); (L.P.)
- Correspondence:
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Bordhan P, Razavi Bazaz S, Jin D, Ebrahimi Warkiani M. Advances and enabling technologies for phase-specific cell cycle synchronisation. LAB ON A CHIP 2022; 22:445-462. [PMID: 35076046 DOI: 10.1039/d1lc00724f] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Cell cycle synchronisation is the process of isolating cell populations at specific phases of the cell cycle from heterogeneous, asynchronous cell cultures. The process has important implications in targeted gene-editing and drug efficacy of cells and in studying cell cycle events and regulatory mechanisms involved in the cell cycle progression of multiple cell species. Ideally, cell cycle synchrony techniques should be applicable for all cell types, maintain synchrony across multiple cell cycle events, maintain cell viability and be robust against metabolic and physiological perturbations. In this review, we categorize cell cycle synchronisation approaches and discuss their operational principles and performance efficiencies. We highlight the advances and technological development trends from conventional methods to the more recent microfluidics-based systems. Furthermore, we discuss the opportunities and challenges for implementing high throughput cell synchronisation and provide future perspectives on synchronisation platforms, specifically hybrid cell synchrony modalities, to allow the highest level of phase-specific synchrony possible with minimal alterations in diverse types of cell cultures.
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Affiliation(s)
- Pritam Bordhan
- School of Biomedical Engineering, University of Technology Sydney, Sydney, New South Wales 2007, Australia.
- Institute for Biomedical Materials & Devices, Faculty of Science, University of Technology Sydney, New South Wales 2007, Australia
| | - Sajad Razavi Bazaz
- School of Biomedical Engineering, University of Technology Sydney, Sydney, New South Wales 2007, Australia.
- Institute for Biomedical Materials & Devices, Faculty of Science, University of Technology Sydney, New South Wales 2007, Australia
| | - Dayong Jin
- Institute for Biomedical Materials & Devices, Faculty of Science, University of Technology Sydney, New South Wales 2007, Australia
| | - Majid Ebrahimi Warkiani
- School of Biomedical Engineering, University of Technology Sydney, Sydney, New South Wales 2007, Australia.
- Institute for Biomedical Materials & Devices, Faculty of Science, University of Technology Sydney, New South Wales 2007, Australia
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Sakurai R, Singh H, Wang Y, Harb A, Gornes C, Liu J, Rehan VK. Effect of Perinatal Vitamin D Deficiency on Lung Mesenchymal Stem Cell Differentiation and Injury Repair Potential. Am J Respir Cell Mol Biol 2021; 65:521-531. [PMID: 34126864 PMCID: PMC8641851 DOI: 10.1165/rcmb.2020-0183oc] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 04/22/2021] [Indexed: 11/24/2022] Open
Abstract
Stem cells, including the resident lung mesenchymal stem cells (LMSCs), are critically important for injury repair. Compelling evidence links perinatal vitamin D (VD) deficiency to reactive airway disease; however, the effects of perinatal VD deficiency on LMSC function is unknown. We tested the hypothesis that perinatal VD deficiency alters LMSC proliferation, differentiation, and function, leading to an enhanced myogenic phenotype. We also determined whether LMSCs' effects on alveolar type II (ATII) cell function are paracrine. Using an established rat model of perinatal VD deficiency, we studied the effects of four dietary regimens (0, 250, 500, or 1,000 IU/kg cholecalciferol-supplemented groups). At Postnatal Day 21, LMSCs were isolated, and cell proliferation and differentiation (under basal and adipogenic induction conditions) were determined. LMSC paracrine effects on ATII cell proliferation and differentiation were determined by culturing ATII cells in LMSC-conditioned media from different experimental groups. Using flow cytometry, >95% of cells were CD45-ve, >90% were CD90 + ve, >58% were CD105 + ve, and >64% were Stro-1 + ve, indicating their stem cell phenotype. Compared with the VD-supplemented groups, LMSCs from the VD-deficient group demonstrated suppressed PPARγ, but enhanced Wnt signaling, under basal and adipogenic induction conditions. LMSCs from 250 VD- and 500 VD-supplemented groups effectively blocked the effects of perinatal VD deficiency. LMSC-conditioned media from the VD-deficient group inhibited ATII cell proliferation and differentiation compared with those from the 250 VD- and 500 VD-supplemented groups. These data support the concept that perinatal VD deficiency alters LMSC proliferation and differentiation, potentially contributing to increased respiratory morbidity seen in children born to mothers with VD deficiency.
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Affiliation(s)
- Reiko Sakurai
- Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles Medical Center, David Geffen School of Medicine at University of California Los Angeles, Torrance, California
| | - Himanshu Singh
- Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles Medical Center, David Geffen School of Medicine at University of California Los Angeles, Torrance, California
| | - Ying Wang
- Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles Medical Center, David Geffen School of Medicine at University of California Los Angeles, Torrance, California
| | - Amir Harb
- Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles Medical Center, David Geffen School of Medicine at University of California Los Angeles, Torrance, California
| | - Christine Gornes
- Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles Medical Center, David Geffen School of Medicine at University of California Los Angeles, Torrance, California
| | - Jie Liu
- Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles Medical Center, David Geffen School of Medicine at University of California Los Angeles, Torrance, California
| | - Virender K Rehan
- Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles Medical Center, David Geffen School of Medicine at University of California Los Angeles, Torrance, California
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Lee S, Chae DS, Song BW, Lim S, Kim SW, Kim IK, Hwang KC. ADSC-Based Cell Therapies for Musculoskeletal Disorders: A Review of Recent Clinical Trials. Int J Mol Sci 2021; 22:10586. [PMID: 34638927 PMCID: PMC8508846 DOI: 10.3390/ijms221910586] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/24/2021] [Accepted: 09/25/2021] [Indexed: 01/04/2023] Open
Abstract
Recently published clinical trials involving the use of adipose-derived stem cells (ADSCs) indicated that approximately one-third of the studies were conducted on musculoskeletal disorders (MSD). MSD refers to a wide range of degenerative conditions of joints, bones, and muscles, and these conditions are the most common causes of chronic disability worldwide, being a major burden to the society. Conventional treatment modalities for MSD are not sufficient to correct the underlying structural abnormalities. Hence, ADSC-based cell therapies are being tested as a form of alternative, yet more effective, therapies in the management of MSDs. Therefore, in this review, MSDs subjected to the ADSC-based therapy were further categorized as arthritis, craniomaxillofacial defects, tendon/ligament related disorders, and spine disorders, and their brief characterization as well as the corresponding conventional therapeutic approaches with possible mechanisms with which ADSCs produce regenerative effects in disease-specific microenvironments were discussed to provide an overview of under which circumstances and on what bases the ADSC-based cell therapy was implemented. Providing an overview of the current status of ADSC-based cell therapy on MSDs can help to develop better and optimized strategies of ADSC-based therapeutics for MSDs as well as help to find novel clinical applications of ADSCs in the near future.
