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Zununi Vahed S, Hejazian SM, Bakari WN, Landon R, Gueguen V, Meddahi-Pellé A, Anagnostou F, Barzegari A, Pavon-Djavid G. Milking mesenchymal stem cells: Updated protocols for cell lysate, secretome, and exosome extraction, and comparative analysis of their therapeutic potential. Methods 2025; 238:40-60. [PMID: 40058715 DOI: 10.1016/j.ymeth.2025.03.004] [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: 11/05/2024] [Revised: 02/28/2025] [Accepted: 03/04/2025] [Indexed: 03/21/2025] Open
Abstract
The potential of the cell lysate, secretome, and extracellular vesicles (EVs) of mesenchymal stem cells (MSCs) to modulate the immune response and promote tissue regeneration has positioned them as a promising option for cell-free therapy. Currently, many clinical trials in stem cells-derived EVs and secretome are in progress various diseases and sometimes the results are failing. The major challenge on this roadmap is the lack of a standard extraction method for exosome, secretome, and lysate. The most optimal method for obtaining the secretome of MSCs for clinical utilization involves a comprehensive approach that includes non-destructive collection methods, time optimization, multiple collection rounds, optimization of culture conditions, and quality control measures. Further research and clinical studies are warranted to validate and refine these methods for safe and effective utilization of the MSC exosome, secretome, and lysate in various clinical applications. To address these challenges, it is imperative to establish a standardized and unified methodology to ensure reliable evaluation of these extractions in clinical trials. This review seeks to outline the pros and cons of methods for the preparation of MSCs-derived exosome, and secretome/lysate, and comparative analysis of their therapeutic potential.
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Affiliation(s)
| | | | - William Ndjidda Bakari
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Nanotechnologies for Vascular Medicine and Imaging Team, 99 Av. Jean-Baptiste Clément 93430 Villetaneuse, France; Université Paris Cité, CNRS UMR7052, INSERM U1271, ENVA, B3OA, F-75010 Paris, France
| | - Rebecca Landon
- Université Paris Cité, CNRS UMR7052, INSERM U1271, ENVA, B3OA, F-75010 Paris, France
| | - Virginie Gueguen
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Nanotechnologies for Vascular Medicine and Imaging Team, 99 Av. Jean-Baptiste Clément 93430 Villetaneuse, France
| | - Anne Meddahi-Pellé
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Nanotechnologies for Vascular Medicine and Imaging Team, 99 Av. Jean-Baptiste Clément 93430 Villetaneuse, France
| | - Fani Anagnostou
- Université Paris Cité, CNRS UMR7052, INSERM U1271, ENVA, B3OA, F-75010 Paris, France
| | - Abolfazl Barzegari
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Research Center for Pharmaceutical Nanotechnology (RCPN), Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Graciela Pavon-Djavid
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Nanotechnologies for Vascular Medicine and Imaging Team, 99 Av. Jean-Baptiste Clément 93430 Villetaneuse, France.
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Inami N. Safety assessment of multiple systemic administration of human mesenchymal stem cell-conditioned medium for various chronic diseases. PLoS One 2025; 20:e0322497. [PMID: 40327651 PMCID: PMC12054860 DOI: 10.1371/journal.pone.0322497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 03/21/2025] [Indexed: 05/08/2025] Open
Abstract
Conditioned medium (CM) derived from human mesenchymal stem cells (MSCs) has shown potential as a therapeutic agent. However, the safety of its administration in human remains largely unexplored. This study evaluated the safety of multiple systemic administrations of MSC-CM, specifically adipose-derived and umbilical cord-derived MSC-CM, in 55 patients with various chronic diseases. Symptom assessments and blood tests were conducted before and after administration to monitor adverse events and measure the inflammatory marker C-reactive protein (CRP), respectively. The results demonstrated no serious adverse events attributed to MSC-CM administration. Although minor adverse events were observed, their causal relationship with MSC-CM remained unclear. Additionally, MSC-CM administration slightly reduced CRP levels, regardless of the administration route (intraarterial, intravenous, or inhalation). Additionally, a significant reduction in CRP levels was observed in patients with elevated CRP levels (CRP > 0.3) following MSC-CM administration. These findings suggest that repeated systemic administration of MSC-CM is likely safe and may have anti-inflammatory effects.
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Affiliation(s)
- Norihito Inami
- Seihoku Clinic, 775 Takawa, Oshibedani, Nishi-ku, Kobe, Hyogo, Japan
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Shih JH, Chern E. Decellularized Porcine Aorta as a Scaffold for Human Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells in Tissue Engineering. Stem Cell Rev Rep 2025:10.1007/s12015-025-10875-y. [PMID: 40227487 DOI: 10.1007/s12015-025-10875-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] [Accepted: 04/02/2025] [Indexed: 04/15/2025]
Abstract
Tissue engineering has been an integral part of regenerative medicine. Functional biomimetic structures were assembled by combining appropriate scaffolds with specific cells. The decellularization of animal tissue preserved the natural biochemical components and structural properties of the extracellular matrix (ECM) of specific organs, thereby providing a suitable niche for tissue-specific cell differentiation and growth. In this study, the extracellular matrix (ECM) of the porcine aorta was obtained through trypsin-based decellularization. The resulting porcine aortic ECM retained a favorable collagen composition, exhibited no cytotoxicity, and demonstrated chemophilic properties for mesenchymal stem cells. Human adipose-derived mesenchymal stem cells (hADSCs) and human induced pluripotent stem cell-derived mesenchymal stem cells (hiMSCs) were transplanted onto the decellularized porcine aortic ECM, where successful differentiation into a mature cartilage layer was observed. These findings suggested that the porcine aortic ECM could serve as a potential scaffold with tubular and linear structures for tissue engineering applications. Functional human iMSCs (induced-mesenchymal stem cells) were generated from human iPSCs (induced-pluripotent stem cells) and analyzed for differences compared to primary MSCs via RNA-seq. The hiMSCs were applied to decellularized porcine aortic ECM (extracellular matrix), demonstrating chondrogenic differentiation and confirming the usability of xenogeneic ECM.
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Affiliation(s)
- Jheng-Hong Shih
- niChe Lab for Stem Cell and Regenerative Medicine, Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei, 10617, Taiwan
| | - Edward Chern
- niChe Lab for Stem Cell and Regenerative Medicine, Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei, 10617, Taiwan.
- Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, No. 1, Sec. 4 Roosevelt Road, Taipei, 10617, Taiwan.
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Zhang S, Wang L, Feng Z, Wang Z, Wang Y, Wei B, Liu H, Zhao W, Li J. Engineered MXene Biomaterials for Regenerative Medicine. ACS NANO 2025; 19:9590-9635. [PMID: 40040439 DOI: 10.1021/acsnano.4c16136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/06/2025]
Abstract
MXene-based materials have attracted significant interest due to their distinct physical and chemical properties, which are relevant to fields such as energy storage, environmental science, and biomedicine. MXene has shown potential in the area of tissue regenerative medicine. However, research on its applications in tissue regeneration is still in its early stages, with a notable absence of comprehensive reviews. This review begins with a detailed description of the intrinsic properties of MXene, followed by a discussion of the various nanostructures that MXene can form, spanning from 0 to 3 dimensions. The focus then shifts to the applications of MXene-based biomaterials in tissue engineering, particularly in immunomodulation, wound healing, bone regeneration, and nerve regeneration. MXene's physicochemical properties, including conductivity, photothermal characteristics, and antibacterial properties, facilitate interactions with different cell types, influencing biological processes. These interactions highlight its potential in modulating cellular functions essential for tissue regeneration. Although the research on MXene in tissue regeneration is still developing, its versatile structural and physicochemical attributes suggest its potential role in advancing regenerative medicine.
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Affiliation(s)
- Shengmin Zhang
- Institute for Advanced Interdisciplinary Research (iAIR), School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, China
| | - Liang Wang
- State Key Laboratory of Crystal Materials, Shandong University, Jinan, Shandong 250100, China
| | - Zhichao Feng
- Institute for Advanced Interdisciplinary Research (iAIR), School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, China
| | - Zhiqi Wang
- Department of Head and Neck Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Yingxue Wang
- Institute for Advanced Interdisciplinary Research (iAIR), School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, China
| | - Benjie Wei
- Institute for Advanced Interdisciplinary Research (iAIR), School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, China
| | - Hong Liu
- Institute for Advanced Interdisciplinary Research (iAIR), School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, China
- State Key Laboratory of Crystal Materials, Shandong University, Jinan, Shandong 250100, China
| | - Weiwei Zhao
- Department of Biomaterials, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan 250012, China
| | - Jianhua Li
- Department of Biomaterials, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan 250012, China
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Starch-Jensen T, Aludden H, Dahlin C, Bruun NH, Fink T. Histomorphometric outcome following sinus floor augmentation with allogeneic adipose tissue-derived stem cells. A randomized controlled experimental study. J Craniomaxillofac Surg 2025; 53:104-113. [PMID: 39603898 DOI: 10.1016/j.jcms.2024.11.008] [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: 09/24/2024] [Revised: 10/28/2024] [Accepted: 11/15/2024] [Indexed: 11/29/2024] Open
Abstract
The aim of this pre-clinical study was to test the hypothesis of no difference in histomorphometric outcome following sinus floor augmentation (SFA) with allogeneic adipose tissue-derived stem cells (AASCs) seeded on deproteinized bovine bone mineral (DBBM) (test) compared with excipient on DBBM (control). Eighteen minipigs were allocated into three groups of six animals and euthanised after one month (T1), two months (T2), and four months (T3). The sinuses of each animal were randomly assigned to either test or control with identical graft volume. Percentage of newly formed bone (NFB), non-mineralized tissue, residual DBBM, and bone-to-implant contact (BIC) were estimated by histomorphometric analysis in a randomly selected region of interest and summarized as mean percentage with 95% confidence interval. Test group, mean percentage of NFB and BIC was 8.8 and 19.5 (T1), 17.7 and 23.2 (T2), 37.1 and 30.4 (T3). Control group, corresponding values were 8.9 and 13.9 (T1), 18.7 and 23.3 (T2), 36.8 and 36.6 (T3). There were no significant differences in NFB or BIC at T1 (P = 0.964; 0.551), T2 (P = 0.927; 0.992), and T3 (P = 0.971; 0.557) between test or control. Percentage of NFB was significantly higher at T3 compared with T1, in test (P = 0.001) and control (P = 0.004), while no significant difference in BIC was disclosed between T1, T2, and T3, in test and control, respectively. In conclusion, adding AASCs to DBBM seem not to improve NFB or BIC compared with DBBM alone in conjunction with SFA.
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Affiliation(s)
- Thomas Starch-Jensen
- Department of Oral and Maxillofacial Surgery, Aalborg University Hospital and Department of Clinical Medicine, The Faculty of Medicine, Aalborg University, Aalborg, Denmark.
| | - Hanna Aludden
- Department of Biomaterials, Institute for Surgical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg and Department of Oral and Maxillofacial Surgery, NU-Hospital-Organization, Trollhättan, Sweden
| | - Christer Dahlin
- Department of Biomaterials, Institute for Surgical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg and Department of Oral and Maxillofacial Surgery, NU-Hospital-Organization, Trollhättan, Sweden
| | - Niels Henrik Bruun
- Unit of Clinical Biostatistics, Aalborg University Hospital, Aalborg, Denmark
| | - Trine Fink
- Regenerative Medicine Group, Department of Health Science and Technology, The Faculty of Medicine, Aalborg University, Aalborg, Denmark
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Hung M, Sadri M, Katz M, Schwartz C, Mohajeri A. A Systematic Review of Stem Cell Applications in Maxillofacial Regeneration. Dent J (Basel) 2024; 12:315. [PMID: 39452443 PMCID: PMC11505667 DOI: 10.3390/dj12100315] [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: 07/02/2024] [Revised: 08/27/2024] [Accepted: 09/27/2024] [Indexed: 10/26/2024] Open
Abstract
INTRODUCTION Regenerative medicine is revolutionizing oral and maxillofacial surgeries with stem cells, particularly mesenchymal stem cells, for tissue and bone regeneration. Despite promising in-vitro results, human trials are limited. A systematic review is needed to evaluate stem cell efficacy in maxillofacial issues, aiming to improve surgical outcomes and patient satisfaction. METHODS Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines, this review included peer-reviewed articles (2013-2023) on stem cells in oral surgery, excluding non-English publications, abstracts, reviews, and opinion pieces. Searches were conducted in PubMed, Web of Science, OVID, Cochrane, Dentistry & Oral Sciences Source-Ebscohost, and Scopus. Two authors independently screened titles and abstracts, resolving disagreements by consensus. Full-text analysis involved extracting key data, verified by a secondary reviewer and additional quality checks. RESULTS From 3540 initial articles, 2528 were screened after removing duplicates, and 7 met the inclusion criteria after excluding irrelevant studies. Key themes included the safety and efficacy of stem cell therapy, and bone regeneration and quality. Studies predominantly used mesenchymal stem cells. Findings showed positive outcomes in clinical safety and effectiveness and significant potential for bone regeneration. CONCLUSIONS This systematic review highlights the potential of stem cell therapies in maxillofacial applications, supporting their safety, efficacy, and bone regeneration capabilities. Further research is needed to standardize protocols and confirm long-term benefits.
