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Teck Tan T, Kiang Lim S. Relevance of RNA to the therapeutic efficacy of mesenchymal stromal/stem cells extracellular vesicles. RNA Biol 2025; 22:1-7. [PMID: 39719370 PMCID: PMC12064053 DOI: 10.1080/15476286.2024.2446868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 11/12/2024] [Accepted: 12/18/2024] [Indexed: 12/26/2024] Open
Abstract
Mesenchymal Stromal/Stem Cells (MSCs) are among the most frequently studied cell types in clinical trials, and their small extracellular vesicles (sEVs) are now being extensively investigated for therapeutic applications. The RNA cargo of MSC-sEVs, particularly miRNAs and mRNAs, is widely believed to be a key therapeutic component of these vesicles. In this review, we critically examine using first principles and peer-reviewed literature, whether MSC- extracellular vesicles (MSC-EVs) can deliver sufficient quantity of functional miRNA or mRNA to target compartments within recipient cells to elicit a pharmacological response. Several RNA sequencing studies reveal that miRNAs are underrepresented in the small RNA population of MSC-sEVs compared to the parent MSCs. Additionally, the majority of miRNAs are mature forms that are not associated with Argonaute (AGO) proteins, essential for their function in RNA-induced silencing complexes (RISCs). Compounding this, cellular uptake of EVs is generally inefficient, with less than 1% being internalized, and only a fraction of these reaching the cytosol. This suggests that EVs may not deliver miRNAs in sufficient quantities to meaningfully interact with AGO proteins, either through canonical or non-canonical pathways, or with other proteins like Toll-like receptors (TLRs). Further, MSC-sEV RNAs are generally small, with sizes less than 500 nucleotides indicating that any mRNA present is likely fragmented as the average mammalian mRNA is approximately 2000 nucleotides, a fact confirmed by RNA sequencing data. Together, these findings challenge the notion that RNA, particularly miRNAs and mRNAs, are primary therapeutic attributes of MSC-sEVs.
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Affiliation(s)
- Thong Teck Tan
- Paracrine Therapeutics Pte. Ltd, Tai Seng Exchange, Singapore, Singapore
| | - Sai Kiang Lim
- Paracrine Therapeutics Pte. Ltd, Tai Seng Exchange, Singapore, Singapore
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore C/O NUHS Tower Block, Singapore, Republic of Singapore
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Choy EYW, Leong CO, Cheong SK, Then KL, Then KY. Adeno-Associated Virus-Engineered Umbilical Cord-Derived Mesenchymal Stromal Cells Overexpressing Human sFlt-1 for Anti-Angiogenesis. Life (Basel) 2025; 15:728. [PMID: 40430157 PMCID: PMC12113553 DOI: 10.3390/life15050728] [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: 03/07/2025] [Revised: 03/31/2025] [Accepted: 04/09/2025] [Indexed: 05/29/2025] Open
Abstract
PURPOSE Genetic engineering of mesenchymal stromal cells (MSCs) using viral vectors has emerged as a promising approach to enhance the efficacy of anti-angiogenic gene therapies. Umbilical cord-derived MSCs are an attractive cell source due to their easy accessibility and potential for genetic modification. Adeno-associated viruses (AAVs) have been utilized in clinical settings to deliver therapeutic genes due to its characteristic of transient integration into the genome. In this study, we investigated the efficacy of using recombinant AAV-engineered umbilical cord-derived MSCs overexpressing anti-angiogenic factor, hsFlt-1 (MSCs.hsFlt1). METHODS The plasmid containing the hsFlt-1 gene was cloned into the AAV2 target backbone and validated using Sanger sequencing. The transduction process was studied to determine the optimal conditions, including the effect of MOI, media serum percentage, and attachment of MSCs, to achieve higher transduction efficiency. The functionality of MSCs.hsFtl1 was analyzed using qPCR, ELISA, and tube formation assays. RESULTS MSCs.hsFtl1 transduced at an MOI of 1 × 106 demonstrated high transduction efficiency and exhibited robust gene and protein expression of hsFlt-1. The results revealed significant inhibition of growth in human umbilical vein endothelial cells (HUVECs) using a remarkably low dose of MSCs.hsFlt1 at 12.3 ng/mL. This observed anti-angiogenic effect was comparable to the clinically used Bevacizumab. CONCLUSIONS The anti-angiogenic potential of MSCs.hsFlt1 effectively demonstrated in this study suggests their promising utility for targeted anti-angiogenic gene therapy approaches.