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Affiliation(s)
- Seahyoung Lee
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Dong-Sik Chae
- Department of Orthopedic Surgery, International St. Mary’s Hospital, Catholic Kwandong University, Gangneung 210-701, Korea;
| | - Byeong-Wook Song
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Soyeon Lim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Sang Woo Kim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Il-Kwon Kim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Ki-Chul Hwang
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
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Matheakakis A, Batsali A, Papadaki HA, Pontikoglou CG. Therapeutic Implications of Mesenchymal Stromal Cells and Their Extracellular Vesicles in Autoimmune Diseases: From Biology to Clinical Applications. Int J Mol Sci 2021; 22:10132. [PMID: 34576296 PMCID: PMC8468750 DOI: 10.3390/ijms221810132] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are perivascular multipotent stem cells originally identified in the bone marrow (BM) stroma and subsequently in virtually all vascularized tissues. Because of their ability to differentiate into various mesodermal lineages, their trophic properties, homing capacity, and immunomodulatory functions, MSCs have emerged as attractive candidates in tissue repair and treatment of autoimmune disorders. Accumulating evidence suggests that the beneficial effects of MSCs may be primarily mediated via a number of paracrine-acting soluble factors and extracellular vesicles (EVs). EVs are membrane-coated vesicles that are increasingly being acknowledged as playing a key role in intercellular communication via their capacity to carry and deliver their cargo, consisting of proteins, nucleic acids, and lipids to recipient cells. MSC-EVs recapitulate the functions of the cells they originate, including immunoregulatory effects but do not seem to be associated with the limitations and concerns of cell-based therapies, thereby emerging as an appealing alternative therapeutic option in immune-mediated disorders. In the present review, the biology of MSCs will be outlined and an overview of their immunomodulatory functions will be provided. In addition, current knowledge on the features of MSC-EVs and their immunoregulatory potential will be summarized. Finally, therapeutic applications of MSCs and MSC-EVs in autoimmune disorders will be discussed.
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Affiliation(s)
- Angelos Matheakakis
- Department of Hematology, School of Medicine, University of Crete, 71500 Heraklion, Greece; (A.M.); (H.A.P.)
- Haemopoiesis Research Laboratory, School of Medicine, University of Crete, 71500 Heraklion, Greece;
| | - Aristea Batsali
- Haemopoiesis Research Laboratory, School of Medicine, University of Crete, 71500 Heraklion, Greece;
| | - Helen A. Papadaki
- Department of Hematology, School of Medicine, University of Crete, 71500 Heraklion, Greece; (A.M.); (H.A.P.)
- Haemopoiesis Research Laboratory, School of Medicine, University of Crete, 71500 Heraklion, Greece;
| | - Charalampos G. Pontikoglou
- Department of Hematology, School of Medicine, University of Crete, 71500 Heraklion, Greece; (A.M.); (H.A.P.)
- Haemopoiesis Research Laboratory, School of Medicine, University of Crete, 71500 Heraklion, Greece;
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Adipose-Derived Extract Suppresses IL-1β-Induced Inflammatory Signaling Pathways in Human Chondrocytes and Ameliorates the Cartilage Destruction of Experimental Osteoarthritis in Rats. Int J Mol Sci 2021; 22:ijms22189781. [PMID: 34575945 PMCID: PMC8470808 DOI: 10.3390/ijms22189781] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/04/2021] [Accepted: 09/08/2021] [Indexed: 12/18/2022] Open
Abstract
We investigated the effects of adipose-derived extract (AE) on cultured chondrocytes and in vivo cartilage destruction. AE was prepared from human adipose tissues using a nonenzymatic approach. Cultured human chondrocytes were stimulated with interleukin-1 beta (IL-1β) with or without different concentrations of AE. The effects of co-treatment with AE on intracellular signaling pathways and their downstream gene and protein expressions were examined using real-time PCR, Western blotting, and immunofluorescence staining. Rat AE prepared from inguinal adipose tissues was intra-articularly delivered to the knee joints of rats with experimental osteoarthritis (OA), and the effect of AE on cartilage destruction was evaluated histologically. In vitro, co-treatment with IL-1β combined with AE reduced activation of the p38 and ERK mitogen-activated protein kinase (MAPK) pathway and nuclear translocation of the p65 subunit of nuclear factor-kappa B (NF-κB), and subsequently downregulated the expressions of matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, IL-6, and IL-8, whereas it markedly upregulated the expression of IL-1 receptor type 2 (IL-1R2) in chondrocytes. Intra-articular injection of homologous AE significantly ameliorated cartilage destruction six weeks postoperatively in the rat OA model. These results suggested that AE may exert a chondroprotective effect, at least in part, through modulation of the IL-1β-induced inflammatory signaling pathway by upregulation of IL-1R2 expression.