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Affiliation(s)
- Man Hung
- College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT 84095, USA
- Division of Public Health, University of Utah, Salt Lake City, UT 84108, USA
- Department of Orthopaedics, University of Utah, Salt Lake City, UT 84108, USA
- Huntsman Cancer Institute, Salt Lake City, UT 84112, USA
- The Wharton School, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Mahsa Sadri
- College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT 84095, USA
| | - Melanie Katz
- College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT 84095, USA
| | - Connor Schwartz
- Library, Roseman University of Health Sciences, South Jordan, UT 84095, USA
| | - Amir Mohajeri
- College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT 84095, USA
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Moghaddam A, Bahrami M, Mirzadeh M, Khatami M, Simorgh S, Chimehrad M, Kruppke B, Bagher Z, Mehrabani D, Khonakdar HA. Recent trends in bone tissue engineering: a review of materials, methods, and structures. Biomed Mater 2024; 19:042007. [PMID: 38636500 DOI: 10.1088/1748-605x/ad407d] [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: 09/23/2023] [Accepted: 04/18/2024] [Indexed: 04/20/2024]
Abstract
Bone tissue engineering (BTE) provides the treatment possibility for segmental long bone defects that are currently an orthopedic dilemma. This review explains different strategies, from biological, material, and preparation points of view, such as using different stem cells, ceramics, and metals, and their corresponding properties for BTE applications. In addition, factors such as porosity, surface chemistry, hydrophilicity and degradation behavior that affect scaffold success are introduced. Besides, the most widely used production methods that result in porous materials are discussed. Gene delivery and secretome-based therapies are also introduced as a new generation of therapies. This review outlines the positive results and important limitations remaining in the clinical application of novel BTE materials and methods for segmental defects.
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Affiliation(s)
| | - Mehran Bahrami
- Department of Mechanical Engineering and Mechanics, Lehigh University, 27 Memorial Dr W, Bethlehem, PA 18015, United States of America
| | | | - Mehrdad Khatami
- Iran Polymer and Petrochemical Institute (IPPI), Tehran 14965-115, Iran
| | - Sara Simorgh
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Chimehrad
- Department of Mechanical & Aerospace Engineering, College of Engineering & Computer Science, University of Central Florida, Orlando, FL, United States of America
| | - Benjamin Kruppke
- Max Bergmann Center of Biomaterials and Institute of Materials Science, Technische Universität Dresden, 01069 Dresden, Germany
| | - Zohreh Bagher
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Davood Mehrabani
- Burn and Wound Healing Research Center, Shiraz University of Medical Sciences, Shiraz, Fars 71348-14336, Iran
- Stem Cell Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Fars 71345-1744, Iran
| | - Hossein Ali Khonakdar
- Iran Polymer and Petrochemical Institute (IPPI), Tehran 14965-115, Iran
- Max Bergmann Center of Biomaterials and Institute of Materials Science, Technische Universität Dresden, 01069 Dresden, Germany
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Mahajan A, Bhattacharyya S. Immunomodulation by mesenchymal stem cells during osteogenic differentiation: Clinical implications during bone regeneration. Mol Immunol 2023; 164:143-152. [PMID: 38011783 DOI: 10.1016/j.molimm.2023.11.006] [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: 06/12/2023] [Revised: 11/08/2023] [Accepted: 11/12/2023] [Indexed: 11/29/2023]
Abstract
Critical bone defects resulting in delayed and non-union are a major concern in the field of orthopedics. Over the past decade, mesenchymal stem cells (MSCs) have become a promising frontier for bone repair and regeneration owing to their high expansion rate and osteogenic differentiation potential ex vivo. MSCs have also long been associated with their ability to modulate immune response in the recipients. These can even skew the immune response towards pro-inflammatory or anti-inflammatory type by sensing their local microenvironment. MSCs adopt anti-inflammatory phenotype at bone injury site and secrete various immunomodulatory factors such as IDO, NO, TGFβ1 and PGE-2 which have redundant role in osteoblast differentiation and bone formation. As such, several studies have also sought to decipher the immunomodulatory effects of osteogenically differentiated MSCs. The present review discusses the immunomodulatory status of MSCs during their osteogenic differentiation and summarizes few mechanisms that cause immunosuppression by osteogenically differentiated MSCs and its implication during bone healing.
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Affiliation(s)
- Aditi Mahajan
- Department of Biophysics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Shalmoli Bhattacharyya
- Department of Biophysics, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
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Bello SA, Cruz-Lebrón J, Rodríguez-Rivera OA, Nicolau E. Bioactive Scaffolds as a Promising Alternative for Enhancing Critical-Size Bone Defect Regeneration in the Craniomaxillofacial Region. ACS APPLIED BIO MATERIALS 2023; 6:4465-4503. [PMID: 37877225 DOI: 10.1021/acsabm.3c00432] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2023]
Abstract
Reconstruction of critical-size bone defects (CSDs) in the craniomaxillofacial (CMF) region remains challenging. Scaffold-based bone-engineered constructs have been proposed as an alternative to the classical treatments made with autografts and allografts. Scaffolds, a key component of engineered constructs, have been traditionally viewed as biologically passive temporary replacements of deficient bone lacking intrinsic cues to promote osteogenesis. Nowadays, scaffolds are functionalized, giving rise to bioactive scaffolds promoting bone regeneration more effectively than conventional counterparts. This review focuses on the three approaches most used to bioactivate scaffolds: (1) conferring microarchitectural designs or surface nanotopography; (2) loading bioactive molecules; and (3) seeding stem cells on scaffolds, providing relevant examples of in vivo (preclinical and clinical) studies where these methods are employed to enhance CSDs healing in the CMF region. From these, adding bioactive molecules (specifically bone morphogenetic proteins or BMPs) to scaffolds has been the most explored to bioactivate scaffolds. Nevertheless, the downsides of grafting BMP-loaded scaffolds in patients have limited its successful translation into clinics. Despite these drawbacks, scaffolds containing safer, cheaper, and more effective bioactive molecules, combined with stem cells and topographical cues, remain a promising alternative for clinical use to treat CSDs in the CMF complex replacing autografts and allografts.
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Affiliation(s)
- Samir A Bello
- Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, San Juan, Puerto Rico 00931, United States
- Molecular Sciences Research Center, University of Puerto Rico, 1390 Ponce De León Ave, Suite 1-7, San Juan, Puerto Rico 00926, United States
| | - Junellie Cruz-Lebrón
- Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, San Juan, Puerto Rico 00931, United States
- Molecular Sciences Research Center, University of Puerto Rico, 1390 Ponce De León Ave, Suite 1-7, San Juan, Puerto Rico 00926, United States
| | - Osvaldo A Rodríguez-Rivera
- Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, San Juan, Puerto Rico 00931, United States
- Molecular Sciences Research Center, University of Puerto Rico, 1390 Ponce De León Ave, Suite 1-7, San Juan, Puerto Rico 00926, United States
| | - Eduardo Nicolau
- Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, San Juan, Puerto Rico 00931, United States
- Molecular Sciences Research Center, University of Puerto Rico, 1390 Ponce De León Ave, Suite 1-7, San Juan, Puerto Rico 00926, United States
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Wang X, Sun L, Qin X, You J, Zhang J, Xia Y. Enhanced Anti-inflammatory Capacity of the Conditioned Medium Derived from Periodontal Ligament Stem Cells Modified with an Iron-Based Nanodrug. Adv Biol (Weinh) 2023; 7:e2300044. [PMID: 37409394 DOI: 10.1002/adbi.202300044] [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: 01/29/2023] [Revised: 04/28/2023] [Indexed: 07/07/2023]
Abstract
Cell-free therapy using conditioned medium (CM) from mesenchymal stem cells takes full advantage of the bioactive factors secreted by the cells while avoiding disadvantages such as immune rejection and tumor formation due to cell transplantation. In this study, human periodontal ligament stem cells (PDLSCs) are modified with the superparamagnetic iron oxide nanoparticle (SPION)-based nanodrug ferumoxytol (PDLSC-SPION). Compared with PDLSCs, PDLSC-SPION showed good cell viability and better osteogenic differentiation ability. Cell-free CM is collected and the anti-inflammatory capacity of PDLSC CM and PDLSC-SPION CM is assessed by treatment of lipopolysaccharide-stimulated macrophages and IL-17-stimulated human gingival fibroblasts. Both CMs inhibited the expression of proinflammatory cytokines in cells, and the therapeutic effect is more distinct for PDLSC-SPION CM than PDLSC CM, which may be due to their different proteomic compositions. Therefore, modification of PDLSCs with ferumoxytol enhances the anti-inflammatory capacity of its CM, making it more potentially useful for the treatment of inflammatory diseases such as periodontitis.
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Affiliation(s)
- Xinyue Wang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, 210029, China
| | - Liuxu Sun
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, 210029, China
| | - Xuan Qin
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, 210029, China
| | - Jiayi You
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, 210029, China
| | - Jing Zhang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, 210029, China
| | - Yang Xia
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, 210029, China
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11
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Buss LF, de Martin GS, Martinez EF, Filgueiras IADAAP, Magnabosco JL, Alves BF, de Macedo Almeida B, Kotaka T, Teixeira ML, Ferreira JRM, da Rocha DN, Canal R, Aloise AC, Holliday LS, Pelegrine AA. Conditioned Media from Human Pulp Stem Cell Cultures Improve Bone Regeneration in Rat Calvarial Critical-Size Defects. J Funct Biomater 2023; 14:396. [PMID: 37623641 PMCID: PMC10455841 DOI: 10.3390/jfb14080396] [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: 07/07/2023] [Revised: 07/20/2023] [Accepted: 07/21/2023] [Indexed: 08/26/2023] Open
Abstract
The aim of this study was to test whether lyophilized conditioned media from human dental pulp mesenchymal stem cell cultures promote the healing of critical-size defects created in the calvaria of rats. Prior to the surgical procedure, the medium in which dental pulp stem cells were cultured was frozen and lyophilized. After general anesthesia, an 8 mm diameter bone defect was created in the calvaria of twenty-four rats. The defects were filled with the following materials: xenograft alone (G1) or xenograft associated with lyophilized conditioned medium (G2). After 14 or 42 days, the animals were euthanized, and the specimens processed for histologic and immunohistochemical analysis. Bone formation at the center of the defect was observed only in the G2 at 42 days. At both timepoints, increased staining for VEGF, a marker for angiogenesis, was observed in G2. Consistent with this, at 14 days, G2 also had a higher number of blood vessels detected by immunostaining with an anti-CD34 antibody. In conclusion, conditioned media from human dental pulp mesenchymal stem cell cultures had a positive effect on the regenerative process in rat critical-size bone defects. Both the formation of bone and enhancement of vascularization were stimulated by the conditioned media.
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Affiliation(s)
- Leonardo Fernandes Buss
- Faculdade de Odontologia São Leopoldo Mandic, Campinas 13045-755, SP, Brazil; (L.F.B.); (G.S.d.M.); (I.A.d.A.A.P.F.); (J.L.M.); (B.F.A.); (B.d.M.A.); (T.K.)
| | - Gustavo Sigrist de Martin
- Faculdade de Odontologia São Leopoldo Mandic, Campinas 13045-755, SP, Brazil; (L.F.B.); (G.S.d.M.); (I.A.d.A.A.P.F.); (J.L.M.); (B.F.A.); (B.d.M.A.); (T.K.)
| | | | | | - José Luiz Magnabosco
- Faculdade de Odontologia São Leopoldo Mandic, Campinas 13045-755, SP, Brazil; (L.F.B.); (G.S.d.M.); (I.A.d.A.A.P.F.); (J.L.M.); (B.F.A.); (B.d.M.A.); (T.K.)
| | - Bruno Frenhan Alves
- Faculdade de Odontologia São Leopoldo Mandic, Campinas 13045-755, SP, Brazil; (L.F.B.); (G.S.d.M.); (I.A.d.A.A.P.F.); (J.L.M.); (B.F.A.); (B.d.M.A.); (T.K.)
| | - Bruno de Macedo Almeida
- Faculdade de Odontologia São Leopoldo Mandic, Campinas 13045-755, SP, Brazil; (L.F.B.); (G.S.d.M.); (I.A.d.A.A.P.F.); (J.L.M.); (B.F.A.); (B.d.M.A.); (T.K.)
| | - Tatiana Kotaka
- Faculdade de Odontologia São Leopoldo Mandic, Campinas 13045-755, SP, Brazil; (L.F.B.); (G.S.d.M.); (I.A.d.A.A.P.F.); (J.L.M.); (B.F.A.); (B.d.M.A.); (T.K.)
| | | | | | | | | | - Antonio Carlos Aloise
- Division of Oral Implantology, Faculdade São Leopoldo Mandic, Campinas 13045-755, SP, Brazil;
| | | | - André Antonio Pelegrine
- Division of Oral Implantology, Faculdade São Leopoldo Mandic, Campinas 13045-755, SP, Brazil;
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12
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Wang R, Wang H, Mu J, Yuan H, Pang Y, Wang Y, Du Y, Han F. Molecular events in the jaw vascular unit: A traditional review of the mechanisms involved in inflammatory jaw bone diseases. J Biomed Res 2023; 37:313-325. [PMID: 37226540 PMCID: PMC10541772 DOI: 10.7555/jbr.36.20220266] [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: 12/27/2022] [Revised: 02/28/2023] [Accepted: 03/08/2023] [Indexed: 05/26/2023] Open
Abstract
Inflammatory jaw bone diseases are common in stomatology, including periodontitis, peri-implantitis, medication-related osteonecrosis of the jaw, radiation osteomyelitis of the jaw, age-related osteoporosis, and other specific infections. These diseases may lead to tooth loss and maxillofacial deformities, severely affecting patients' quality of life. Over the years, the reconstruction of jaw bone deficiency caused by inflammatory diseases has emerged as a medical and socioeconomic challenge. Therefore, exploring the pathogenesis of inflammatory diseases associated with jaw bones is crucial for improving prognosis and developing new targeted therapies. Accumulating evidence indicates that the integrated bone formation and dysfunction arise from complex interactions among a network of multiple cell types, including osteoblast-associated cells, immune cells, blood vessels, and lymphatic vessels. However, the role of these different cells in the inflammatory process and the 'rules' with which they interact are still not fully understood. Although many investigations have focused on specific pathological processes and molecular events in inflammatory jaw diseases, few articles offer a perspective of integration. Here, we review the changes and mechanisms of various cell types in inflammatory jaw diseases, with the hope of providing insights to drive future research in this field.