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Affiliation(s)
- Ewa Yee-Wa Choy
- School of Postgraduate Studies, Faculty of Medicine and Health, IMU University, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia;
- CryoCord Sdn Bhd, 1, Bio X Centre, Persiaran Cyber Point Selatan, Cyberjaya 63000, Selangor, Malaysia
| | - Chee-Onn Leong
- AGTC Genomics, J2-1, Pusat Perdagangan Bandar, Persiaran Jalil 1, Kuala Lumpur 57000, Malaysia
| | - Soon-Keng Cheong
- Hematology Department, National University of Malaysia (UKM), Jalan Ya’acob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia
- Department of Medicine, M. Kandiah Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Jalan Sungai Long, Bandar Sungai Long Cheras, Kajang 43000, Selangor, Malaysia
| | - Khong-Lek Then
- CryoCord Sdn Bhd, 1, Bio X Centre, Persiaran Cyber Point Selatan, Cyberjaya 63000, Selangor, Malaysia
| | - Kong-Yong Then
- CryoCord Sdn Bhd, 1, Bio X Centre, Persiaran Cyber Point Selatan, Cyberjaya 63000, Selangor, Malaysia
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3
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Taenaka H, Matthay MA. Mechanisms of impaired alveolar fluid clearance. Anat Rec (Hoboken) 2025; 308:1026-1039. [PMID: 36688689 PMCID: PMC10564110 DOI: 10.1002/ar.25166] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/09/2022] [Accepted: 01/04/2023] [Indexed: 01/24/2023]
Abstract
Impaired alveolar fluid clearance (AFC) is an important cause of alveolar edema fluid accumulation in patients with acute respiratory distress syndrome (ARDS). Alveolar edema leads to insufficient gas exchange and worse clinical outcomes. Thus, it is important to understand the pathophysiology of impaired AFC in order to develop new therapies for ARDS. Over the last few decades, multiple experimental studies have been done to understand the molecular, cellular, and physiological mechanisms that regulate AFC in the normal and the injured lung. This review provides a review of AFC in the normal lung, focuses on the mechanisms of impaired AFC, and then outlines the regulation of AFC. Finally, we summarize ongoing challenges and possible future research that may offer promising therapies for ARDS.
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Affiliation(s)
- Hiroki Taenaka
- Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California, USA
- Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California, USA
- Department of Anesthesiology and Intensive Care Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Michael A. Matthay
- Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California, USA
- Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California, USA
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Qin J, Wang R, Liang W, Man Z, Li W, An Y, Chen H. Adipose-Derived Stem Cell Specific Affinity Peptide-Modified Adipose Decellularized Scaffolds for Promoting Adipogenesis. ACS Biomater Sci Eng 2025; 11:1705-1720. [PMID: 39969077 DOI: 10.1021/acsbiomaterials.4c02161] [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] [Indexed: 02/20/2025]
Abstract
Adipose-derived stem cells (ADSCs) are known to promote angiogenesis and adipogenesis. However, their limited ability to efficiently target and integrate into specific tissues poses a major challenge for ADSC-based therapies. In this study, we identified a seven-amino acid peptide sequence (P7) with high specificity for ADSCs using phage display technology. P7 was then covalently conjugated to decellularized adipose-derived matrix (DAM), creating an "ADSC homing device" designed to recruit ADSCs both in vitro and in vivo. The P7-conjugated DAM significantly enhanced ADSC adhesion and proliferation in vitro. After being implanted into rat subcutaneous tissue, immunofluorescence staining after 14 days revealed that P7-conjugated DAM recruited a greater number of ADSCs, promoting angiogenesis and adipogenesis in the surrounding tissue. Moreover, CD206 immunostaining at 14 days indicated that P7-conjugated DAM facilitated the polarization of macrophages to the M2 phenotype at the implantation site. These findings demonstrate that the P7 peptide has a high affinity for ADSCs, and its conjugation with DAM significantly improves ADSC recruitment in vivo. This approach holds great potential for a wide range of applications in material surface modification.