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Polisetti N, Gießl A, Zenkel M, Heger L, Dudziak D, Naschberger E, Stich L, Steinkasserer A, Kruse FE, Schlötzer-Schrehardt U. Melanocytes as emerging key players in niche regulation of limbal epithelial stem cells. Ocul Surf 2021; 22:172-189. [PMID: 34425298 DOI: 10.1016/j.jtos.2021.08.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/05/2021] [Accepted: 08/14/2021] [Indexed: 02/09/2023]
Abstract
PURPOSE Limbal melanocytes (LMel) represent essential components of the corneal epithelial stem cell niche and are known to protect limbal epithelial stem/progenitor cells (LEPCs) from UV damage by transfer of melanosomes. Here, we explored additional functional roles for LMel in niche homeostasis, immune regulation and angiostasis. METHODS Human corneoscleral tissues were morphologically analyzed in normal, inflammatory and wound healing conditions. The effects of LMel on LEPCs were analyzed in direct and indirect co-culture models using electron microscopy, immunocytochemistry, qRT-PCR, Western blotting and functional assays; limbal mesenchymal stromal cells and murine embryonic 3T3 fibroblasts served as controls. The immunophenotype of LMel was assessed by flow cytometry before and after interferon-γ stimulation, and their immunomodulatory properties were analyzed by mixed lymphocytes reaction, monocyte adhesion assays and cytometric bead arrays. Their angiostatic effects on human umbilical cord endothelial cells (HUVECs) were evaluated by proliferation, migration, and tube formation assays. RESULTS LMel and LEPCs formed structural units in the human limbal stem cell niche in situ, which could be functionally replicated, including melanosome transfer, by co-cultivation in vitro. LMel supported LEPCs during clonal expansion and during epithelial wound healing by stimulating proliferation and migration, and suppressed their differentiation through direct contact and paracrine effects. Under inflammatory conditions, LMel were increased in numbers and upregulated expression of ICAM-1 and MHC II molecules (HLA-DR), but lacked expression of HLA-G, -DP, -DQ and costimulatory molecules CD80 and CD86. They were also found to be potent suppressors of alloreactive T- cell proliferation and cytokine secretion, which largely depended on direct cell-cell interaction. Moreover, the LMel secretome exerted angiostatic activity by inhibiting vascular endothelial cell proliferation and capillary network formation. CONCLUSION These findings suggest that LMel are not only professional melanin-producing cells, but exert various non-canonical functions in limbal niche homeostasis by regulating LEPC maintenance, immune responses, and angiostasis. Their potent regulatory, immunomodulatory and anti-angiogenic properties may have important implications for future regenerative cell therapies.
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Affiliation(s)
- Naresh Polisetti
- Department of Ophthalmology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany; Eye Center, Medical Center - Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Andreas Gießl
- Department of Ophthalmology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Matthias Zenkel
- Department of Ophthalmology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Lukas Heger
- Laboratory of Dendritic Cell Biology, Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Diana Dudziak
- Laboratory of Dendritic Cell Biology, Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany; Medical Immunology Campus Erlangen, Erlangen, Germany
| | - Elisabeth Naschberger
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Lena Stich
- Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Alexander Steinkasserer
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany; Medical Immunology Campus Erlangen, Erlangen, Germany; Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Friedrich E Kruse
- Department of Ophthalmology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Ursula Schlötzer-Schrehardt
- Department of Ophthalmology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany.
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El-Derany MO, Said RS, El-Demerdash E. Bone Marrow-Derived Mesenchymal Stem Cells Reverse Radiotherapy-Induced Premature Ovarian Failure: Emphasis on Signal Integration of TGF-β, Wnt/β-Catenin and Hippo Pathways. Stem Cell Rev Rep 2021; 17:1429-1445. [PMID: 33594662 DOI: 10.1007/s12015-021-10135-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/08/2021] [Indexed: 11/29/2022]
Abstract
Radiotherapy is an indispensable cancer treatment approach. However, it is associated with hazardous consequences on multiple organs characterized by insidious worsening severity over time. This study aimed to examine the potential therapeutic effects of bone marrow mesenchymal stem cells (BM-MSCs) in radiation-induced premature ovarian failure (POF). Exposing female rats to 3.2 Gy whole-body ϒ-rays successfully induced POF. One week later, a single intravenous injection of BM-MSCs (2*106) cells was administered. BM-MSCs perfectly home to the damaged ovaries, enhanced ovarian follicle pool, and preserved the ovarian function manifested by restoring serum estradiol and follicle stimulating hormone levels, besides, rescuing the fertility outcomes of irradiated rats. These events have been associated with inhibiting ovarian apoptosis (Bax/Bcl2, caspase 3) and enhancing proliferation (PCNA). Interestingly, BM-MSCs reversed the inhibition of ovarian FOXO3 expression induced by radiation which resulted in increased primordial follicles stock. Moreover, BM-MSCs recovered the suppressed folliculogenesis process induced by radiation through upregulating FOXO1, GDF-9, and Fst genes expression accompanied by downregulating TGF-β which enhanced granulosa cells proliferation and secondary follicle development. Mechanistically, BM-MSCs miRNAs epigenetically upregulate Wnt/β-catenin and Hippo signaling pathways which are implicated in ovarian follicles growth and maturation. Therefore, BM-MSCs presented a ray of hope in the treatment of radiation-associated POF through genetic and epigenetic modulation of the integrated TGF-β, Wnt/β-catenin, and Hippo pathways which control apoptosis, proliferation, and differentiation of ovarian follicles.
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Affiliation(s)
- Marwa O El-Derany
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt
| | - Riham S Said
- Department of Drug Radiation Research, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo, Egypt
| | - Ebtehal El-Demerdash
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt.
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Chance TC, Wu X, Keesee JD, Garcia-Marcano J, Salgado CL, Liu B, Moseley JJ, Peck KA, R-Borlado L, Atai NA, Gould SJ, Marban LS, Cap AP, Rathbone CR, Bynum JA. Extracellular vesicles derived from cardiosphere-derived cells as a potential antishock therapeutic. J Trauma Acute Care Surg 2021; 91:S81-S88. [PMID: 34108422 DOI: 10.1097/ta.0000000000003218] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND Extracellular vesicles (EVs) isolated from cardiosphere-derived cells (CDC-EVs) are coming to light as a unique cell-free therapeutic. Because of their novelty, however, there still exist prominent gaps in knowledge regarding their therapeutic potential. Herein the therapeutic potential of CDC-EVs in a rat model of acute traumatic coagulopathy induced by multiple injuries and hemorrhagic shock is outlined. METHODS Extracellular vesicle surface expression of procoagulant molecules (tissue factor and phosphatidylserine) was evaluated by flow cytometry. Extracellular vesicle thrombogenicity was tested using calibrated thrombogram, and clotting parameters were assessed using a flow-based adhesion model simulating blood flow over a collagen-expressing surface. The therapeutic efficacy of EVs was then determined in a rat model of acute traumatic coagulopathy induced by multiple injuries and hemorrhagic shock. RESULTS Extracellular vesicles isolated from cardiosphere-derived cells are not functionally procoagulant and do not interfere with platelet function. In a rat model of multiple injuries and hemorrhagic shock, early administration of EVs significantly reduced the elevation of lactate and creatinine and did not significantly enhance coagulopathy in rats with acute traumatic coagulopathy. CONCLUSION The results of this study are of great relevance to the development of EV products for use in combat casualty care, as our studies show that CDC-EVs have the potential to be an antishock therapeutic if administered early. These results demonstrate that research using CDC-EVs in trauma care needs to be considered and expanded beyond their reported cardioprotective benefits.