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Affiliation(s)
- Ruyu Wang
- Department of Oral and Maxillofacial Surgery, the Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, Jiangsu 210029, China
| | - Haoran Wang
- Department of Oral and Maxillofacial Surgery, the Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, Jiangsu 210029, China
| | - Junyu Mu
- International Joint Laboratory for Drug Target of Critical Illnesses, Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Hua Yuan
- Department of Oral and Maxillofacial Surgery, the Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, Jiangsu 210029, China
| | - Yongchu Pang
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, Jiangsu 210029, China
- Department of Orthodontics, the Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Yuli Wang
- Department of Oral and Maxillofacial Surgery, the Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, Jiangsu 210029, China
| | - Yifei Du
- Department of Oral and Maxillofacial Surgery, the Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, Jiangsu 210029, China
| | - Feng Han
- International Joint Laboratory for Drug Target of Critical Illnesses, Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu 211166, China
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13
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Gao J, Liu X, Cheng J, Deng J, Han Z, Li M, Wang X, Liu J, Zhang L. Application of photocrosslinkable hydrogels based on photolithography 3D bioprinting technology in bone tissue engineering. Regen Biomater 2023; 10:rbad037. [PMID: 37250979 PMCID: PMC10219790 DOI: 10.1093/rb/rbad037] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/02/2023] [Accepted: 04/16/2023] [Indexed: 05/31/2023] Open
Abstract
Bone tissue engineering (BTE) has been proven to be an effective method for the treatment of bone defects caused by different musculoskeletal disorders. Photocrosslinkable hydrogels (PCHs) with good biocompatibility and biodegradability can significantly promote the migration, proliferation and differentiation of cells and have been widely used in BTE. Moreover, photolithography 3D bioprinting technology can notably help PCHs-based scaffolds possess a biomimetic structure of natural bone, meeting the structural requirements of bone regeneration. Nanomaterials, cells, drugs and cytokines added into bioinks can enable different functionalization strategies for scaffolds to achieve the desired properties required for BTE. In this review, we demonstrate a brief introduction of the advantages of PCHs and photolithography-based 3D bioprinting technology and summarize their applications in BTE. Finally, the challenges and potential future approaches for bone defects are outlined.
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Affiliation(s)
| | | | | | - Junhao Deng
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing 100036, China
| | - Zhenchuan Han
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing 100036, China
| | - Ming Li
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing 100036, China
| | - Xiumei Wang
- Correspondence address: E-mail: (X.W); (J.L.); (L.Z.)
| | - Jianheng Liu
- Correspondence address: E-mail: (X.W); (J.L.); (L.Z.)
| | - Licheng Zhang
- Correspondence address: E-mail: (X.W); (J.L.); (L.Z.)
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14
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Liu F, Sun T, An Y, Ming L, Li Y, Zhou Z, Shang F. The potential therapeutic role of extracellular vesicles in critical-size bone defects: Spring of cell-free regenerative medicine is coming. Front Bioeng Biotechnol 2023; 11:1050916. [PMID: 36733961 PMCID: PMC9887316 DOI: 10.3389/fbioe.2023.1050916] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 01/02/2023] [Indexed: 01/19/2023] Open
Abstract
In recent years, the incidence of critical-size bone defects has significantly increased. Critical-size bone defects seriously affect patients' motor functions and quality of life and increase the need for additional clinical treatments. Bone tissue engineering (BTE) has made great progress in repairing critical-size bone defects. As one of the main components of bone tissue engineering, stem cell-based therapy is considered a potential effective strategy to regenerate bone tissues. However, there are some disadvantages including phenotypic changes, immune rejection, potential tumorigenicity, low homing efficiency and cell survival rate that restrict its wider clinical applications. Evidence has shown that the positive biological effects of stem cells on tissue repair are largely mediated through paracrine action by nanostructured extracellular vesicles (EVs), which may overcome the limitations of traditional stem cell-based treatments. In addition to stem cell-derived extracellular vesicles, the potential therapeutic roles of nonstem cell-derived extracellular vesicles in critical-size bone defect repair have also attracted attention from scholars in recent years. Currently, the development of extracellular vesicles-mediated cell-free regenerative medicine is still in the preliminary stage, and the specific mechanisms remain elusive. Herein, the authors first review the research progress and possible mechanisms of extracellular vesicles combined with bone tissue engineering scaffolds to promote bone regeneration via bioactive molecules. Engineering modified extracellular vesicles is an emerging component of bone tissue engineering and its main progression and clinical applications will be discussed. Finally, future perspectives and challenges of developing extracellular vesicle-based regenerative medicine will be given. This review may provide a theoretical basis for the future development of extracellular vesicle-based biomedicine and provide clinical references for promoting the repair of critical-size bone defects.
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Affiliation(s)
- Fen Liu
- Department of Periodontology, Shenzhen Stomatological Hospital (Pingshan), Southern Medical University, Shenzhen, Guangdong, China
| | - Tianyu Sun
- Department of Periodontology, Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Ying An
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture and Department of Periodontology, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Leiguo Ming
- Department of Research and Development, Shaanxi Zhonghong Institute of Regenerative Medicine, Xi’an, Shaanxi, China
| | - Yinghui Li
- Department of Orthodontics, Stomatological Hospital, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Zhifei Zhou
- Department of Stomatology, General Hospital of Tibetan Military Command, Lhasa, Tibet, China,*Correspondence: Fengqing Shang, ; Zhifei Zhou,
| | - Fengqing Shang
- Department of Stomatology, Air Force Medical Center, Fourth Military Medical University, Beijing, China,*Correspondence: Fengqing Shang, ; Zhifei Zhou,
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15
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Zhong Y, Huang S, Feng Z, Fu Y, Mo A. Recent advances and trends in the applications of MXene nanomaterials for tissue engineering and regeneration. J Biomed Mater Res A 2022; 110:1840-1859. [PMID: 35975580 DOI: 10.1002/jbm.a.37438] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 07/14/2022] [Accepted: 08/03/2022] [Indexed: 11/08/2022]
Abstract
MXene, as a new two-dimensional nanomaterial, is endowed with lots of particular properties, such as large surface area, excellent conductivity, biocompatibility, biodegradability, hydrophilicity, antibacterial activity, and so on. In the past few years, MXene nanomaterials have become a rising star in biomedical fields including biological imaging, tumor diagnosis, biosensor, and tissue engineering. In this review, we sum up the recent applications of MXene nanomaterials in the field of tissue engineering and regeneration. First, we briefly introduced the synthesis and surface modification engineering of MXene. Then we focused on the application and development of MXene and MXene-based composites in skin, bone, nerve and heart tissue engineering. Uniquely, we also paid attention to some research on MXene with few achievements at present but might become a new trend in tissue engineering and regeneration in the future. Finally, this paper will also discuss several challenges faced by MXene nanomaterials in the clinical application of tissue engineering.
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Affiliation(s)
- Yongjin Zhong
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Si Huang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zeru Feng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yu Fu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Anchun Mo
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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16
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Kim JH, Yang H, Kim MW, Cho KS, Kim DS, Yim HE, Atala Z, Ko IK, Yoo JJ. The Delivery of the Recombinant Protein Cocktail Identified by Stem Cell-Derived Secretome Analysis Accelerates Kidney Repair After Renal Ischemia-Reperfusion Injury. Front Bioeng Biotechnol 2022; 10:848679. [PMID: 35646873 PMCID: PMC9130839 DOI: 10.3389/fbioe.2022.848679] [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: 01/04/2022] [Accepted: 04/27/2022] [Indexed: 12/14/2022] Open
Abstract
Recent advances in cell therapy have shown the potential to treat kidney diseases. As the treatment effects of the cell therapies are mainly attributed to secretomes released from the transplanted cells, the delivery of secretomes or conditioned medium (CM) has emerged as a promising treatment option for kidney disease. We previously demonstrated that the controlled delivery of human placental stem cells (hPSC)-derived CM using platelet-rich plasma (PRP) ameliorated renal damages and restored kidney function in an acute kidney injury (AKI) model in rats. The proteomics study of the hPSC-CM revealed that hPSC secrets several proteins that contribute to kidney tissue repair. Based on our results, this study proposed that the proteins expressed in the hPSC-CM and effective for kidney repair could be used as a recombinant protein cocktail to treat kidney diseases as an alternative to CM. In this study, we analyzed the secretome profile of hPSC-CM and identified five proteins (follistatin, uPAR, ANGPLT4, HGF, VEGF) that promote kidney repair. We investigated the feasibility of delivering the recombinant protein cocktail to improve structural and functional recovery after AKI. The pro-proliferative and anti-apoptotic effects of the protein cocktail on renal cells are demonstrated in vitro and in vivo. The intrarenal delivery of these proteins with PRP ameliorates the renal tubular damage and improved renal function in the AKI-induced rats, yielding similar therapeutic effects compared to the CM delivery. These results indicate that our strategy may provide a therapeutic solution to many challenges associated with kidney repair resulting from the lack of suitable off-the-shelf regenerative medicine products.
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Affiliation(s)
- Ji Hyun Kim
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Heejo Yang
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States.,Department of Urology, Soonchunhyang University College of Medicine, Cheonan, South Korea
| | - Michael W Kim
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Kang Su Cho
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States.,Department of Urology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Doo Sang Kim
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States.,Department of Urology, Soonchunhyang University College of Medicine, Cheonan, South Korea
| | - Hyung Eun Yim
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States.,Department of Pediatrics, Korea University College of Medicine, Seoul, South Korea
| | - Zachary Atala
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - In Kap Ko
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - James J Yoo
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
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17
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Nambiar J, Jana S, Nandi SK. Strategies for Enhancing Vascularization of Biomaterial-Based Scaffold in Bone Regeneration. CHEM REC 2022; 22:e202200008. [PMID: 35352873 DOI: 10.1002/tcr.202200008] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/12/2022] [Indexed: 12/29/2022]
Abstract
Despite the recent advances in reconstructive orthopedics; fracture union is a challenge to bone regeneration. Concurrent angiogenesis is a complex process governed by events, delicately entwined with osteogenesis. However, poorly perfused scaffolds have lower success rates; necessitating the need for a better vascular component, which is important for the delivery of nutrients, oxygen, waste elimination, recruitment of cells for optimal bone repair. This review highlights the latest strategies to promote biomaterial-based scaffold vascularization by incorporation of cells, growth factors, inorganic ions, etc. into natural or synthetic polymers, ceramic materials, or composites of organic and inorganic compounds. Furthermore, it emphasizes structural modifications, biophysical stimuli, and natural molecules to fabricate scaffolds aiding the genesis of dense vascularization following their implantation to manifest a compatible regenerative microenvironment without graft rejection.
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Affiliation(s)
- Jasna Nambiar
- Department of Veterinary Surgery and Radiology, West Bengal University of Animal & Fishery Sciences, Kolkata, 700037, India
| | - Sonali Jana
- Department of Veterinary Physiology, West Bengal University of Animal & Fishery Sciences, Kolkata, 700037, India
| | - Samit Kumar Nandi
- Department of Veterinary Surgery and Radiology, West Bengal University of Animal & Fishery Sciences, Kolkata, 700037, India
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18
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Han Y, Yang J, Fang J, Zhou Y, Candi E, Wang J, Hua D, Shao C, Shi Y. The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Signal Transduct Target Ther 2022; 7:92. [PMID: 35314676 PMCID: PMC8935608 DOI: 10.1038/s41392-022-00932-0] [Citation(s) in RCA: 328] [Impact Index Per Article: 109.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 11/18/2021] [Accepted: 02/20/2022] [Indexed: 02/06/2023] Open
Abstract
AbstractMesenchymal stromal/stem cells (MSCs) possess multi-lineage differentiation and self-renewal potentials. MSCs-based therapies have been widely utilized for the treatment of diverse inflammatory diseases, due to the potent immunoregulatory functions of MSCs. An increasing body of evidence indicates that MSCs exert their therapeutic effects largely through their paracrine actions. Growth factors, cytokines, chemokines, extracellular matrix components, and metabolic products were all found to be functional molecules of MSCs in various therapeutic paradigms. These secretory factors contribute to immune modulation, tissue remodeling, and cellular homeostasis during regeneration. In this review, we summarize and discuss recent advances in our understanding of the secretory behavior of MSCs and the intracellular communication that accounts for their potential in treating human diseases.