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Affiliation(s)
- Jiahang Qin
- Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China
| | - Ruoxi Wang
- Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China
| | - Wei Liang
- Department of Plastic Surgery, Peking University Third Hospital, Beijing 100191, China
| | - Zhentao Man
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
| | - Wei Li
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
| | - Yang An
- Department of Plastic Surgery, Peking University Third Hospital, Beijing 100191, China
| | - Haifeng Chen
- Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China
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5
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Schultz IC, Dos Santos Pereira Andrade AC, Dubuc I, Laroche A, Allaeys I, Doré E, Bertrand N, Vallières L, Fradette J, Flamand L, Wink MR, Boilard E. Targeting Cytokines: Evaluating the Potential of Mesenchymal Stem Cell Derived Extracellular Vesicles in the Management of COVID-19. Stem Cell Rev Rep 2025; 21:564-580. [PMID: 39340739 DOI: 10.1007/s12015-024-10794-4] [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] [Accepted: 09/24/2024] [Indexed: 09/30/2024]
Abstract
The Coronavirus Disease 2019 (COVID-19), caused by virus SARS-CoV-2, is characterized by massive inflammation and immune system imbalance. Despite the implementation of vaccination protocols, the accessibility of treatment remains uneven. Furthermore, the persistent threat of new variants underscores the urgent need for expanded research into therapeutic options for SARS-CoV-2. Mesenchymal stem cells (MSCs) are known for their immunomodulatory potential through the release of molecules into the extracellular space, either as soluble elements or carried by extracellular vesicles (EVs). The aim of this study was to evaluate the anti-inflammatory potential of EVs obtained from human adipose tissue (ASC-EVs) against SARS-CoV-2 infection. ASC-EVs were purified by size-exclusion chromatography, and co-culture assays confirmed that ASC-EVs were internalized by human lung cells and could colocalize with SARS-CoV-2 into early and late endosomes. To determine the functionality of ASC-EVs, lung cells were infected with SARS-CoV-2 in the presence of increasing concentrations of ASC-EVs, and the release of cytokines, chemokines and viruses were measured. While SARS-CoV-2 replication was significantly reduced only at the highest concentrations tested, multiplex analysis highlighted that lower concentrations of ASC-EV sufficed to prevent the production of immune modulators. Importantly, ASC-EVs did not contain detectable inflammatory cytokines, nor did they trigger inflammatory mediators, nor affect cellular viability. In conclusion, this work suggests that ASC-EVs have the potential to attenuate inflammation by decreasing the production of pro-inflammatory cytokines in lung cells following SARS-CoV-2 infection.
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Affiliation(s)
- Iago Carvalho Schultz
- Axe Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec, QC, Canada
- Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil
| | - Ana Claudia Dos Santos Pereira Andrade
- Axe Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec, QC, Canada
- Département de Microbiologie-Infectiologie et d'Immunologie, Faculté de Médecine de l'Université Laval, Québec, QC, Canada
| | - Isabelle Dubuc
- Axe Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec, QC, Canada
- Département de Microbiologie-Infectiologie et d'Immunologie, Faculté de Médecine de l'Université Laval, Québec, QC, Canada
| | - Audrée Laroche
- Axe Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec, QC, Canada
- Département de Microbiologie-Infectiologie et d'Immunologie, Faculté de Médecine de l'Université Laval, Québec, QC, Canada
| | - Isabelle Allaeys
- Axe Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec, QC, Canada
- Département de Microbiologie-Infectiologie et d'Immunologie, Faculté de Médecine de l'Université Laval, Québec, QC, Canada
| | - Etienne Doré
- Axe Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec, QC, Canada
- Département de Microbiologie-Infectiologie et d'Immunologie, Faculté de Médecine de l'Université Laval, Québec, QC, Canada
| | - Nicolas Bertrand
- Axe Endocrinologie et Néphrologie, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec, QC, Canada
- Faculté de Pharmacie, Université Laval, Québec, QC, Canada
| | - Luc Vallières
- Axe Neurosciences, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec, QC, Canada
| | - Julie Fradette
- Centre de recherche en organogénèse expérimentale de l'Université Laval/LOEX, Québec, QC, Canada
- Département de Chirurgie, Faculté de Médecine de l'Université Laval, Québec, QC, Canada
- Division of Regenerative Medicine, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec, QC, Canada
| | - Louis Flamand
- Axe Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec, QC, Canada
- Département de Microbiologie-Infectiologie et d'Immunologie, Faculté de Médecine de l'Université Laval, Québec, QC, Canada
| | - Marcia Rosangela Wink
- Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil
| | - Eric Boilard
- Axe Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec, QC, Canada.