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Affiliation(s)
- Tiffani C Chance
- From the Coagulation and Blood Research (Blood) (T.C.C., X.W., J.D.K., J.G.-M., C.L.S., B.L., A.P.C., J.A.B.), United States Army Institute of Surgical Research, San Antonio, Texas; Capricor Therapeutics Institute (J.J.M., K.A.P., L.R.-B., N.A.A., L.S.M.), Beverly Hills, California; Department of Biological Chemistry (S.J.G.), Johns Hopkins, Baltimore, Maryland; and Department of Biomedical Engineering (C.R.R.), The University of Texas at San Antonio, San Antonio, Texas
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Li ZJ, Yang QQ, Zhou YL. Basic Research on Tendon Repair: Strategies, Evaluation, and Development. Front Med (Lausanne) 2021; 8:664909. [PMID: 34395467 PMCID: PMC8359775 DOI: 10.3389/fmed.2021.664909] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 06/30/2021] [Indexed: 01/07/2023] Open
Abstract
Tendon is a fibro-elastic structure that links muscle and bone. Tendon injury can be divided into two types, chronic and acute. Each type of injury or degeneration can cause substantial pain and the loss of tendon function. The natural healing process of tendon injury is complex. According to the anatomical position of tendon tissue, the clinical results are different. The wound healing process includes three overlapping stages: wound healing, proliferation and tissue remodeling. Besides, the healing tendon also faces a high re-tear rate. Faced with the above difficulties, management of tendon injuries remains a clinical problem and needs to be solved urgently. In recent years, there are many new directions and advances in tendon healing. This review introduces tendon injury and sums up the development of tendon healing in recent years, including gene therapy, stem cell therapy, Platelet-rich plasma (PRP) therapy, growth factor and drug therapy and tissue engineering. Although most of these therapies have not yet developed to mature clinical application stage, with the repeated verification by researchers and continuous optimization of curative effect, that day will not be too far away.
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Affiliation(s)
- Zhi Jie Li
- Research for Frontier Medicine and Hand Surgery Research Center, The Nanomedicine Research Laboratory, Research Center of Clinical Medicine, Department of Hand Surgery, Affiliated Hospital of Nantong University, Nantong, China.,Medical School of Nantong University, Nantong, China
| | - Qian Qian Yang
- Research for Frontier Medicine and Hand Surgery Research Center, The Nanomedicine Research Laboratory, Research Center of Clinical Medicine, Department of Hand Surgery, Affiliated Hospital of Nantong University, Nantong, China.,Medical School of Nantong University, Nantong, China
| | - You Lang Zhou
- Research for Frontier Medicine and Hand Surgery Research Center, The Nanomedicine Research Laboratory, Research Center of Clinical Medicine, Department of Hand Surgery, Affiliated Hospital of Nantong University, Nantong, China.,Medical School of Nantong University, Nantong, China
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Abstract
Knee osteoarthritis is a degenerative condition characterized by progressive cartilage degradation, subchondral damage, and bone remodelling. Among the approaches implemented to achieve symptomatic and functional improvements, injection treatments have gained increasing attention due to the possibility of intra-articular delivery with reduced side effects compared to systemic therapies. In addition to well-established treatment options such as hyaluronic acid (HA), cortico-steroids (CS) and oxygen-ozone therapy, many other promising products have been employed in the last decades such as polydeoxyribonucleotide (PDRN) and biologic agents such as platelet-rich plasma (PRP) and mesenchymal stem cells (MSCs). Moreover, ultrasound-guided intra-meniscal injection and X-ray-guided subchondral injection techniques have been introduced into clinical practice. Even when not supported by high evidence consensus, intra-articular CS and HA injections have gained precise indications for symptomatic relief and clinical improvement in OA. Biological products are strongly supported by in vitro evidence but there is still a lack of robust clinical evidence. PRP and MSCs seem to relieve OA symptoms through a regulation of the joint homeostasis, even if their capability to restore articular cartilage is still to be proved in vivo. Due to increasing interest in the subchondral bone pathology, subchondral injections have been developed with promising results in delaying joint replacement. Nevertheless, due to their recent development and the heterogeneity of the injected products (biologic agents or calcium phosphate), this approach still lacks strong enough evidence to be fully endorsed. Combined biological treatments, nano-molecular approaches, monoclonal antibodies and ‘personalized’ target therapies are currently under development or under investigation with the aim of expanding our armamentarium against knee OA. Cite this article: EFORT Open Rev 2021;6:501-509. DOI: 10.1302/2058-5241.6.210026
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Affiliation(s)
- Gerardo Fusco
- Humanitas University, Department of Biomedical Sciences, Milan, Italy.,IRCCS Humanitas Research Hospital, Milan, Italy.,These authors contributed equally to the article and should both be considered first authors
| | - Francesco M Gambaro
- Humanitas University, Department of Biomedical Sciences, Milan, Italy.,IRCCS Humanitas Research Hospital, Milan, Italy.,These authors contributed equally to the article and should both be considered first authors
| | - Berardo Di Matteo
- Humanitas University, Department of Biomedical Sciences, Milan, Italy.,First Moscow State Medical University - Sechenov University, Moscow, Russia
| | - Elizaveta Kon
- Humanitas University, Department of Biomedical Sciences, Milan, Italy.,IRCCS Humanitas Research Hospital, Milan, Italy
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Mesenchymal stromal cells in hematopoietic cell transplantation. Blood Adv 2021; 4:5877-5887. [PMID: 33232479 DOI: 10.1182/bloodadvances.2020002646] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 10/14/2020] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are widely recognized to possess potent immunomodulatory activity, as well as to stimulate repair and regeneration of diseased or damaged tissue. These fundamental properties suggest important applications in hematopoietic cell transplantation. Although the mechanisms of therapeutic activity in vivo are yet to be fully elucidated, MSCs seem to suppress lymphocytes by paracrine mechanisms, including secreted mediators and metabolic modulators. Most recently, host macrophage engulfment of apoptotic MSCs has emerged as an important contributor to the immune suppressive microenvironment. Although bone marrow-derived MSCs are the most commonly studied, the tissue source of MSCs may be a critical determinant of immunomodulatory function. The key application of MSC therapy in hematopoietic cell transplantation is to prevent or treat graft-versus-host disease (GVHD). The pathogenesis of GVHD reveals multiple potential targets. Moreover, the recently proposed concept of tissue tolerance suggests a new possible mechanism of MSC therapy for GVHD. Beyond GVHD, MSCs may facilitate hematopoietic stem cell engraftment, which could gain greater importance with increasing use of haploidentical transplantation. Despite many challenges and much doubt, commercial MSC products for pediatric steroid-refractory GVHD have been licensed in Japan, conditionally licensed in Canada and New Zealand, and have been recommended for approval by an FDA Advisory Committee in the United States. Here, we review key historical data in the context of the most salient recent findings to present the current state of MSCs as adjunct cell therapy in hematopoietic cell transplantation.