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19
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Li F, Zhang J, Yi K, Wang H, Wei H, Chan HF, Tao Y, Li M. Delivery of Stem Cell Secretome for Therapeutic Applications. ACS APPLIED BIO MATERIALS 2022; 5:2009-2030. [PMID: 35285638 DOI: 10.1021/acsabm.1c01312] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Intensive studies on stem cell therapy reveal that benefits of stem cells attribute to the paracrine effects. Hence, direct delivery of stem cell secretome to the injured site shows the comparative therapeutic efficacy of living cells while avoiding the potential limitations. However, conventional systemic administration of stem cell secretome often leads to rapid clearance in vivo. Therefore, a variety of different biomaterials are developed for sustained and controllable delivery of stem cell secretome to improve therapeutic efficiency. In this review, we first introduce current approaches for the preparation and characterization of stem cell secretome as well as strategies to improve their therapeutic efficacy and production. The up-to-date delivery platforms are also summarized, including nanoparticles, injectable hydrogels, microneedles, and scaffold patches. Meanwhile, we discuss the underlying therapeutic mechanism of stem cell secretome for the treatment of various diseases. In the end, future opportunities and challenges are proposed.
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Affiliation(s)
- Fenfang Li
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Jiabin Zhang
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Ke Yi
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Haixia Wang
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Hongyan Wei
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Hon Fai Chan
- Institute for Tissue Engineering and Regenerative Medicine, School of Biomedical Science, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Yu Tao
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Mingqiang Li
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.,Guangdong Provincial Key Laboratory of Liver Disease, Guangzhou 510630, China
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20
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Migration and phenotype switching of macrophages at early-phase of bone-formation by secretomes from bone marrow derived mesenchymal stem cells using rat calvaria bone defect model. J Dent Sci 2022; 17:421-429. [PMID: 35028066 PMCID: PMC8739749 DOI: 10.1016/j.jds.2021.08.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 08/17/2021] [Indexed: 01/08/2023] Open
Abstract
Background/purpose Conditioned media of cultured mesenchymal stem cells (MSCs) contain numerous kinds of secretomes such as cytokines and chemokines. We previously reported that conditioned media of bone marrow-derived MSCs (MSC-CM) promote bone formation. Recently, macrophage phenotype switching from the pro-inflammatory M1 type to the anti-inflammatory M2 type has been reported to be an important phenomenon during tissue regeneration. Some studies reported that this phenotype switching is regulated by secretomes. In this study, macrophage phenotype during bone formation by MSC-CM was investigated. Materials and methods Human MSCs (hMSCs) were cultured in serum-free medium and the collected medium was defined as MSC-CM. Macrophage-related gene expressions in hMSCs cultured with MSC-CM were evaluated by quantitative real-time polymerase chain reaction. MSC-CM was implanted and the evaluations by micro-CT and immunohistochemistry were performed using a rat the calvaria bone defect model. Results Two and four weeks after implantation, the MSC-CM group demonstrated enhanced bone regeneration. Gene expressions of C–C motif chemokine 2 (CCL2), colony-stimulating factor 2 (CSF2) and CD163 was significantly upregulated in cells exposed to MSC-CM. Immunohistochemical staining revealed that iNOS-positive M1 macrophages were reduced, while CD204-positive M2 macrophages were increased in the MSC-CM group at 72 h after implantation, and the M2/M1 ratio increased only in the MSC-CM group. Conclusion MSC-CM enhances macrophage migration and induces M1 to M2 type macrophage switching at an early stage of osteogenesis. Such phenotype switching provides a favorable environment for angiogenesis, cellular migration, and osteogenesis and contributes to MSC-CM-induced early bone formation.
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21
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González-González A, García-Sánchez D, Alfonso-Fernández A, Haider KH, Rodríguez-Rey JC, Pérez-Campo FM. Regenerative Medicine Applied to the Treatment of Musculoskeletal Pathologies. HANDBOOK OF STEM CELL THERAPY 2022:1123-1158. [DOI: 10.1007/978-981-19-2655-6_50] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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22
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Peng Y, Li J, Lin H, Tian S, Liu S, Pu F, Zhao L, Ma K, Qing X, Shao Z. Endogenous repair theory enriches construction strategies for orthopaedic biomaterials: a narrative review. BIOMATERIALS TRANSLATIONAL 2021; 2:343-360. [PMID: 35837417 PMCID: PMC9255795 DOI: 10.12336/biomatertransl.2021.04.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 11/19/2021] [Indexed: 02/06/2023]
Abstract
The development of tissue engineering has led to new strategies for mitigating clinical problems; however, the design of the tissue engineering materials remains a challenge. The limited sources and inadequate function, potential risk of microbial or pathogen contamination, and high cost of cell expansion impair the efficacy and limit the application of exogenous cells in tissue engineering. However, endogenous cells in native tissues have been reported to be capable of spontaneous repair of the damaged tissue. These cells exhibit remarkable plasticity, and thus can differentiate or be reprogrammed to alter their phenotype and function after stimulation. After a comprehensive review, we found that the plasticity of these cells plays a major role in establishing the cell source in the mechanism involved in tissue regeneration. Tissue engineering materials that focus on assisting and promoting the natural self-repair function of endogenous cells may break through the limitations of exogenous seed cells and further expand the applications of tissue engineering materials in tissue repair. This review discusses the effects of endogenous cells, especially stem cells, on injured tissue repairing, and highlights the potential utilisation of endogenous repair in orthopaedic biomaterial constructions for bone, cartilage, and intervertebral disc regeneration.
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Affiliation(s)
- Yizhong Peng
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Jinye Li
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Hui Lin
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Shuo Tian
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Sheng Liu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Feifei Pu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Lei Zhao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Kaige Ma
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xiangcheng Qing
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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Conditioned Medium from Bone Marrow Mesenchymal Stem Cells Restored Oxidative Stress-Related Impaired Osteogenic Differentiation. Int J Mol Sci 2021; 22:ijms222413458. [PMID: 34948255 PMCID: PMC8706339 DOI: 10.3390/ijms222413458] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/29/2021] [Accepted: 12/10/2021] [Indexed: 12/16/2022] Open
Abstract
Oxidative stress from high levels of intracellular reactive oxygen species (ROS) has been linked to various bone diseases. Previous studies indicate that mesenchymal stem cells (MSC) secrete bioactive factors (conditioned medium (MSC-CM)) that have antioxidant effects. However, the antioxidant role of MSC-CM on osteogenesis has not been fully studied. We aimed to identify antioxidant proteins in MSC-CM using mass spectrometry-based proteomics and to explore their effects on osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSC) exposed to oxidative stress induced by hydrogen peroxide (H2O2). Our analysis revealed that MSC-CM is comprised of antioxidant proteins that are involved in several biological processes, including negative regulation of apoptosis and positive regulation of cell proliferation. Then, hBMSC exposed to H2O2 were treated with MSC-CM, and the effects on their osteogenic differentiation were evaluated. MSC-CM restored H2O2-induced damage to hBMSC by increasing the antioxidant enzyme-SOD production and the mRNA expression level of the anti-apoptotic BCL-2. A decrease in ROS production and cellular apoptosis was also shown. MSC-CM also modulated mRNA expression levels of osteogenesis-related genes, runt-related transcription factor 2, collagen type I, bone morphogenic protein 2, and osteopontin. Furthermore, collagen type I protein secretion, alkaline phosphatase activity, and in vitro mineralization were increased. These results indicate that MSC-CM contains several proteins with antioxidant and anti-apoptotic properties that restored the impaired hBMSC osteogenic differentiation associated with oxidative stress.
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Lin H, Chen H, Zhao X, Chen Z, Zhang P, Tian Y, Wang Y, Ding T, Wang L, Shen Y. Advances in mesenchymal stem cell conditioned medium-mediated periodontal tissue regeneration. J Transl Med 2021; 19:456. [PMID: 34736500 PMCID: PMC8567704 DOI: 10.1186/s12967-021-03125-5] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 10/22/2021] [Indexed: 12/19/2022] Open
Abstract
Periodontitis is a chronic inflammatory disease that leads to the destruction of both soft and hard periodontal tissues. Complete periodontal regeneration in clinics using the currently available treatment approaches is still a challenge. Mesenchymal stem cells (MSCs) have shown promising potential to regenerate periodontal tissue in various preclinical and clinical studies. The poor survival rate of MSCs during in vivo transplantation and host immunogenic reaction towards MSCs are the main drawbacks of direct use of MSCs in periodontal tissue regeneration. Autologous MSCs have limited sources and possess patient morbidity during harvesting. Direct use of allogenic MSCs could induce host immune reaction. Therefore, the MSC-based indirect treatment approach could be beneficial for periodontal regeneration in clinics. MSC culture conditioned medium (CM) contains secretomes that had shown immunomodulatory and tissue regenerative potential in pre-clinical and clinical studies. MSC-CM contains a cocktail of growth factors, cytokines, chemokines, enzymes, and exosomes, extracellular vesicles, etc. MSC-CM-based indirect treatment has the potential to eliminate the drawbacks of direct use of MSCs for periodontal tissue regeneration. MSC-CM holds the tremendous potential of bench-to-bed translation in periodontal regeneration applications. This review focuses on the accumulating evidence indicating the therapeutic potential of the MSC-CM in periodontal regeneration-related pre-clinical and clinical studies. Recent advances on MSC-CM-based periodontal regeneration, existing challenges, and prospects are well summarized as guidance to improve the effectiveness of MSC-CM on periodontal regeneration in clinics.
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Affiliation(s)
- Hongbing Lin
- Department of Periodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, 510182, China
| | - Huishan Chen
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, Jilin, 130021, People's Republic of China
| | - Xuetao Zhao
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, Jilin, 130021, People's Republic of China
| | - Zhen Chen
- Department of Periodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, 510182, China
| | - Peipei Zhang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, Jilin, 130021, People's Republic of China
| | - Yue Tian
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, Jilin, 130021, People's Republic of China
| | - Yawei Wang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, Jilin, 130021, People's Republic of China
| | - Tong Ding
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, Jilin, 130021, People's Republic of China
| | - Lijing Wang
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China.,Vascular Biology Research Institute, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yuqin Shen
- Department of Periodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, 510182, China.
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25
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Cheng J, Liu J, Wu B, Liu Z, Li M, Wang X, Tang P, Wang Z. Graphene and its Derivatives for Bone Tissue Engineering: In Vitro and In Vivo Evaluation of Graphene-Based Scaffolds, Membranes and Coatings. Front Bioeng Biotechnol 2021; 9:734688. [PMID: 34660555 PMCID: PMC8511325 DOI: 10.3389/fbioe.2021.734688] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 09/14/2021] [Indexed: 01/14/2023] Open
Abstract
Bone regeneration or replacement has been proved to be one of the most effective methods available for the treatment of bone defects caused by different musculoskeletal disorders. However, the great contradiction between the large demand for clinical therapies and the insufficiency and deficiency of natural bone grafts has led to an urgent need for the development of synthetic bone graft substitutes. Bone tissue engineering has shown great potential in the construction of desired bone grafts, despite the many challenges that remain to be faced before safe and reliable clinical applications can be achieved. Graphene, with outstanding physical, chemical and biological properties, is considered a highly promising material for ideal bone regeneration and has attracted broad attention. In this review, we provide an introduction to the properties of graphene and its derivatives. In addition, based on the analysis of bone regeneration processes, interesting findings of graphene-based materials in bone regenerative medicine are analyzed, with special emphasis on their applications as scaffolds, membranes, and coatings in bone tissue engineering. Finally, the advantages, challenges, and future prospects of their application in bone regenerative medicine are discussed.
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Affiliation(s)
- Junyao Cheng
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing, China.,Chinese PLA Medical School, Beijing, China
| | - Jianheng Liu
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing, China
| | - Bing Wu
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing, China
| | - Zhongyang Liu
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing, China
| | - Ming Li
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing, China
| | - Xing Wang
- Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Peifu Tang
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing, China
| | - Zheng Wang
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing, China
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26
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Pranskunas M, Simoliunas E, Alksne M, Kaupinis A, Juodzbalys G. Periosteum-Derived Mesenchymal Stem Cells Secretome - Cell-Free Strategy for Endogenous Bone Regeneration: Proteomic Analysis in Vitro. EJOURNAL OF ORAL MAXILLOFACIAL RESEARCH 2021; 12:e2. [PMID: 34377379 PMCID: PMC8326881 DOI: 10.5037/jomr.2021.12202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 06/22/2021] [Indexed: 12/29/2022]
Abstract
Objectives Millions of people worldwide are affected by diseases or injuries which lead to bone/tooth loss and defects. While such clinical situations are daily practice in most of the hospitals, the widely used treatment methods still have disadvantages. Therefore, this field of medicine is actively searching new tissue regeneration techniques, one of which could be stem cell secretome. Thus, the purpose of this research study was to perform the detail proteomic analysis of periosteum-derived mesenchymal stem cells secretome in order to evaluate if it is capable to induce osteo-regenerative process. Material and Methods Periosteum-derived mesenchymal stem cells (PMSCs) were extracted from adult male New Zealand White rabbits. Cells were characterised by evaluating their differentiation potential. After characterisation PMSCs secretomes were collected and their proteomic analysis was performed. Results PMSCs were extracted from adult male New Zealand White rabbits. In order to characterise the extracted PMSCs, they were differentiated in the directions which mainly describes MSC multipotency - osteogenic, myogenic and adipogenic. A total of 146 proteins were detected. After characterisation PMSCs secretomes were collected and their proteomic analysis was performed. The resulting protein composition indicates the ability to promote bone regeneration to fully mature bone. Conclusions Bioactive molecules detected in periosteum-derived mesenchymal stem cells secretome initiates the processes required for the formation of a fully functional bone.