- Département de Microbiologie-Infectiologie et d'Immunologie, Faculté de Médecine de l'Université Laval, Québec, QC, Canada.
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6
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Okuyan HM, Coşkun A, Begen MA. Current status, opportunities, and challenges of exosomes in diagnosis and treatment of osteoarthritis. Life Sci 2025; 362:123365. [PMID: 39761740 DOI: 10.1016/j.lfs.2024.123365] [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: 06/20/2024] [Revised: 11/22/2024] [Accepted: 12/31/2024] [Indexed: 01/19/2025]
Abstract
Osteoarthritis (OA) is a progressive joint disease that is a frequent reason for pain and physical dysfunction in adults, with enormous social and economic burden. Although ongoing scientific efforts in recent years have made considerable progress towards understanding of the disease's molecular mechanism, the pathogenesis of OA is still not fully known, and its clinical challenge remains. Thus, elucidating molecular events underlying the initiation and progression of OA is crucial for developing novel diagnostic and therapeutic approaches that could facilitate effective clinical management of the illness. Exosomes, extracellular vesicles containing various cellular components with approximately a diameter of 100 nm, act as essential mediators in physiological and pathological processes by modulating cell-to-cell communications. Exosomes have crucial roles in biological events such as intercellular communication, regulation of gene expression, apoptosis, inflammation, immunity, maturation and differentiation due to their inner composition, which includes nucleic acids, proteins, and lipids. We focus on the roles of exosomes in OA pathogenesis and discuss how they might be used in clinical practice for OA diagnosis and treatment. Our paper not only provides a comprehensive review of exosomes in OA but also contributes to the development efforts of diagnostic and therapeutic tools for OA.
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Affiliation(s)
- Hamza Malik Okuyan
- Department of Physiotherapy and Rehabilitation - Faculty of Health Sciences, Biomedical Technologies Application and Research Center, Physiotherapy and Rehabilitation Application and Research Center, Sakarya University of Applied Sciences, Sakarya, Türkiye.
| | - Ayça Coşkun
- Department of Physiotherapy and Rehabilitation - Faculty of Health Sciences, Physiotherapy and Rehabilitation Application and Research Center, Sakarya University of Applied Sciences, Sakarya, Türkiye
| | - Mehmet A Begen
- Department of Epidemiology and Biostatistics-Schulich School of Medicine and Dentistry, Ivey Business School, University of Western Ontario, London, ON, Canada
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7
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Sukegawa M, Miyagawa Y, Kuroda S, Yamazaki Y, Yamamoto M, Adachi K, Sato H, Sato Y, Taniai N, Yoshida H, Umezawa A, Sakai M, Okada T. Mesenchymal stem cell origin contributes to the antitumor effect of oncolytic virus carriers. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200896. [PMID: 39554905 PMCID: PMC11568361 DOI: 10.1016/j.omton.2024.200896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 08/18/2024] [Accepted: 10/16/2024] [Indexed: 11/19/2024]
Abstract
Oncolytic virotherapy shows promise as a cancer treatment approach; however, its systemic application is hindered by antibody neutralization. This issue can be overcome by using mesenchymal stem cells (MSCs) as carrier cells for oncolytic viruses (OVs). However, it remains elusive whether MSC source influences the antitumor effect. Here, we demonstrate that their source affects the migration ability and oncolytic activity of OV-loaded MSCs. Among human MSCs derived from different tissues, bone marrow-derived MSCs (BMMSCs) showed a high migration ability toward cancer cells in two- and three-dimensional MSC-cancer cell co-culture models. Comprehensive gene expression and Gene Ontology-based functional analyses suggested that genes involved in cell migration and cytokine response influence the cancer-specific tropism of BMMSCs. Furthermore, MSC origin affected the susceptibility to OVs, including cytotoxicity resistance and OV release from MSCs. MSC-mediated OV delivery significantly increased the viral spread and antitumor activity compared with delivery by OVs alone, and OV-loaded BMMSCs demonstrated the most potent antitumor effect among OV-loaded MSCs. Our results offer promising insights into cancer gene therapy with carrier cells and can help with the selection of an appropriate MSC source for MSC-based OV therapy.