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Hasgur S, Desbourdes L, Relation T, Overholt KM, Stanek JR, Guess AJ, Yu M, Patel P, Roback L, Dominici M, Otsuru S, Horwitz EM. Splenic macrophage phagocytosis of intravenously infused mesenchymal stromal cells attenuates tumor localization. Cytotherapy 2021; 23:411-422. [PMID: 33781710 DOI: 10.1016/j.jcyt.2020.04.102] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 04/17/2020] [Accepted: 04/28/2020] [Indexed: 12/13/2022]
Abstract
Mesenchymal stromal cells (MSCs) possess remarkable tumor tropism, making them ideal vehicles to deliver tumor-targeted therapeutic agents; however, their value in clinical medicine has yet to be realized. A barrier to clinical utilization is that only a small fraction of infused MSCs ultimately localize to the tumor. In an effort to overcome this obstacle, we sought to enhance MSC trafficking by focusing on the factors that govern MSC arrival within the tumor microenvironment. Our findings show that MSC chemoattraction is only present in select tumors, including osteosarcoma, and that the chemotactic potency among similar tumors varies substantially. Using an osteosarcoma xenograft model, we show that human MSCs traffic to the tumor within several hours of infusion. After arrival, MSCs are observed to localize in clusters near blood vessels and MSC-associated bioluminescence signal intensity is increased, suggesting that the seeded cells expand after engraftment. However, our studies reveal that a significant portion of MSCs are eliminated en route by splenic macrophage phagocytosis, effectively limiting the number of cells available for tumor engraftment. To increase MSC survival, we transiently depleted macrophages with liposomal clodronate, which resulted in increased tumor localization without substantial reduction in tumor-associated macrophages. Our data suggest that transient macrophage depletion will significantly increase the number of MSCs in the spleen and thus improve MSC localization within a tumor, theoretically increasing the effective dose of an anti-cancer agent. This strategy may subsequently improve the clinical efficacy of MSCs as vehicles for the tumor-directed delivery of therapeutic agents.
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Affiliation(s)
- Suheyla Hasgur
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Laura Desbourdes
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Theresa Relation
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Kathleen M Overholt
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Joseph R Stanek
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Adam J Guess
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Minjun Yu
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Pratik Patel
- Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Linda Roback
- Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Massimo Dominici
- Department of Medical and Surgical Sciences of Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Satoru Otsuru
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Edwin M Horwitz
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA; Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA.
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Effects of different detergent-containing children's toothpastes on the viability, osteogenic and chondrogenic differentiation of human dental periodontal ligament stem cells and gingival stem cells in vitro. Tissue Cell 2021; 72:101538. [PMID: 33878638 DOI: 10.1016/j.tice.2021.101538] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/22/2021] [Accepted: 03/23/2021] [Indexed: 01/09/2023]
Abstract
BACKGROUND Detergents are the most commonly used compounds in toothpastes due to their foaming and cleaning peoperties. This study aimed to investigate the effects of children's toothpastes with different detergent content on the viability, the osteogenic and chondrogenic differentiation potentials of human mesenchymal stem cells. METHODS The necessary tissues for human periodontal ligament mesenchymal stem cells (hPDLMSCs) and human gingival mesenchymal stem cells (hGMSCs) isolation were obtained during extraction of 10 impacted third molar teeth. The viability of the cells stimulated with different concentratiaons of Colgate, Sensodyne, Splat, Nenedent, Perlodent toothpaste solutions and complete Dulbocco's modified eagle medium (control group) were evaluated by using the flow cytometer. In addition, the osteogenic and chondrogenic differentiation potential of human gingival and periodontal ligament mesenchymal stem cells exposed to toothpaste solutions were examined morphologically. Datas were analyzed with IBM SPSS V23. One way ANOVA test was used to determine the differences between the groups for multiple comparisons, while the Tukey post-hoc test was used for pair wise comparisons in determining which groups differed. RESULTS A higher percentage of cell viability was detected in Control group at 20 %, 50 % and 80 % (p = 0.000) on hGMSCs. After the Control group, the highest cell viability ratios were observed in the detergent-free Splat group (p = 0.000) followed by the Sensodyne experimental group containing CABP (p = 0.000). While the cell viability rates in Nenedent group was found significantly higher than the Perlodent group at other concentrations except for 20 % concentration (p = 0.000). Colgate group had the lowest percentage of cell viability among the experimental groups at all concentrations on hPDMSCs (p = 0.000). The highest live cell ratios was detected in Control group (p = 0.000), followed by Splat and Sensodyne groups (p = 0.000). The cell viability ratios at 50 % concentration were higher in Perlodent group than Nenedent group (p = 0.000). The highest osteogenic and chondrogenic differentiation potential of mesenchymal stem cells stimulated with different toothpaste was determined in Control and Splat group. CONCLUSIONS As a result of the findings, it was observed that toothpaste containing SLS had a more negative effect on the viability of the cells and the differentiation potentials than the other groups.