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Affiliation(s)
- Mindaugas Pranskunas
- Department of Oral and Maxillofacial Surgery, Faculty of Odontology, Medical Academy, Lithuanian University of Health Sciences, KaunasLithuania.,32:Baltic dental clinic, VilniusLithuania.,These authors contributed equally to this work
| | - Egidijus Simoliunas
- Department of Biological Models, Institute of Biochemistry, Life Sciences Center, Vilnius University, VilniusLithuania.,These authors contributed equally to this work
| | - Milda Alksne
- Department of Biological Models, Institute of Biochemistry, Life Sciences Center, Vilnius University, VilniusLithuania.,These authors contributed equally to this work
| | - Algirdas Kaupinis
- Proteomics Centre, Institute of Biochemistry, Life Sciences Center, Vilnius University, Saulėtekio av. 7, LT-10257 VilniusLithuania
| | - Gintaras Juodzbalys
- Department of Oral and Maxillofacial Surgery, Faculty of Odontology, Medical Academy, Lithuanian University of Health Sciences, KaunasLithuania.,These authors contributed equally to this work
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27
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Grigorita O, Omer L, Juodzbalys G. Complications and Management of Patients with Inherited Bleeding Disorders During Dental Extractions: a Systematic Literature Review. EJOURNAL OF ORAL MAXILLOFACIAL RESEARCH 2021; 12:e1. [PMID: 34377378 PMCID: PMC8326879 DOI: 10.5037/jomr.2021.12201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 06/21/2021] [Indexed: 12/26/2022]
Abstract
Objectives The systematic literature review aims to assess patients' dental extraction with inherited bleeding disorders, to understand the type, dosage, and modality of administration of the haemostatic agents for safe intra- and postoperational results. Material and Methods The search was undertaken in MEDLINE (PubMed) databases and Cochrane library for articles published in English from 1 January, 2010 till 31 October, 2020. Before the full-text articles were considered, titles and abstracts were screened. Results A total of 78 articles were screened, from which 3 met the necessary criteria and were used for the review. Minor complications, such as postoperative bleedings from the socket and epistaxis, were observed, but they were resolved with proper medical care. No major fatal complications were reported. Generally, all the articles provided evidence of successful extractions with correct treatment plans made by haematologists and surgeons. Conclusions Available clinical trials demonstrate that local and systemic haemostatic therapies in combination are effective in preventing bleeding during dental extractions in patients with coagulopathies.
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Affiliation(s)
- Olga Grigorita
- Department of Oral and Maxillofacial Surgery, Lithuanian University of Health SciencesLithuania
| | - Loran Omer
- Department of Oral and Maxillofacial Surgery, Lithuanian University of Health SciencesLithuania
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28
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Oral Bone Tissue Regeneration: Mesenchymal Stem Cells, Secretome, and Biomaterials. Int J Mol Sci 2021; 22:ijms22105236. [PMID: 34063438 PMCID: PMC8156243 DOI: 10.3390/ijms22105236] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/07/2021] [Accepted: 05/13/2021] [Indexed: 12/12/2022] Open
Abstract
In the last few decades, tissue engineering has become one of the most studied medical fields. Even if bone shows self-remodeling properties, in some cases, due to injuries or anomalies, bone regeneration can be required. In particular, oral bone regeneration is needed in the dentistry field, where the functional restoration of tissues near the tooth represents a limit for many dental implants. In this context, the application of biomaterials and mesenchymal stem cells (MSCs) appears promising for bone regeneration. This review focused on in vivo studies that evaluated bone regeneration using biomaterials with MSCs. Different biocompatible biomaterials were enriched with MSCs from different sources. These constructs showed an enhanced bone regenerative power in in vivo models. However, we discussed also a future perspective in tissue engineering using the MSC secretome, namely the conditioned medium and extracellular vesicles. This new approach has already shown promising results for bone tissue regeneration in experimental models.
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29
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Amodeo G, Niada S, Moschetti G, Franchi S, Savadori P, Brini AT, Sacerdote P. Secretome of human adipose-derived mesenchymal stem cell relieves pain and neuroinflammation independently of the route of administration in experimental osteoarthritis. Brain Behav Immun 2021; 94:29-40. [PMID: 33737173 DOI: 10.1016/j.bbi.2021.03.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 03/08/2021] [Accepted: 03/11/2021] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Treatment of pain associated with osteoarthritis (OA) is unsatisfactory and innovative approaches are needed. The secretome from human adipose-derived mesenchymal stem cells (hASC-Conditioned Medium, CM) has been successfully used to relieve painful symptoms in models of chronic pain. The aim of this study was to explore the efficacy of the hASC-CM to control pain and neuroinflammation in an animal model of OA. METHODS OA was induced in mice by intra-articular monosodium-iodoacetate (MIA) injection. Thermal hyperalgesia and mechanical allodynia were assessed. Once hypersensitivity was established (7 days after MIA), hASC-CM was injected by IA, IPL and IV route and its effect monitored over time. Neuroinflammation in nerve, dorsal root ganglia and spinal cord was evaluated measuring proinflammatory markers and mediators by RT-qPCR. Protein content analysis of secretome by Mass Spectrometry was performed. RESULTS A single injection with hASC-CM induced a fast and long lasting antihyperalgesic and antiallodynic effect. The IV route of administration appeared to be the most efficacious although all the treatments were effective. The effect on pain correlated with the ability of hASC-CM to reduce the neuroinflammatory condition in both the peripheral and central nervous system. Furthermore, the secretome analysis revealed 101 factors associated with immune regulation. CONCLUSION We suggest that hASC-CM is a valid treatment option for controlling OA-related hypersensitivity, exerting a rapid and long lasting pain relief. The mechanisms underpinning its effects are likely linked to the positive modulation of neuroinflammation in peripheral and central nervous system that sustains peripheral and central sensitization.
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Affiliation(s)
- Giada Amodeo
- Dipartimento di Scienze Farmacologiche e Biomolecolari, University of Milano, Milano, Italy
| | | | - Giorgia Moschetti
- Dipartimento di Scienze Farmacologiche e Biomolecolari, University of Milano, Milano, Italy
| | - Silvia Franchi
- Dipartimento di Scienze Farmacologiche e Biomolecolari, University of Milano, Milano, Italy
| | | | - Anna T Brini
- IRCCS Istituto Ortopedico Galeazzi, Milano, Italy; Dipartimento di Scienze Biomediche Chirurgiche e Odontoiatriche, University of Milano, Milano, Italy
| | - Paola Sacerdote
- Dipartimento di Scienze Farmacologiche e Biomolecolari, University of Milano, Milano, Italy.
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30
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Rodríguez-Fuentes N, Alcántara-Quintana LE, Hernández-Ramírez DF, Piña-Barba MC, Cervantes-Uc JM, Núñez-Álvarez CA, Ambrosio JR. Cytokines secretion from human mesenchymal stem cells induced by bovine bone matrix. Biomed Mater Eng 2021; 32:217-228. [PMID: 33780360 DOI: 10.3233/bme-218000] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Bovine bone matrix is a natural material that has been used in the treatment of bone lesions. In this study, bovine bone matrix Nukbone® (NKB) was investigated due its osteoconductive and osteoinductive properties. This biomaterial induces CBFA-1 activation and osteogenic differentiation, although the cytokines involved in these processes is still unknown. OBJECTIVE The aim of this work was to determine the influence of NKB on the pro-osteoblastic and anti-osteoblastic cytokines secretion from human mesenchymal stem cells (hMSCs). METHODS The hMSCs were cultured onto NKB and cytokines IL-2, IL-4, IL-6, IL-10, IL-12, IFN-γ and TNF-α were analized at 0-14 days by immunoassay. In addition, hemocompatibility of NKB and characterization of hMSCs were evaluated. RESULTS NKB induces an increase on pro-osteoblastic cytokine secretion IL-4 and a decrease on anti-osteoblastic cytokine IL-6 secretion, at days 7 and 14 of cell culture. Interestingly, there was no statistical difference between secretion profiles of others cytokines analized. CONCLUSIONS The up-regulation of IL-4 and down-regulation of IL-6, and the secretion profiles of other cytokines examined in this work, are findings that will contribute to the understanding of the role of NKB, and similar biomaterials, in bone homeostasis and in the osteoblastic differentiation of hMSCs.
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Affiliation(s)
| | - Luz E Alcántara-Quintana
- CONACYT, Facultad de Enfermería y Nutrición, Universidad Autónoma de San Luis Potosí, San Luis Potosí, México
| | | | - María C Piña-Barba
- Instituto de Investigaciones en Materiales, UNAM, Ciudad de México, México
| | | | - Carlos A Núñez-Álvarez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México.,Facultad de Medicina, UNAM, Ciudad de México, México
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31
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3D-microtissue derived secretome as a cell-free approach for enhanced mineralization of scaffolds in the chorioallantoic membrane model. Sci Rep 2021; 11:5418. [PMID: 33686145 PMCID: PMC7940489 DOI: 10.1038/s41598-021-84123-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 02/11/2021] [Indexed: 12/16/2022] Open
Abstract
Bone regeneration is a complex process and the clinical translation of tissue engineered constructs (TECs) remains a challenge. The combination of biomaterials and mesenchymal stem cells (MSCs) may enhance the healing process through paracrine effects. Here, we investigated the influence of cell format in combination with a collagen scaffold on key factors in bone healing process, such as mineralization, cell infiltration, vascularization, and ECM production. MSCs as single cells (2D-SCs), assembled into microtissues (3D-MTs) or their corresponding secretomes were combined with a collagen scaffold and incubated on the chicken embryo chorioallantoic membrane (CAM) for 7 days. A comprehensive quantitative analysis was performed on a cellular level by histology and by microcomputed tomography (microCT). In all experimental groups, accumulation of collagen and glycosaminoglycan within the scaffold was observed over time. A pronounced cell infiltration and vascularization from the interface to the surface region of the CAM was detected. The 3D-MT secretome showed a significant mineralization of the biomaterial using microCT compared to all other conditions. Furthermore, it revealed a homogeneous distribution pattern of mineralization deposits in contrast to the cell-based scaffolds, where mineralization was only at the surface. Therefore, the secretome of MSCs assembled into 3D-MTs may represent an interesting therapeutic strategy for a next-generation bone healing concept.
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32
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Mesgarzadeh AH, Nasiri I, Jarolmasjed S, Naghibi M, Shafaei H. Evaluation of bone regeneration in mandible large defect using undifferentiated adipose stem cells loaded on gelatin carrier: An animal model case study. J Dent Res Dent Clin Dent Prospects 2021; 15:22-29. [PMID: 33927837 PMCID: PMC8058160 DOI: 10.34172/joddd.2021.005] [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: 07/14/2020] [Accepted: 08/22/2020] [Indexed: 11/09/2022] Open
Abstract
Background. Large mandibular defects are considered difficult reconstructive challenges for oral and maxillofacial surgeons. Cell therapy, as an alternative technique, might increase the speed of bone regeneration. This study aimed to investigate bone regeneration in large defects of dog mandibles using allogenic adipose-derived stem cells on gelatin foam as a cell carrier. Methods. The tissue engineering phase consisted of the sampling of adult dogs' adipose tissue that can easily be isolated from adipose stem cells (ASCs) of the dogs, ASCs were cultured in Dulbecco's Modified Eagle's Medium (DMEM, Gibco, USA) with low glucose, containing 10% fetal bovine serum (FBS) (Sigma, USA) and 1% penicillin-streptomycin (Gibco, USA), with the characterization of dog ASCs and gelatin-transplanted ASCs. Six dogs were included in this experimental study in the next step and randomly assigned to the treatment and control groups. The samples in both groups underwent surgery under general anesthesia to create uniform 3-cm bony defects. The samples in both groups were reconstructed with titanium reconstruction plates and screws. A large bone gap filled with ASCs (5×106 ) was seeded on gelatin (ASCs) in the treatment group. In the control group, bony defects were filled with a cell delivery carrier without ASCs. Six months after transplantation, the animals' mandibles were evaluated by CT scan imaging, and the results were quantified through the Hounsfield unit (HU). The data were analyzed with t-test. Results. Before transplantation, the nature of the stem cells was confirmed by the expression of CD44 and CD105 cell markers at 71.9% and 89.3%, respectively, and a lack of the CD45 cell marker expression at 2.2%. Evaluation of CT scan images showed significantly higher bone repair in the ASCs group (920.25±572.92 HU) than in the control group (-94.746± 08.42). Conclusion. The bone regeneration of the ASCs group was significantly higher than that in the control group.