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Affiliation(s)
- Makoto Sukegawa
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
- Department of Gastrointestinal Surgery, Graduate School of Medicine, Nippon Medical School Musashikosugi Hospital, Kawasaki, Japan
- Department of Surgery, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Yoshitaka Miyagawa
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Seiji Kuroda
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Yoshiyuki Yamazaki
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Motoko Yamamoto
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Kumi Adachi
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Hirofumi Sato
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Yuriko Sato
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Nobuhiko Taniai
- Department of Gastrointestinal Surgery, Graduate School of Medicine, Nippon Medical School Musashikosugi Hospital, Kawasaki, Japan
| | - Hiroshi Yoshida
- Department of Surgery, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Akihiro Umezawa
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Tokyo, Japan
| | - Mashito Sakai
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Takashi Okada
- Division of Molecular and Medical Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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8
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Tang X, Zhou F, Wang S, Wang G, Bai L, Su J. Bioinspired injectable hydrogels for bone regeneration. J Adv Res 2024:S2090-1232(24)00486-7. [PMID: 39505143 DOI: 10.1016/j.jare.2024.10.032] [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: 01/07/2024] [Revised: 09/28/2024] [Accepted: 10/27/2024] [Indexed: 11/08/2024] Open
Abstract
The effective regeneration of bone/cartilage defects remains a significant clinical challenge, causing irreversible damage to millions annually.Conventional therapies such as autologous or artificial bone grafting often yield unsatisfactory outcomes, emphasizing the urgent need for innovative treatment methods. Biomaterial-based strategies, including hydrogels and active scaffolds, have shown potential in promoting bone/cartilage regeneration. Among them, injectable hydrogels have garnered substantial attention in recent years on account of their minimal invasiveness, shape adaptation, and controlled spatiotemporal release. This review systematically discusses the synthesis of injectable hydrogels, bioinspired approaches-covering microenvironment, structural, compositional, and bioactive component-inspired strategies-and their applications in various bone/cartilage disease models, highlighting bone/cartilage regeneration from an innovative perspective of bioinspired design. Taken together, bioinspired injectable hydrogels offer promising and feasible solutions for promoting bone/cartilage regeneration, ultimately laying the foundations for clinical applications. Furthermore, insights into further prospective directions for AI in injectable hydrogels screening and organoid construction are provided.
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Affiliation(s)
- Xuan Tang
- Organoid Research Center, Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China
| | - Fengjin Zhou
- Department of Orthopaedics, Honghui Hospital, Xi'an Jiao Tong University, Xi'an 710000, China
| | - Sicheng Wang
- National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China; Department of Orthopedics Trauma, Shanghai Zhongye Hospital, Shanghai 201900, China
| | - Guangchao Wang
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
| | - Long Bai
- Organoid Research Center, Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China; Wenzhou Institute of Shanghai University, Wenzhou 325000, China.
| | - Jiacan Su
- Organoid Research Center, Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China.
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9
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Wu Q, Kan J, Fu C, Liu X, Cui Z, Wang S, Le Y, Li Z, Liu Q, Zhang Y, Du J. Insights into the unique roles of extracellular vesicles for gut health modulation: Mechanisms, challenges, and perspectives. CURRENT RESEARCH IN MICROBIAL SCIENCES 2024; 7:100301. [PMID: 39525958 PMCID: PMC11550031 DOI: 10.1016/j.crmicr.2024.100301] [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] [Indexed: 11/16/2024] Open
Abstract
Extracellular vesicles (EVs), which play significant regulatory roles in maintaining homeostasis and influencing immune responses, significantly impact gut microbiota composition and function, affecting overall gut health. Despite considerable progress, there are still knowledge gaps regarding the mechanisms by which EVs, including plant-derived EVs (PDEVs), animal-derived EVs (ADEVs), and microbiota-derived EVs (MDEVs), modulate gut health. This review delves into the roles and mechanisms of EVs from diverse sources in regulating gut health, focusing on their contributions to maintaining epithelial barrier integrity, facilitating tissue healing, eliciting immune responses, controlling pathogens, and shaping microbiota. We emphasize open challenges and future perspectives for harnessing EVs in the modulation of gut health to gain a deeper understanding of their roles and impact. Importantly, a comprehensive research framework is presented to steer future investigations into the roles and implications of EVs on gut health, facilitating a more profound comprehension of this emerging field.