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Konoplyannikov MA, Knyazev OV, Baklaushev VP. MSC therapy for inflammatory bowel disease. КЛИНИЧЕСКАЯ ПРАКТИКА 2021; 12:53-65. [DOI: 10.17816/clinpract64530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Inflammatory bowel disease (IBD) belongs to the group of diseases characterized by idiopathic inflammation of the digestive tract organs. Two basic IBD types are distinguished: ulcerative colitis and Crohns disease. The IBD symptoms including vomiting and diarrhea, abdominal pain, rectal bleeding, anemia have a significant negative impact on the general patients state of health. Besides, IBD patients are susceptible to the risk of a number of serious diseases such as colorectal cancer, thrombosis and primary sclerosing cholangitis. More than 4 million people in the USA and Europe suffer from IBD, with 70000 new cases diagnosed yearly in the USA only.
In some cases, a surgical removal of the damaged digestive tract fragments is required to treat severe IBD forms. However, drug therapy of IBD has mainly been used in the last decades. The rate of remission with application of traditional IBD therapy is estimated as 20-30%, and is still no higher than 50% with the combined therapy. Cell therapy has been proven to be a very promising approach in the IBD treatment. In our review, we discuss mesenchymal stromal cells (MSC) and the most important preclinical and clinical results of their application for the IBD therapy.
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Marimuthu C, Pushpa Rani V. Elucidating the role of cell-mediated inflammatory cytokines on allogeneic mouse-derived nucleus pulposus mesenchymal stem cells. J Food Biochem 2021; 45:e13681. [PMID: 33694170 DOI: 10.1111/jfbc.13681] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/11/2021] [Accepted: 02/16/2021] [Indexed: 12/28/2022]
Abstract
In this present study, our aim was to evaluate the cell-mediated specific anti-donor antibody and its associated inflammatory cytokine secretion along with its succeeding effects on Nucleus pulposus-derived mesenchymal stem cells (NPMSCs). Tissue from the NP compartment of 12 normal mice was isolated, expanded in cell culture, and the cell phenotypes were confirmed by flow cytometry. Multipotent differentiation and its specific gene expression analysis were confirmed by reverse transcriptase PCR. T and B cells were monitored for both donor and recipient mouse and further analysis of anti-donor antibody secretion was confirmed by lymphocyte crossmatch. In conjunction with anti-donor-specific antibody analysis, the associated inflammatory cytokine expression was analyzed by ELISA. In co-culture, cell-mediated antibody secretion was elevated in T and B cells positive mouse group, when compared to control mouse group. Allogeneic-derived donor NPMSCs were found to be stimulated the secretion of pro-inflammatory cytokines and the level of pro-inflammatory cytokines showed reduced expression in control mouse serum. In co-culture group the concentration of the cell-mediated pro- and anti-inflammatory cytokines found to be increased. PRACTICAL APPLICATIONS: Mesenchymal stem cell exhibit good regeneration capacity for many types of disease, and the mechanism belongs to regeneration is not clear. In intervertebral disc, the nucleus pulposus-derived mesenchymal stem cells showed a better regeneration capacity. On the contrary, the NP cells-based therapy, the Mesenchymal stem cells showed expanded anabolic and reduced catabolic activity together with induced anti-inflammatory effect. In this study, the T & B cells were used to evaluate the anti-donor antibody secretion and also to study how it stimulates the production of anti-donor antibodies against the donor cells. Finally, it was found that T & B cells lead the synthesis of inflammatory cytokines are IL-1, IL-6, and TNF-α. From this study, the results proved that the cell-mediated pro- and anti-inflammatory cytokines to be monitored in allogeneic stem cells-based therapy of intervertebral disc degeneration.
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Affiliation(s)
- Chinnarasu Marimuthu
- Department of Advanced Zoology and Biotechnology, Loyola College, Chennai, India
| | - Vedham Pushpa Rani
- Department of Advanced Zoology and Biotechnology, Loyola College, Chennai, India
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Laurent A, Abdel-Sayed P, Ducrot A, Hirt-Burri N, Scaletta C, Jaccoud S, Nuss K, de Buys Roessingh AS, Raffoul W, Pioletti D, von Rechenberg B, Applegate LA, Darwiche S. Development of Standardized Fetal Progenitor Cell Therapy for Cartilage Regenerative Medicine: Industrial Transposition and Preliminary Safety in Xenogeneic Transplantation. Biomolecules 2021; 11:250. [PMID: 33572428 PMCID: PMC7916236 DOI: 10.3390/biom11020250] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/04/2021] [Accepted: 02/04/2021] [Indexed: 12/27/2022] Open
Abstract
Diverse cell therapy approaches constitute prime developmental prospects for managing acute or degenerative cartilaginous tissue affections, synergistically complementing specific surgical solutions. Bone marrow stimulation (i.e., microfracture) remains a standard technique for cartilage repair promotion, despite incurring the adverse generation of fibrocartilagenous scar tissue, while matrix-induced autologous chondrocyte implantation (MACI) and alternative autologous cell-based approaches may partly circumvent this effect. Autologous chondrocytes remain standard cell sources, yet arrays of alternative therapeutic biologicals present great potential for regenerative medicine. Cultured human epiphyseal chondro-progenitors (hECP) were proposed as sustainable, safe, and stable candidates for chaperoning cartilage repair or regeneration. This study describes the development and industrial transposition of hECP multi-tiered cell banking following a single organ donation, as well as preliminary preclinical hECP safety. Optimized cell banking workflows were proposed, potentially generating millions of safe and sustainable therapeutic products. Furthermore, clinical hECP doses were characterized as non-toxic in a standardized chorioallantoic membrane model. Lastly, a MACI-like protocol, including hECPs, was applied in a three-month GLP pilot safety evaluation in a caprine model of full-thickness articular cartilage defect. The safety of hECP transplantation was highlighted in xenogeneic settings, along with confirmed needs for optimal cell delivery vehicles and implantation techniques favoring effective cartilage repair or regeneration.
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Affiliation(s)
- Alexis Laurent
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, CH-1015 Lausanne, Switzerland; (A.L.); (P.A.-S.); (A.D.); (N.H.-B.); (C.S.); (S.J.); (L.A.A.)