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Affiliation(s)
- Ali Hossein Mesgarzadeh
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Islam Nasiri
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyedhosein Jarolmasjed
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehran Naghibi
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hajar Shafaei
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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33
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Daneshmandi L, Barajaa M, Tahmasbi Rad A, Sydlik SA, Laurencin CT. Graphene-Based Biomaterials for Bone Regenerative Engineering: A Comprehensive Review of the Field and Considerations Regarding Biocompatibility and Biodegradation. Adv Healthc Mater 2021; 10:e2001414. [PMID: 33103370 PMCID: PMC8218309 DOI: 10.1002/adhm.202001414] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 09/21/2020] [Indexed: 12/15/2022]
Abstract
Graphene and its derivatives have continued to garner worldwide interest due to their unique characteristics. Having expanded into biomedical applications, there have been efforts to employ their exceptional properties for the regeneration of different tissues, particularly bone. This article presents a comprehensive review on the usage of graphene-based materials for bone regenerative engineering. The graphene family of materials (GFMs) are used either alone or in combination with other biomaterials in the form of fillers in composites, coatings for both scaffolds and implants, or vehicles for the delivery of various signaling and therapeutic agents. The applications of the GFMs in each of these diverse areas are discussed and emphasis is placed on the characteristics of the GFMs that have implications in this regard. In tandem and of importance, this article evaluates the safety and biocompatibility of the GFMs and carefully elucidates how various factors influence the biocompatibility and biodegradability of this new class of nanomaterials. In conclusion, the challenges and opportunities regarding the use of the GFMs in regenerative engineering applications are discussed, and future perspectives for the developments in this field are proposed.
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Affiliation(s)
- Leila Daneshmandi
- Connecticut Convergence Institute for Translation in Regenerative Engineering, UConn Health, Farmington, CT, 06030, USA
- Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, UConn Health, Farmington, CT, 06030, USA
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT, 06269, USA
- Department of Orthopaedic Surgery, UConn Health, Farmington, CT, 06030, USA
| | - Mohammed Barajaa
- Connecticut Convergence Institute for Translation in Regenerative Engineering, UConn Health, Farmington, CT, 06030, USA
- Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, UConn Health, Farmington, CT, 06030, USA
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT, 06269, USA
- Department of Orthopaedic Surgery, UConn Health, Farmington, CT, 06030, USA
| | - Armin Tahmasbi Rad
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT, 06269, USA
- Institute of Materials Science, University of Connecticut, Storrs, CT, 06269, USA
| | - Stefanie A Sydlik
- Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA, 15213, USA
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, 15213, USA
| | - Cato T Laurencin
- Connecticut Convergence Institute for Translation in Regenerative Engineering, UConn Health, Farmington, CT, 06030, USA
- Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, UConn Health, Farmington, CT, 06030, USA
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT, 06269, USA
- Department of Orthopaedic Surgery, UConn Health, Farmington, CT, 06030, USA
- Institute of Materials Science, University of Connecticut, Storrs, CT, 06269, USA
- Department of Materials Science and Engineering, University of Connecticut, Storrs, CT, 06269, USA
- Department of Chemical and Biomolecular Engineering, University of Connecticut, Storrs, CT, 06269, USA
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González-González A, García-Sánchez D, Dotta M, Rodríguez-Rey JC, Pérez-Campo FM. Mesenchymal stem cells secretome: The cornerstone of cell-free regenerative medicine. World J Stem Cells 2020; 12:1529-1552. [PMID: 33505599 PMCID: PMC7789121 DOI: 10.4252/wjsc.v12.i12.1529] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 10/07/2020] [Accepted: 11/11/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are the most frequently used stem cells in clinical trials due to their easy isolation from various adult tissues, their ability of homing to injury sites and their potential to differentiate into multiple cell types. However, the realization that the beneficial effect of MSCs relies mainly on their paracrine action, rather than on their engraftment in the recipient tissue and subsequent differentiation, has opened the way to cell-free therapeutic strategies in regenerative medicine. All the soluble factors and vesicles secreted by MSCs are commonly known as secretome. MSCs secretome has a key role in cell-to-cell communication and has been proven to be an active mediator of immune-modulation and regeneration both in vitro and in vivo. Moreover, the use of secretome has key advantages over cell-based therapies, such as a lower immunogenicity and easy production, handling and storage. Importantly, MSCs can be modulated to alter their secretome composition to better suit specific therapeutic goals, thus, opening a large number of possibilities. Altogether these advantages now place MSCs secretome at the center of an important number of investigations in different clinical contexts, enabling rapid scientific progress in this field.
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Affiliation(s)
- Alberto González-González
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - Daniel García-Sánchez
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - Monica Dotta
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - José C Rodríguez-Rey
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - Flor M Pérez-Campo
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain.
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Leng Q, Liang Z, Lv Y. Demineralized bone matrix scaffold modified with mRNA derived from osteogenically pre-differentiated MSCs improves bone repair. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 119:111601. [PMID: 33321645 DOI: 10.1016/j.msec.2020.111601] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 09/25/2020] [Accepted: 10/05/2020] [Indexed: 12/13/2022]
Abstract
Gene therapy based on mRNA provides a promising approach for bone regeneration. Quick mRNA translation and controlled protein production could be earned by implantation of mRNA-activated scaffold in bone remodeling region. Furthermore, the expression levels of osteogenic-related mRNA in the cytoplasm of osteogenically pre-differentiated mesenchymal stem cells (MSCs) were high and the expression levels were different at different stages of osteogenically differentiated MSCs. This study intended to investigate the effect of osteoinductive-mRNAs (Oi-mRNAs), derived from osteogenically pre-differentiated MSCs at various stages (Day 1 (Oi1-mRNA), Day 3 (Oi3-mRNA), Day 7 (Oi7-mRNA), Day 14 (Oi14-mRNA) and Day 21 (Oi21-mRNA), respectively), on the osteogenic differentiation of MSCs. Further, the Oi-mRNAs combined with cationic polymer polyethylenimine (PEI) were loaded onto demineralized bone matrix (DBM) scaffold (Oi-mRNA/DBM). The results revealed that the Oi1-mRNA, Oi3-mRNA and Oi21-mRNA had no obvious effect on the osteogenic differentiation of MSCs, while the Oi7-mRNA increased the expression of alkaline phosphatase (ALP) and the Oi14-mRNA significantly promoted the expression of osteocalcin (OC) and osteopontin (OPN), and calcium deposition. In addition, the Oi14-mRNA/DBM scaffold could significantly enhance extracellular matrix (ECM) secretion and new collagen formation of MSCs. After being implanted into rat critical-sized cranium defect model, the Oi14-mRNA/DBM scaffold could promote the infiltration of cells and repair of bone defect in vivo. The DBM scaffold loaded with mRNA encoding osteoinductive protein may provide a powerful tool for bone defect repair.
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Affiliation(s)
- Qiuping Leng
- Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing 400044, PR China; Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044, PR China.
| | - Zhuo Liang
- Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing 400044, PR China; Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044, PR China.
| | - Yonggang Lv
- Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing 400044, PR China; Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044, PR China.
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Giannasi C, Niada S, Magagnotti C, Ragni E, Andolfo A, Brini AT. Comparison of two ASC-derived therapeutics in an in vitro OA model: secretome versus extracellular vesicles. Stem Cell Res Ther 2020; 11:521. [PMID: 33272318 PMCID: PMC7711257 DOI: 10.1186/s13287-020-02035-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 11/18/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND In the last years, several clinical trials have proved the safety and efficacy of adipose-derived stem/stromal cells (ASC) in contrasting osteoarthritis (OA). Since ASC act mainly through paracrine mechanisms, their secretome (conditioned medium, CM) represents a promising therapeutic alternative. ASC-CM is a complex cocktail of proteins, nucleic acids, and lipids released as soluble factors and/or conveyed into extracellular vesicles (EV). Here, we investigate its therapeutic potential in an in vitro model of OA. METHODS Human articular chondrocytes (CH) were induced towards an OA phenotype by 10 ng/ml TNFα in the presence of either ASC-CM or EV, both deriving from 5 × 105 cells, to evaluate the effect on hypertrophic, catabolic, and inflammatory markers. RESULTS Given the same number of donor cells, our data reveal a higher therapeutic potential of ASC-CM compared to EV alone that was confirmed by its enrichment in chondroprotective factors among which TIMP-1 and -2 stand out. In details, only ASC-CM significantly decreased MMP activity (22% and 29% after 3 and 6 days) and PGE2 expression (up to 40% at day 6) boosted by the inflammatory cytokine. Conversely, both treatments down-modulated of ~ 30% the hypertrophic marker COL10A1. CONCLUSIONS These biological and molecular evidences of ASC-CM beneficial action on CH with an induced OA phenotype may lay the basis for its future clinical translation as a cell-free therapeutic in the management of OA.
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Affiliation(s)
- Chiara Giannasi
- Laboratorio di Applicazioni Biotecnologiche, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.
| | - Stefania Niada
- Laboratorio di Applicazioni Biotecnologiche, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Cinzia Magagnotti
- Proteomics and Metabolomics Facility (ProMeFa), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Enrico Ragni
- Laboratorio di Biotecnologie Applicate all'Ortopedia, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Annapaola Andolfo
- Proteomics and Metabolomics Facility (ProMeFa), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Anna Teresa Brini
- Laboratorio di Applicazioni Biotecnologiche, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.,Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Milan, Italy
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Daneshmandi L, Shah S, Jafari T, Bhattacharjee M, Momah D, Saveh-Shemshaki N, Lo KWH, Laurencin CT. Emergence of the Stem Cell Secretome in Regenerative Engineering. Trends Biotechnol 2020; 38:1373-1384. [PMID: 32622558 PMCID: PMC7666064 DOI: 10.1016/j.tibtech.2020.04.013] [Citation(s) in RCA: 124] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 04/27/2020] [Accepted: 04/28/2020] [Indexed: 02/07/2023]
Abstract
The secretome is defined as the set of molecules and biological factors that are secreted by cells into the extracellular space. In the past decade, secretome-based therapies have emerged as a promising approach to overcome the limitations associated with cell-based therapies for tissue and organ regeneration. Considering the growing number of recent publications related to secretome-based therapies, this review takes a step-by-step engineering approach to evaluate the role of the stem cell secretome in regenerative engineering. We discuss the functional benefits of the secretome, the techniques used to engineer the secretome and tailor its therapeutic effects, and the delivery systems and strategies that have been developed to use the secretome for tissue regeneration.
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Affiliation(s)
- Leila Daneshmandi
- Connecticut Convergence Institute for Translation in Regenerative Engineering, UConn Health, Farmington, CT 06030, USA; Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, UConn Health, Farmington, CT 06030, USA; Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06269, USA; Department of Orthopaedic Surgery, UConn Health, Farmington, CT 06030, USA
| | - Shiv Shah
- Connecticut Convergence Institute for Translation in Regenerative Engineering, UConn Health, Farmington, CT 06030, USA; Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, UConn Health, Farmington, CT 06030, USA; Department of Orthopaedic Surgery, UConn Health, Farmington, CT 06030, USA; Department of Chemical and Biomolecular Engineering, University of Connecticut, Storrs, CT 06269, USA
| | - Tahereh Jafari
- Connecticut Convergence Institute for Translation in Regenerative Engineering, UConn Health, Farmington, CT 06030, USA; Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, UConn Health, Farmington, CT 06030, USA; Department of Orthopaedic Surgery, UConn Health, Farmington, CT 06030, USA
| | - Maumita Bhattacharjee
- Connecticut Convergence Institute for Translation in Regenerative Engineering, UConn Health, Farmington, CT 06030, USA; Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, UConn Health, Farmington, CT 06030, USA; Department of Orthopaedic Surgery, UConn Health, Farmington, CT 06030, USA
| | - Deandra Momah
- Connecticut Convergence Institute for Translation in Regenerative Engineering, UConn Health, Farmington, CT 06030, USA; Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, UConn Health, Farmington, CT 06030, USA
| | - Nikoo Saveh-Shemshaki
- Connecticut Convergence Institute for Translation in Regenerative Engineering, UConn Health, Farmington, CT 06030, USA; Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, UConn Health, Farmington, CT 06030, USA; Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06269, USA; Department of Orthopaedic Surgery, UConn Health, Farmington, CT 06030, USA
| | - Kevin W-H Lo
- Connecticut Convergence Institute for Translation in Regenerative Engineering, UConn Health, Farmington, CT 06030, USA; Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, UConn Health, Farmington, CT 06030, USA; Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06269, USA; Institute of Materials Science, University of Connecticut, Storrs, CT 06269
| | - Cato T Laurencin
- Connecticut Convergence Institute for Translation in Regenerative Engineering, UConn Health, Farmington, CT 06030, USA; Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, UConn Health, Farmington, CT 06030, USA; Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06269, USA; Department of Orthopaedic Surgery, UConn Health, Farmington, CT 06030, USA; Department of Chemical and Biomolecular Engineering, University of Connecticut, Storrs, CT 06269, USA; Institute of Materials Science, University of Connecticut, Storrs, CT 06269; Department of Materials Science and Engineering, University of Connecticut, Storrs, CT 06269, USA; Department of Medicine, UConn Health, Farmington, CT 06030, USA.