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Affiliation(s)
- Qiming Wu
- Nutrilite Health Institute, Shanghai 200031, China
| | - Juntao Kan
- Nutrilite Health Institute, Shanghai 200031, China
| | - Caili Fu
- Department of Food Science and Technology, National University of Singapore Suzhou Research Institute, Suzhou 215123, China
| | - Xin Liu
- Department of Food Science and Technology, National University of Singapore Suzhou Research Institute, Suzhou 215123, China
| | - Zhengying Cui
- Department of Food Science and Technology, National University of Singapore Suzhou Research Institute, Suzhou 215123, China
| | - Sixu Wang
- Department of Food Science and Technology, National University of Singapore Suzhou Research Institute, Suzhou 215123, China
| | - Yi Le
- Department of Food Science and Technology, National University of Singapore Suzhou Research Institute, Suzhou 215123, China
| | - Zhanming Li
- Department of Food Quality and Safety, Jiangsu University of Science and Technology, Zhenjiang 212100, China
| | - Qin Liu
- Centre for Chinese Medicine Drug Development Limited, Hong Kong Baptist University, 999077, Hong Kong Special Administrative Region of China
| | - Yuyu Zhang
- Key Laboratory of Geriatric Nutrition and Health, Beijing Technology and Business University, Beijing 100048, China
| | - Jun Du
- Nutrilite Health Institute, Shanghai 200031, China
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10
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Pal D, Das P, Roy S, Mukherjee P, Halder S, Ghosh D, Nandi SK. Recent trends of stem cell therapies in the management of orthopedic surgical challenges. Int J Surg 2024; 110:6330-6344. [PMID: 38716973 PMCID: PMC11487011 DOI: 10.1097/js9.0000000000001524] [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: 12/29/2023] [Accepted: 04/14/2024] [Indexed: 10/20/2024]
Abstract
Emerged health-related problems especially with increasing population and with the wider occurrence of these issues have always put the utmost concern and led medicine to outgrow its usual mode of treatment, to achieve better outcomes. Orthopedic interventions are one of the most concerning hitches, requiring advancement in several issues, that show complications with conventional approaches. Advanced studies have been undertaken to address the issue, among which stem cell therapy emerged as a better area of growth. The capacity of the stem cells to renovate themselves and adapt into different cell types made it possible to implement its use as a regenerative slant. Harvesting the stem cells, particularly mesenchymal stem cells (MSCs) is easier and can be further grown in vitro . In this review, we have discussed orthopedic-related issues including bone defects and fractures, nonunions, ligament and tendon injuries, degenerative changes, and associated conditions, which require further approaches to execute better outcomes, and the advanced strategies that can be tagged along with various ways of application of MSCs. It aims to objectify the idea of stem cells, with a major focus on the application of MSCs from different sources in various orthopedic interventions. It also discusses the limitations, and future scopes for further approaches in the field of regenerative medicine. The involvement of MSCs may transition the procedures in orthopedic interventions from predominantly surgical substitution and reconstruction to bio-regeneration and prevention. Nevertheless, additional improvements and evaluations are required to explore the effectiveness and safety of mesenchymal stem cell treatment in orthopedic regenerative medicine.
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Affiliation(s)
| | - Pratik Das
- Department of Veterinary Surgery and Radiology
| | - Subhasis Roy
- Department of Veterinary Clinical Complex, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal
| | - Prasenjit Mukherjee
- Department of Veterinary Clinical Complex, West Bengal University of Animal and Fishery Sciences, Kolkata, West Bengal
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Younesi FS, Hinz B. The Myofibroblast Fate of Therapeutic Mesenchymal Stromal Cells: Regeneration, Repair, or Despair? Int J Mol Sci 2024; 25:8712. [PMID: 39201399 PMCID: PMC11354465 DOI: 10.3390/ijms25168712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 07/31/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Mesenchymal stromal cells (MSCs) can be isolated from various tissues of healthy or patient donors to be retransplanted in cell therapies. Because the number of MSCs obtained from biopsies is typically too low for direct clinical application, MSC expansion in cell culture is required. However, ex vivo amplification often reduces the desired MSC regenerative potential and enhances undesired traits, such as activation into fibrogenic myofibroblasts. Transiently activated myofibroblasts restore tissue integrity after organ injury by producing and contracting extracellular matrix into scar tissue. In contrast, persistent myofibroblasts cause excessive scarring-called fibrosis-that destroys organ function. In this review, we focus on the relevance and molecular mechanisms of myofibroblast activation upon contact with stiff cell culture plastic or recipient scar tissue, such as hypertrophic scars of large skin burns. We discuss cell mechanoperception mechanisms such as integrins and stretch-activated channels, mechanotransduction through the contractile actin cytoskeleton, and conversion of mechanical signals into transcriptional programs via mechanosensitive co-transcription factors, such as YAP, TAZ, and MRTF. We further elaborate how prolonged mechanical stress can create persistent myofibroblast memory by direct mechanotransduction to the nucleus that can evoke lasting epigenetic modifications at the DNA level, such as histone methylation and acetylation. We conclude by projecting how cell culture mechanics can be modulated to generate MSCs, which epigenetically protected against myofibroblast activation and transport desired regeneration potential to the recipient tissue environment in clinical therapies.