- Preclinical Research Department, LAM Biotechnologies SA, CH-1066 Épalinges, Switzerland
| | - Philippe Abdel-Sayed
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, CH-1015 Lausanne, Switzerland; (A.L.); (P.A.-S.); (A.D.); (N.H.-B.); (C.S.); (S.J.); (L.A.A.)
| | - Aurélie Ducrot
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, CH-1015 Lausanne, Switzerland; (A.L.); (P.A.-S.); (A.D.); (N.H.-B.); (C.S.); (S.J.); (L.A.A.)
| | - Nathalie Hirt-Burri
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, CH-1015 Lausanne, Switzerland; (A.L.); (P.A.-S.); (A.D.); (N.H.-B.); (C.S.); (S.J.); (L.A.A.)
| | - Corinne Scaletta
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, CH-1015 Lausanne, Switzerland; (A.L.); (P.A.-S.); (A.D.); (N.H.-B.); (C.S.); (S.J.); (L.A.A.)
| | - Sandra Jaccoud
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, CH-1015 Lausanne, Switzerland; (A.L.); (P.A.-S.); (A.D.); (N.H.-B.); (C.S.); (S.J.); (L.A.A.)
- Laboratory of Biomechanical Orthopedics, Ecole Polytechnique Fédérale de Lausanne, CH-2002 Neuchâtel, Switzerland;
| | - Katja Nuss
- Musculoskeletal Research Unit, Zurich Tierspital, University of Zurich, CH-8952 Schlieren, Switzerland; (K.N.); (B.v.R.)
| | - Anthony S. de Buys Roessingh
- Children and Adolescent Surgery Service, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland;
| | - Wassim Raffoul
- Plastic, Reconstructive, and Hand Surgery Service, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland;
| | - Dominique Pioletti
- Laboratory of Biomechanical Orthopedics, Ecole Polytechnique Fédérale de Lausanne, CH-2002 Neuchâtel, Switzerland;
| | - Brigitte von Rechenberg
- Musculoskeletal Research Unit, Zurich Tierspital, University of Zurich, CH-8952 Schlieren, Switzerland; (K.N.); (B.v.R.)
- Center for Applied Biotechnology and Molecular Medicine, University of Zurich, CH-8057 Zurich, Switzerland
| | - Lee Ann Applegate
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, CH-1015 Lausanne, Switzerland; (A.L.); (P.A.-S.); (A.D.); (N.H.-B.); (C.S.); (S.J.); (L.A.A.)
- Center for Applied Biotechnology and Molecular Medicine, University of Zurich, CH-8057 Zurich, Switzerland
- Oxford OSCAR Suzhou Center, Oxford University, Suzhou 215123, Jiangsu, China
| | - Salim Darwiche
- Musculoskeletal Research Unit, Zurich Tierspital, University of Zurich, CH-8952 Schlieren, Switzerland; (K.N.); (B.v.R.)
- Center for Applied Biotechnology and Molecular Medicine, University of Zurich, CH-8057 Zurich, Switzerland
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Human mesenchymal stromal cell source and culture conditions influence extracellular vesicle angiogenic and metabolic effects on human endothelial cells in vitro. J Trauma Acute Care Surg 2021; 89:S100-S108. [PMID: 32176171 DOI: 10.1097/ta.0000000000002661] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Mesenchymal stem/stromal cell (MSC)-derived extracellular vesicles (EVs) are a possible cell-free alternative to MSCs because they retain the regenerative potential of MSCs, while still mitigating some of their limitations (such as the possible elicitation of host immune responses). The promotion and restoration of angiogenesis, however, is an important component in treating trauma-related injuries, and has not been fully explored with EVs. Herein, we describe the effects of monolayer adipose-derived EVs, spheroid adipose-derived EVs (SAd-EVs), monolayer bone marrow-derived EVs (MBM-EVs), and spheroid bone marrow-derived EVs (SBM-EVs) on human umbilical vein endothelial cell (HUVEC) tube formation and mitochondrial respiration. METHODS The successful isolation of EVs derived from adipose MSCs or bone marrow MSCs in monolayer or spheroid cultures was confirmed by NanoSight (particle size distribution) and Western blot (surface marker expression). The EV angiogenic potential was measured using a 24-hour HUVEC tube formation assay. The EV effects on HUVEC mitochondrial function were evaluated using the Seahorse respirometer machine. RESULTS The number of junctions, branches, and the average length of branches formed at 24 hours of tube formation were significantly affected by cell and culture type; overall adipose-derived EVs outperformed bone marrow-derived EVs, and spheroid-derived EVs outperformed monolayer-derived EVs. Additionally, adipose-derived EVs resulted in significantly increased HUVEC mitochondrial maximal respiration and adenosine triphosphate (ATP) production, while only MBM-EVs negatively impacted HUVEC proton leak. CONCLUSION Adipose-derived EVs promoted HUVEC tube formation significantly more than bone marrow-derived EVs, while also maximizing HUVEC mitochondria function. Results demonstrate that, as with MSC therapies, it is possible to tailor EV culture and production to optimize therapeutic potential. LEVEL OF EVIDENCE Basic or Foundational Research.
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Burnham AJ, Foppiani EM, Horwitz EM. Key Metabolic Pathways in MSC-Mediated Immunomodulation: Implications for the Prophylaxis and Treatment of Graft Versus Host Disease. Front Immunol 2020; 11:609277. [PMID: 33365034 PMCID: PMC7750397 DOI: 10.3389/fimmu.2020.609277] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 11/10/2020] [Indexed: 01/18/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are spindle-shaped, plastic-adherent cells in vitro with potent immunosuppressive activity both in vitro and in vivo. MSCs have been employed as a cellular immunotherapy in diverse preclinical models and clinical trials, but most commonly as agents for the prophylaxis or therapy of graft versus host disease after hematopoietic cell transplantation. In addition to the oft studied secreted cytokines, several metabolic pathways intrinsic to MSCs, notably indoleamine 2,3-dioxygenase, prostaglandin E2, hypoxia-inducible factor 1 α, heme oxygenase-1, as well as energy-generating metabolism, have been shown to play roles in the immunomodulatory activity of MSCs. In this review, we discuss these key metabolic pathways in MSCs which have been reported to contribute to MSC therapeutic effects in the setting of hematopoietic cell transplantation and graft versus host disease. Understanding the contribution of MSC metabolism to immunomodulatory activity may substantially inform the development of future clinical applications of MSCs.