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Cun X, Hosta-Rigau L. Topography: A Biophysical Approach to Direct the Fate of Mesenchymal Stem Cells in Tissue Engineering Applications. NANOMATERIALS (BASEL, SWITZERLAND) 2020; 10:E2070. [PMID: 33092104 PMCID: PMC7590059 DOI: 10.3390/nano10102070] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/16/2020] [Accepted: 10/16/2020] [Indexed: 12/17/2022]
Abstract
Tissue engineering is a promising strategy to treat tissue and organ loss or damage caused by injury or disease. During the past two decades, mesenchymal stem cells (MSCs) have attracted a tremendous amount of interest in tissue engineering due to their multipotency and self-renewal ability. MSCs are also the most multipotent stem cells in the human adult body. However, the application of MSCs in tissue engineering is relatively limited because it is difficult to guide their differentiation toward a specific cell lineage by using traditional biochemical factors. Besides biochemical factors, the differentiation of MSCs also influenced by biophysical cues. To this end, much effort has been devoted to directing the cell lineage decisions of MSCs through adjusting the biophysical properties of biomaterials. The surface topography of the biomaterial-based scaffold can modulate the proliferation and differentiation of MSCs. Presently, the development of micro- and nano-fabrication techniques has made it possible to control the surface topography of the scaffold precisely. In this review, we highlight and discuss how the main topographical features (i.e., roughness, patterns, and porosity) are an efficient approach to control the fate of MSCs and the application of topography in tissue engineering.
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Affiliation(s)
| | - Leticia Hosta-Rigau
- DTU Health Tech, Centre for Nanomedicine and Theranostics, Technical University of Denmark, Nils Koppels Allé, Building 423, 2800 Kgs. Lyngby, Denmark;
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Biomimetic Aspects of Oral and Dentofacial Regeneration. Biomimetics (Basel) 2020; 5:biomimetics5040051. [PMID: 33053903 PMCID: PMC7709662 DOI: 10.3390/biomimetics5040051] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/09/2020] [Accepted: 10/10/2020] [Indexed: 12/12/2022] Open
Abstract
Biomimetic materials for hard and soft tissues have advanced in the fields of tissue engineering and regenerative medicine in dentistry. To examine these recent advances, we searched Medline (OVID) with the key terms “biomimetics”, “biomaterials”, and “biomimicry” combined with MeSH terms for “dentistry” and limited the date of publication between 2010–2020. Over 500 articles were obtained under clinical trials, randomized clinical trials, metanalysis, and systematic reviews developed in the past 10 years in three major areas of dentistry: restorative, orofacial surgery, and periodontics. Clinical studies and systematic reviews along with hand-searched preclinical studies as potential therapies have been included. They support the proof-of-concept that novel treatments are in the pipeline towards ground-breaking clinical therapies for orofacial bone regeneration, tooth regeneration, repair of the oral mucosa, periodontal tissue engineering, and dental implants. Biomimicry enhances the clinical outcomes and calls for an interdisciplinary approach integrating medicine, bioengineering, biotechnology, and computational sciences to advance the current research to clinics. We conclude that dentistry has come a long way apropos of regenerative medicine; still, there are vast avenues to endeavour, seeking inspiration from other facets in biomedical research.
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Lu H, Merfeld-Clauss S, Jawed Y, March KL, Coleman ME, Bogatcheva NV. Distinct Factors Secreted by Adipose Stromal Cells Protect the Endothelium From Barrier Dysfunction and Apoptosis. Front Cell Dev Biol 2020; 8:584653. [PMID: 33102487 PMCID: PMC7554254 DOI: 10.3389/fcell.2020.584653] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 08/26/2020] [Indexed: 12/11/2022] Open
Abstract
We have shown previously that adipose stromal cell (ASC)-derived conditioned media (CM) limited lung injury, endothelial barrier dysfunction, and apoptosis. Here, we used endothelial hyperpermeability and apoptosis assays to investigate how concentration processes affect endothelium-directed bioactivity of ASC-CM and to gain information on the nature of bioactive factors. Comparison of ASC-CM concentrated with differential molecular weight (MW) cutoff filters showed that endothelial barrier protection depended on the species-specific factors in ASC-CM fractionated with MW > 50 kDa. Known barrier regulators-keratin growth factor (KGF), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF)-were detected in ASC-CM fraction of > 100 kDa. Pretreatment of endothelial monolayers with concentrations of KGF, VEGF, and HGF detected in ASC-CM showed that only KGF and HGF protect the endothelium from barrier dysfunction. Depletion of KGF and HGF from ASC-CM attenuated ASC-CM's ability to protect the endothelial barrier. In contrast to barrier-protective factors, apoptosis-protective factors fractionated with MW < 3 kDa and were not species-specific. Application of donors of apoptosis-mitigating gases showed that the CO donor carbon monoxide-releasing molecule 2 (CORM2) protected the endothelium from apoptosis, while the H2S donor NaSH did not. Knockdown of CO-generating heme oxygenase 1 in ASC attenuated ASC-CM's ability to protect the endothelium from apoptosis. We have shown that tumor necrosis factor alpha (TNFα)-induced apoptosis in endothelium is c-Jun N-terminal kinase (JNK)-dependent, and JNK activation is inhibited by ASC-CM pretreatment of endothelial cells. ASC-CM from heme oxygenase 1-depleted ASC displayed attenuated ability to suppress endothelial JNK activation, suggesting that CO-mediated protection of the endothelium from apoptosis is achieved by the downregulation of the JNK pathway. Altogether, our results demonstrate that the concentration of ASC-CM with low MW cutoff filters significantly reduces its anti-apoptotic activity while preserving its barrier-protective activity.
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Affiliation(s)
- Hongyan Lu
- Division of Cardiology, Department of Medicine, Indiana University, Indianapolis, IN, United States.,Indiana Center for Vascular Biology and Medicine and Vascular and Cardiac Adult Stem Cell Therapy Center, Indianapolis, IN, United States.,Roudebush Veteran Affairs Medical Center, Indianapolis, IN, United States
| | - Stephanie Merfeld-Clauss
- Division of Cardiology, Department of Medicine, Indiana University, Indianapolis, IN, United States.,Indiana Center for Vascular Biology and Medicine and Vascular and Cardiac Adult Stem Cell Therapy Center, Indianapolis, IN, United States.,Roudebush Veteran Affairs Medical Center, Indianapolis, IN, United States
| | - Yameena Jawed
- Division of Cardiology, Department of Medicine, Indiana University, Indianapolis, IN, United States.,Indiana Center for Vascular Biology and Medicine and Vascular and Cardiac Adult Stem Cell Therapy Center, Indianapolis, IN, United States.,Roudebush Veteran Affairs Medical Center, Indianapolis, IN, United States
| | - Keith L March
- Division of Cardiology, Department of Medicine, Indiana University, Indianapolis, IN, United States.,Indiana Center for Vascular Biology and Medicine and Vascular and Cardiac Adult Stem Cell Therapy Center, Indianapolis, IN, United States.,Roudebush Veteran Affairs Medical Center, Indianapolis, IN, United States
| | | | - Natalia V Bogatcheva
- Division of Cardiology, Department of Medicine, Indiana University, Indianapolis, IN, United States.,Indiana Center for Vascular Biology and Medicine and Vascular and Cardiac Adult Stem Cell Therapy Center, Indianapolis, IN, United States.,Roudebush Veteran Affairs Medical Center, Indianapolis, IN, United States.,Division of Pulmonary, Sleep and Critical Care, Department of Medicine, Indiana University, Indianapolis, IN, United States
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Brennan MÁ, Layrolle P, Mooney DJ. Biomaterials functionalized with MSC secreted extracellular vesicles and soluble factors for tissue regeneration. ADVANCED FUNCTIONAL MATERIALS 2020; 30:1909125. [PMID: 32952493 PMCID: PMC7494127 DOI: 10.1002/adfm.201909125] [Citation(s) in RCA: 242] [Impact Index Per Article: 48.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Indexed: 05/05/2023]
Abstract
The therapeutic benefits of mesenchymal stromal cell (MSC) transplantation have been attributed to their secreted factors, including extracellular vesicles (EVs) and soluble factors. The potential of employing the MSC secretome as an alternative acellular approach to cell therapy is being investigated in various tissue injury indications, but EVs administered via bolus injections are rapidly sequestered and cleared. However, biomaterials offer delivery platforms to enhance EV retention rates and healing efficacy. In this review, we highlight the mechanisms underpinning the therapeutic effects of MSC-EVs and soluble factors as effectors of immunomodulation and tissue regeneration, conferred primarily via their nucleic acid and protein contents. We discuss how manipulating the cell culture microenvironment or genetic modification of MSCs can further augment the potency of their secretions. The most recent advances in the development of EV-functionalized biomaterials that mediate enhanced angiogenesis and cell survival, while attenuating inflammation and fibrosis, are presented. Finally, some technical challenges to be considered for the clinical translation of biomaterials carrying MSC-secreted bioactive cargo are discussed.
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Affiliation(s)
- Meadhbh Á Brennan
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA
| | - Pierre Layrolle
- INSERM, UMR 1238, PHY-OS, Bone sarcomas and remodeling of calcified tissues, Faculty of Medicine, University of Nantes, Nantes, France
| | - David J Mooney
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA
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To K, Romain K, Mak C, Kamaraj A, Henson F, Khan W. The Treatment of Cartilage Damage Using Human Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Systematic Review of in vivo Studies. Front Bioeng Biotechnol 2020; 8:580. [PMID: 32596228 PMCID: PMC7300288 DOI: 10.3389/fbioe.2020.00580] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 05/13/2020] [Indexed: 12/21/2022] Open
Abstract
Damage to joints through injury or disease can result in cartilage loss, which if left untreated can lead to inflammation and ultimately osteoarthritis. There is currently no cure for osteoarthritis and management focusses on symptom control. End-stage osteoarthritis can be debilitating and ultimately requires joint replacement in order to maintain function. Therefore, there is growing interest in innovative therapies for cartilage repair. In this systematic literature review, we sought to explore the in vivo evidence for the use of human Mesenchymal Stem Cell-derived Extracellular Vesicles (MSC-EVs) for treating cartilage damage. We conducted a systematic literature review in accordance with the PRISMA protocol on the evidence for the treatment of cartilage damage using human MSC-EVs. Studies examining in vivo models of cartilage damage were included. A risk of bias analysis of the studies was conducted using the SYRCLE tool. Ten case-control studies were identified in our review, including a total of 159 murine subjects. MSC-EVs were harvested from a variety of human tissues. Five studies induced osteoarthritis, including cartilage loss through surgical joint destabilization, two studies directly created osteochondral lesions and three studies used collagenase to cause cartilage loss. All studies in this review reported reduced cartilage loss following treatment with MSC-EVs, and without significant complications. We conclude that transplantation of MSC-derived EVs into damaged cartilage can effectively reduce cartilage loss in murine models of cartilage injury. Additional randomized studies in animal models that recapitulates human osteoarthritis will be necessary in order to establish findings that inform clinical safety in humans.
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Affiliation(s)
- Kendrick To
- Division of Trauma and Orthopaedics, Department of Surgery, University of Cambridge, Cambridge, United Kingdom
| | - Karl Romain
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Christopher Mak
- Division of Trauma and Orthopaedics, Department of Surgery, University of Cambridge, Cambridge, United Kingdom
| | - Achi Kamaraj
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Frances Henson
- Division of Trauma and Orthopaedics, Department of Surgery, University of Cambridge, Cambridge, United Kingdom
| | - Wasim Khan
- Division of Trauma and Orthopaedics, Department of Surgery, University of Cambridge, Cambridge, United Kingdom
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Benavides-Castellanos MP, Garzón-Orjuela N, Linero I. Effectiveness of mesenchymal stem cell-conditioned medium in bone regeneration in animal and human models: a systematic review and meta-analysis. CELL REGENERATION (LONDON, ENGLAND) 2020; 9:5. [PMID: 32588230 PMCID: PMC7306835 DOI: 10.1186/s13619-020-00047-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 11/18/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Given the limitations of current therapies for the reconstruction of bone defects, regenerative medicine has arisen as a new therapeutic strategy along with mesenchymal stem cells (MSCs), which, because of their osteogenic potential and immunomodulatory properties, have emerged as a promising alternative for the treatment of bone injuries. In vivo studies have demonstrated that MSCs have a positive effect on regeneration due to their secretion of cytokines and growth factors that, when collected in conditioned medium (MSC-CM) and applied to an injured tissue, can modulate and promote the formation of new tissue. OBJECTIVE To evaluate the effectiveness of application of conditioned medium derived from mesenchymal stem cells in bone regeneration in animal and human models. METHODS We conducted a systematic review with a comprehensive search through February of 2018 using several electronic databases (MEDLINE, EMBASE, SCOPUS, CENTRAL (Ovid), and LILACS), and we also used the "snowballing technique". Articles that met the inclusion criteria were selected through abstract review and subsequent assessment of the full text. We assessed the risk of bias with the SYRCLE and Cochrane tools, and three meta-analyses were performed. RESULTS We included 21 articles, 19 of which used animal models and 2 of which used human models. In animal models, the application of MSC-CM significantly increased the regeneration of bone defects in comparison with control groups. Human studies reported early mineralization in regenerated bones, and no bone resorption, inflammation, nor local or systemic alterations were observed in any case. The meta-analysis showed an overall favorable effect of the application of MSC-CM. CONCLUSIONS The application of MSC-CM to bone defects has a positive and favorable effect on the repair and regeneration of bone tissue, particularly in animal models. It is necessary to perform additional studies to support the application of MSC-CM in clinical practice.