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Affiliation(s)
- Fereshteh Sadat Younesi
- Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada;
- Keenan Research Institute for Biomedical Science, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada
| | - Boris Hinz
- Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada;
- Keenan Research Institute for Biomedical Science, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada
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12
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Lau CS, Park SY, Ethiraj LP, Singh P, Raj G, Quek J, Prasadh S, Choo Y, Goh BT. Role of Adipose-Derived Mesenchymal Stem Cells in Bone Regeneration. Int J Mol Sci 2024; 25:6805. [PMID: 38928517 PMCID: PMC11204188 DOI: 10.3390/ijms25126805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 06/13/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
Bone regeneration involves multiple factors such as tissue interactions, an inflammatory response, and vessel formation. In the event of diseases, old age, lifestyle, or trauma, bone regeneration can be impaired which could result in a prolonged healing duration or requiring an external intervention for repair. Currently, bone grafts hold the golden standard for bone regeneration. However, several limitations hinder its clinical applications, e.g., donor site morbidity, an insufficient tissue volume, and uncertain post-operative outcomes. Bone tissue engineering, involving stem cells seeded onto scaffolds, has thus been a promising treatment alternative for bone regeneration. Adipose-derived mesenchymal stem cells (AD-MSCs) are known to hold therapeutic value for the treatment of various clinical conditions and have displayed feasibility and significant effectiveness due to their ease of isolation, non-invasive, abundance in quantity, and osteogenic capacity. Notably, in vitro studies showed AD-MSCs holding a high proliferation capacity, multi-differentiation potential through the release of a variety of factors, and extracellular vesicles, allowing them to repair damaged tissues. In vivo and clinical studies showed AD-MSCs favoring better vascularization and the integration of the scaffolds, while the presence of scaffolds has enhanced the osteogenesis potential of AD-MSCs, thus yielding optimal bone formation outcomes. Effective bone regeneration requires the interplay of both AD-MSCs and scaffolds (material, pore size) to improve the osteogenic and vasculogenic capacity. This review presents the advances and applications of AD-MSCs for bone regeneration and bone tissue engineering, focusing on the in vitro, in vivo, and clinical studies involving AD-MSCs for bone tissue engineering.
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Affiliation(s)
- Chau Sang Lau
- National Dental Centre Singapore, National Dental Research Institute Singapore, Singapore 168938, Singapore; (C.S.L.); (S.Y.P.); (L.P.E.); (G.R.)
- Oral Health Academic Clinical Programme, Duke-NUS Medical School, Singapore 169857, Singapore
| | - So Yeon Park
- National Dental Centre Singapore, National Dental Research Institute Singapore, Singapore 168938, Singapore; (C.S.L.); (S.Y.P.); (L.P.E.); (G.R.)
| | - Lalith Prabha Ethiraj
- National Dental Centre Singapore, National Dental Research Institute Singapore, Singapore 168938, Singapore; (C.S.L.); (S.Y.P.); (L.P.E.); (G.R.)