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Affiliation(s)
- Andre J Burnham
- Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, United States.,Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
| | - Elisabetta Manuela Foppiani
- Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, United States.,Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
| | - Edwin M Horwitz
- Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, United States.,Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
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49
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Laurent A, Hirt-Burri N, Scaletta C, Michetti M, de Buys Roessingh AS, Raffoul W, Applegate LA. Holistic Approach of Swiss Fetal Progenitor Cell Banking: Optimizing Safe and Sustainable Substrates for Regenerative Medicine and Biotechnology. Front Bioeng Biotechnol 2020; 8:557758. [PMID: 33195124 PMCID: PMC7644790 DOI: 10.3389/fbioe.2020.557758] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 08/21/2020] [Indexed: 12/17/2022] Open
Abstract
Safety, quality, and regulatory-driven iterative optimization of therapeutic cell source selection has constituted the core developmental bedrock for primary fetal progenitor cell (FPC) therapy in Switzerland throughout three decades. Customized Fetal Transplantation Programs were pragmatically devised as straightforward workflows for tissue procurement, traceability maximization, safety, consistency, and robustness of cultured progeny cellular materials. Whole-cell bioprocessing standardization has provided plethoric insights into the adequate conjugation of modern biotechnological advances with current restraining legislative, ethical, and regulatory frameworks. Pioneer translational advances in cutaneous and musculoskeletal regenerative medicine continuously demonstrate the therapeutic potential of FPCs. Extensive technical and clinical hindsight was gathered by managing pediatric burns and geriatric ulcers in Switzerland. Concomitant industrial transposition of dermal FPC banking, following good manufacturing practices, demonstrated the extensive potential of their therapeutic value. Furthermore, in extenso, exponential revalorization of Swiss FPC technology may be achieved via the renewal of integrative model frameworks. Consideration of both longitudinal and transversal aspects of simultaneous fetal tissue differential processing allows for a better understanding of the quasi-infinite expansion potential within multi-tiered primary FPC banking. Multiple fetal tissues (e.g., skin, cartilage, tendon, muscle, bone, lung) may be simultaneously harvested and processed for adherent cell cultures, establishing a unique model for sustainable therapeutic cellular material supply chains. Here, we integrated fundamental, preclinical, clinical, and industrial developments embodying the scientific advances supported by Swiss FPC banking and we focused on advances made to date for FPCs that may be derived from a single organ donation. A renewed model of single organ donation bioprocessing is proposed, achieving sustained standards and potential production of billions of affordable and efficient therapeutic doses. Thereby, the aim is to validate the core therapeutic value proposition, to increase awareness and use of standardized protocols for translational regenerative medicine, potentially impacting millions of patients suffering from cutaneous and musculoskeletal diseases. Alternative applications of FPC banking include biopharmaceutical therapeutic product manufacturing, thereby indirectly and synergistically enhancing the power of modern therapeutic armamentariums. It is hypothesized that a single qualifying fetal organ donation is sufficient to sustain decades of scientific, medical, and industrial developments, as technological optimization and standardization enable high efficiency.
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Affiliation(s)
- Alexis Laurent
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, Épalinges, Switzerland
- Tec-Pharma SA, Bercher, Switzerland
- LAM Biotechnologies SA, Épalinges, Switzerland
| | - Nathalie Hirt-Burri
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, Épalinges, Switzerland
| | - Corinne Scaletta
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, Épalinges, Switzerland
| | - Murielle Michetti
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, Épalinges, Switzerland
| | - Anthony S. de Buys Roessingh
- Children and Adolescent Surgery Service, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Wassim Raffoul
- Plastic, Reconstructive and Hand Surgery Service, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Lee Ann Applegate
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, Épalinges, Switzerland
- Oxford Suzhou Center for Advanced Research, Science and Technology Co., Ltd., Oxford University, Suzhou, China
- Competence Center for Applied Biotechnology and Molecular Medicine, University of Zurich, Zurich, Switzerland
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50
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Al-Khawaga S, Abdelalim EM. Potential application of mesenchymal stem cells and their exosomes in lung injury: an emerging therapeutic option for COVID-19 patients. Stem Cell Res Ther 2020; 11:437. [PMID: 33059757 PMCID: PMC7558244 DOI: 10.1186/s13287-020-01963-6] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 10/04/2020] [Indexed: 02/06/2023] Open
Abstract
The COVID-19 pandemic has negatively impacted the global public health and the international economy; therefore, there is an urgent need for an effective therapy to treat COVID-19 patients. Mesenchymal stem cells (MSCs) have been proposed as an emerging therapeutic option for the SARS-CoV-2 infection. Recently, numerous clinical trials have been registered to examine the safety and efficacy of different types of MSCs and their exosomes for treating COVID-19 patients, with less published data on the mechanism of action. Although there is no approved effective therapy for COVID-19 as of yet, MSC therapies showed an improvement in the treatment of some COVID-19 patients. MSC’s therapeutic effect is displayed in their ability to reduce the cytokine storm, enhance alveolar fluid clearance, and promote epithelial and endothelial recovery; however, the safest and most effective route of MSC delivery remains unclear. The use of poorly characterized MSC products remains one of the most significant drawbacks of MSC-based therapy, which could theoretically promote the risk for thromboembolism. Optimizing the clinical-grade production of MSCs and establishing a consensus on registered clinical trials based on cell-product characterization and mode of delivery would aid in laying the foundation for a safe and effective therapy in COVID-19. In this review, we shed light on the mechanistic view of MSC therapeutic role based on preclinical and clinical studies on acute lung injury and ARDS; therefore, offering a unique correlation and applicability in COVID-19 patients. We further highlight the challenges and opportunities in the use of MSC-based therapy.
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Affiliation(s)
- Sara Al-Khawaga
- Dermatology Department, Hamad Medical Corporation, Doha, Qatar.,Weill Cornell Medicine-Qatar, Qatar Foundation, Doha, Qatar
| | - Essam M Abdelalim
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar. .,College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, Doha, Qatar.
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