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Affiliation(s)
| | - Nathaly Garzón-Orjuela
- Research Group on Equity in Health, Faculty of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia
| | - Itali Linero
- Research Group of Oral and Maxillofacial Surgery, Faculty of Dentistry, Research Group of Stem Cell Biology, Faculty of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia
- Faculty of Dentistry, Universidad Nacional de Colombia, Ciudad Universitaria, Edificio 210, Bogotá, Colombia
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Bartold M, Gronthos S, Haynes D, Ivanovski S. Mesenchymal stem cells and biologic factors leading to bone formation. J Clin Periodontol 2019; 46 Suppl 21:12-32. [PMID: 30624807 DOI: 10.1111/jcpe.13053] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Revised: 09/23/2018] [Accepted: 10/26/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Physiological bone formation and bone regeneration occurring during bone repair can be considered distinct but similar processes. Mesenchymal stem cells (MSC) and associated biologic factors are crucial to both bone formation and bone regeneration. AIM To perform a narrative review of the current literature regarding the role of MSC and biologic factors in bone formation with the aim of discussing the clinical relevance of in vitro and in vivo animal studies. METHODS The literature was searched for studies on MSC and biologic factors associated with the formation of bone in the mandible and maxilla. The search specifically targeted studies on key aspects of how stem cells and biologic factors are important in bone formation and how this might be relevant to bone regeneration. The results are summarized in a narrative review format. RESULTS Different types of MSC and many biologic factors are associated with bone formation in the maxilla and mandible. CONCLUSION Bone formation and regeneration involve very complex and highly regulated cellular and molecular processes. By studying these processes, new clinical opportunities will arise for therapeutic bone regenerative treatments.
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Affiliation(s)
- Mark Bartold
- School of Dentistry, University of Adelaide, Adelaide, SA, Australia
| | - Stan Gronthos
- Mesenchymal Stem Cell Laboratory, Faculty of Health and Medical Sciences, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - David Haynes
- Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia
| | - Saso Ivanovski
- School of Dentistry, University of Queensland, Brisbane, Qld, Australia
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Bogatcheva NV, Coleman ME. Conditioned Medium of Mesenchymal Stromal Cells: A New Class of Therapeutics. BIOCHEMISTRY (MOSCOW) 2019; 84:1375-1389. [PMID: 31760924 DOI: 10.1134/s0006297919110129] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Mesenchymal stromal cell (MSCs) represent a class of biologics with the prospects for employment as immunomodulatory, tissue-protective, and regenerative therapeutics. In parallel with cellular therapy, cell-free therapy based on MSC-secreted bioactive factors is being actively developed. MSCs secrete a variety of protein, peptide, RNA, and lipid mediators which can be concentrated, frozen, or even lyophilized without loss of activity, which gives them a certain advantage over cellular products requiring liquid nitrogen storage and infrastructure to revive frozen cells. This review (i) describes currently conducted clinical trials of cell-free products containing MSC secretome; (ii) summarizes main approaches to the generation and characterization of conditioned media concentrates and extracellular vesicle isolates; (iii) analyzes a variety of preclinical studies where effectiveness of secretome products has been shown; and (iv) summarizes current knowledge about secretome bioactive components obtained by analysis of in vivo models testing the therapeutic potential of the MSC secretome.
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Affiliation(s)
- N V Bogatcheva
- Division of Pulmonary and Critical Care, Department of Medicine, Indiana University School of Medicine, IUPUI, Indianapolis, IN 46202, USA.
| | - M E Coleman
- Theratome Bio, Inc., Indianapolis, IN 46202, USA.
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Takeuchi R, Katagiri W, Endo S, Kobayashi T. Exosomes from conditioned media of bone marrow-derived mesenchymal stem cells promote bone regeneration by enhancing angiogenesis. PLoS One 2019; 14:e0225472. [PMID: 31751396 PMCID: PMC6872157 DOI: 10.1371/journal.pone.0225472] [Citation(s) in RCA: 141] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 11/04/2019] [Indexed: 12/20/2022] Open
Abstract
Growth factors in serum-free conditioned media from human bone marrow-derived mesenchymal stem cells (MSC-CM) are known to be effective in bone regeneration. However, the secretomes in MSC-CM that act as active ingredients for bone regeneration, as well as their mechanisms, remains unclear. Exosomes, components of MSC-CM, provide the recipient cells with genetic information and enhance the recipient cellular paracrine stimulation, which contributes to tissue regeneration. We hypothesized that MSC-CM-derived exosomes (MSC-Exo) promoted bone regeneration, and that angiogenesis was a key step. Here, we prepared an MSC-Exo group, MSC-CM group, and Exo-antiVEGF group (MSC-Exo with angiogenesis inhibitor), and examined the osteogenic and angiogenic potential in MSCs. Furthermore, we used a rat model of calvaria bone defect and implanted each sample to evaluate bone formation weekly, until week 4 after treatment. Results showed that MSC-Exo enhanced cellular migration and osteogenic and angiogenic gene expression in MSCs compared to that in other groups. In vivo, early bone formation by MSC-Exo was also confirmed. Two weeks after implantation, the newly formed bone area was 31.5 ± 6.5% in the MSC-Exo group while those in the control and Exo-antiVEGF groups were 15.4 ± 4.4% and 8.7 ± 1.1%, respectively. Four weeks after implantation, differences in the area between the MSC-Exo group and the Exo-antiVEGF or control groups were further broadened. Histologically, notable accumulation of osteoblast-like cells and vascular endothelial cells was observed in the MSC-Exo group; however, fewer cells were found in the Exo-antiVEGF and control groups. In conclusion, MSC-Exo promoted bone regeneration during early stages, as well as enhanced angiogenesis. Considering the tissue regeneration with transplanted cells and their secretomes, this study suggests that exosomes might play an important role, especially in angiogenesis.
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Affiliation(s)
- Ryoko Takeuchi
- Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Wataru Katagiri
- Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- * E-mail:
| | - Satoshi Endo
- Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Tadaharu Kobayashi
- Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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Mitxitorena I, Infante A, Gener B, Rodríguez CI. Suitability and limitations of mesenchymal stem cells to elucidate human bone illness. World J Stem Cells 2019; 11:578-593. [PMID: 31616536 PMCID: PMC6789184 DOI: 10.4252/wjsc.v11.i9.578] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 07/31/2019] [Accepted: 08/27/2019] [Indexed: 02/06/2023] Open
Abstract
Functional impairment of mesenchymal stem cells (MSCs), osteoblast progenitor cells, has been proposed to be a pathological mechanism contributing to bone disorders, such as osteoporosis (the most common bone disease) and other rare inherited skeletal dysplasias. Pathological bone loss can be caused not only by an enhanced bone resorption activity but also by hampered osteogenic differentiation of MSCs. The majority of the current treatment options counteract bone loss, and therefore bone fragility by blocking bone resorption. These so-called antiresorptive treatments, in spite of being effective at reducing fracture risk, cannot be administered for extended periods due to security concerns. Therefore, there is a real need to develop osteoanabolic therapies to promote bone formation. Human MSCs emerge as a suitable tool to study the etiology of bone disorders at the cellular level as well as to be used for cell therapy purposes for bone diseases. This review will focus on the most relevant findings using human MSCs as an in vitro cell model to unravel pathological bone mechanisms and the application and outcomes of human MSCs in cell therapy clinical trials for bone disease.
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Affiliation(s)
- Izaskun Mitxitorena
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
| | - Arantza Infante
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
| | - Blanca Gener
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
- Service of Genetics, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
- Centre for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid 28005, Spain
| | - Clara I Rodríguez
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Bizkaia, Spain
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Han Y, Li X, Zhang Y, Han Y, Chang F, Ding J. Mesenchymal Stem Cells for Regenerative Medicine. Cells 2019; 8:E886. [PMID: 31412678 PMCID: PMC6721852 DOI: 10.3390/cells8080886] [Citation(s) in RCA: 721] [Impact Index Per Article: 120.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 08/05/2019] [Accepted: 08/06/2019] [Indexed: 02/06/2023] Open
Abstract
In recent decades, the biomedical applications of mesenchymal stem cells (MSCs) have attracted increasing attention. MSCs are easily extracted from the bone marrow, fat, and synovium, and differentiate into various cell lineages according to the requirements of specific biomedical applications. As MSCs do not express significant histocompatibility complexes and immune stimulating molecules, they are not detected by immune surveillance and do not lead to graft rejection after transplantation. These properties make them competent biomedical candidates, especially in tissue engineering. We present a brief overview of MSC extraction methods and subsequent potential for differentiation, and a comprehensive overview of their preclinical and clinical applications in regenerative medicine, and discuss future challenges.
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Affiliation(s)
- Yu Han
- Department of Orthopedics, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130041, China
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China
| | - Xuezhou Li
- Department of Orthopedics, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130041, China
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China
| | - Yanbo Zhang
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, 126 Xiantai Street, Changchun 130033, China.
| | - Yuping Han
- Department of Urology, China-Japan Union Hospital of Jilin University, 126 Xiantai Street, Changchun 130033, China.
| | - Fei Chang
- Department of Orthopedics, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130041, China.
| | - Jianxun Ding
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China
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Genetically Engineered-MSC Therapies for Non-unions, Delayed Unions and Critical-size Bone Defects. Int J Mol Sci 2019; 20:ijms20143430. [PMID: 31336890 PMCID: PMC6678255 DOI: 10.3390/ijms20143430] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 07/08/2019] [Accepted: 07/09/2019] [Indexed: 12/21/2022] Open
Abstract
The normal bone regeneration process is a complex and coordinated series of events involving different cell types and molecules. However, this process is impaired in critical-size/large bone defects, with non-unions or delayed unions remaining a major clinical problem. Novel strategies are needed to aid the current therapeutic approaches. Mesenchymal stem/stromal cells (MSCs) are able to promote bone regeneration. Their beneficial effects can be improved by modulating the expression levels of specific genes with the purpose of stimulating MSC proliferation, osteogenic differentiation or their immunomodulatory capacity. In this context, the genetic engineering of MSCs is expected to further enhance their pro-regenerative properties and accelerate bone healing. Herein, we review the most promising molecular candidates (protein-coding and non-coding transcripts) and discuss the different methodologies to engineer and deliver MSCs, mainly focusing on in vivo animal studies. Considering the potential of the MSC secretome for bone repair, this topic has also been addressed. Furthermore, the promising results of clinical studies using MSC for bone regeneration are discussed. Finally, we debate the advantages and limitations of using MSCs, or genetically-engineered MSCs, and their potential as promoters of bone fracture regeneration/repair.
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Mizukami A, Thomé CH, Ferreira GA, Lanfredi GP, Covas DT, Pitteri SJ, Swiech K, Faça VM. Proteomic Identification and Time-Course Monitoring of Secreted Proteins During Expansion of Human Mesenchymal Stem/Stromal in Stirred-Tank Bioreactor. Front Bioeng Biotechnol 2019; 7:154. [PMID: 31297369 PMCID: PMC6607109 DOI: 10.3389/fbioe.2019.00154] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 06/10/2019] [Indexed: 12/14/2022] Open
Abstract
The therapeutic potential of mesenchymal stem/stromal cells (MSC) is widely recognized for the treatment of several diseases, including acute graft-vs.-host disease (GVHD), hematological malignancies, cardiovascular, bone, and cartilage diseases. More recently, this therapeutic efficacy has been attributed to the bioactive molecules that these cells secrete (secretome), now being referred as medicinal signaling cells. This fact raises the opportunity of therapeutically using MSC-derived soluble factors rather than cells themselves, enabling their translation into the clinic. Indeed, many clinical trials are now studying the effects of MSC-secretome in the context of cell-free therapy. MSC secretome profile varies between donors, source, and culture conditions, making their therapeutic use very challenging. Therefore, identifying these soluble proteins and evaluating their production in a reproducible and scalable manner is even more relevant. In this work, we analyzed the global profile of proteins secreted by umbilical cord matrix (UCM) derived-MSC in static conditions by using mass spectrometry, enabling the identification of thousands of proteins. Afterwards, relevant proteins were chosen and monitored in the supernatant of a fully-controllable, closed and scalable system (bioreactor) by using multiple reaction monitoring (MRM) mass spectrometric technique in a time-dependent manner. The results showed that the majority of interesting proteins were enriched through time in culture, with the last day of culture being the ideal time for supernatant collection. The use of this regenerative "soup," which is frequently discarded, could represent a step toward a safe, robust and reproducible cell-free product to be used in the medical therapeutic field. The future use of chemically defined culture-media will certainly facilitate secretome production according to Good Manufacturing Practice (GMP) standards.
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Affiliation(s)
- Amanda Mizukami
- Faculty of Medicine of Ribeirão Preto, Hemotherapy Center of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - Carolina Hassibe Thomé
- Faculty of Medicine of Ribeirão Preto, Hemotherapy Center of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.,Department of Biochemistry and Immunology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - Germano Aguiar Ferreira
- Faculty of Medicine of Ribeirão Preto, Hemotherapy Center of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.,Department of Biochemistry and Immunology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - Guilherme Pauperio Lanfredi
- Department of Biochemistry and Immunology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - Dimas Tadeu Covas
- Faculty of Medicine of Ribeirão Preto, Hemotherapy Center of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - Sharon J Pitteri
- Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University School of Medicine, Stanford, CA, United States
| | - Kamilla Swiech
- Faculty of Medicine of Ribeirão Preto, Hemotherapy Center of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.,Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences of Ribeirao Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - Vitor Marcel Faça
- Faculty of Medicine of Ribeirão Preto, Hemotherapy Center of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.,Department of Biochemistry and Immunology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
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