- Oral Health Academic Clinical Programme, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Priti Singh
- National Dental Centre Singapore, National Dental Research Institute Singapore, Singapore 168938, Singapore; (C.S.L.); (S.Y.P.); (L.P.E.); (G.R.)
| | - Grace Raj
- National Dental Centre Singapore, National Dental Research Institute Singapore, Singapore 168938, Singapore; (C.S.L.); (S.Y.P.); (L.P.E.); (G.R.)
| | - Jolene Quek
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore; (J.Q.); (Y.C.)
| | - Somasundaram Prasadh
- Center for Clean Energy Engineering, University of Connecticut, Storrs, CT 06269, USA;
| | - Yen Choo
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore; (J.Q.); (Y.C.)
| | - Bee Tin Goh
- National Dental Centre Singapore, National Dental Research Institute Singapore, Singapore 168938, Singapore; (C.S.L.); (S.Y.P.); (L.P.E.); (G.R.)
- Oral Health Academic Clinical Programme, Duke-NUS Medical School, Singapore 169857, Singapore
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13
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Stone AP, Rand E, Thornes G, Kay AG, Barnes AL, Hitchcock IS, Genever PG. Extracellular matrices of stromal cell subtypes regulate phenotype and contribute to the stromal microenvironment in vivo. Stem Cell Res Ther 2024; 15:178. [PMID: 38886845 PMCID: PMC11184721 DOI: 10.1186/s13287-024-03786-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 06/09/2024] [Indexed: 06/20/2024] Open
Abstract
BACKGROUND Bone marrow stromal cells (BMSCs) are highly heterogeneous, which may reflect their diverse biological functions, including tissue maintenance, haematopoietic support and immune control. The current understanding of the mechanisms that drive the onset and resolution of heterogeneity, and how BMSCs influence other cells in their environment is limited. Here, we determined how the secretome and importantly the extracellular matrix of BMSCs can influence cellular phenotype. METHODS We used two immortalised clonal BMSC lines isolated from the same heterogeneous culture as model stromal subtypes with distinct phenotypic traits; a multipotent stem-cell-like stromal line (Y201) and a nullipotent non-stem cell stromal line (Y202), isolated from the same donor BMSC pool. Label-free quantitative phase imaging was used to track cell morphology and migration of the BMSC lines over 96 h in colony-forming assays. We quantified the secreted factors of each cell line by mass spectrometry and confirmed presence of proteins in human bone marrow by immunofluorescence. RESULTS Transfer of secreted signals from a stem cell to a non-stem cell resulted in a change in morphology and enhanced migration to more closely match stem cell-like features. Mass spectrometry analysis revealed a significant enrichment of extracellular matrix (ECM) proteins in the Y201 stem cell secretome compared to Y202 stromal cells. We confirmed that Y201 produced a more robust ECM in culture compared to Y202. Growth of Y202 on ECM produced by Y201 or Y202 restored migration and fibroblastic morphology, suggesting that it is the deficiency of ECM production that contributes to its phenotype. The proteins periostin and aggrecan, were detected at 71- and 104-fold higher levels in the Y201 versus Y202 secretome and were subsequently identified by immunofluorescence at rare sites on the endosteal surfaces of mouse and human bone, underlying CD271-positive stromal cells. These proteins may represent key non-cellular components of the microenvironment for bona-fide stem cells important for cell maintenance and phenotype in vivo. CONCLUSIONS We identified plasticity in BMSC morphology and migratory characteristics that can be modified through secreted proteins, particularly from multipotent stem cells. Overall, we demonstrate the importance of specific ECM proteins in co-ordination of cellular phenotype and highlight how non-cellular components of the BMSC microenvironment may provide insights into cell population heterogeneity and the role of BMSCs in health and disease.
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Affiliation(s)
- Andrew P Stone
- Department of Biology, York Biomedical Research Institute, University of York, York, UK.
- Brandeis University, Waltham, MA, USA.
| | - Emma Rand
- Department of Biology, York Biomedical Research Institute, University of York, York, UK
| | - Gabriel Thornes
- Department of Biology, York Biomedical Research Institute, University of York, York, UK
| | - Alasdair G Kay
- Department of Biology, York Biomedical Research Institute, University of York, York, UK
| | - Amanda L Barnes
- Department of Biology, York Biomedical Research Institute, University of York, York, UK
| | - Ian S Hitchcock
- Department of Biology, York Biomedical Research Institute, University of York, York, UK
| | - Paul G Genever
- Department of Biology, York Biomedical Research Institute, University of York, York, UK
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14
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Liu Y, Hong J. Mesenchymal Stem Cell-Laden In Situ-Forming Hydrogel for Preventing Corneal Stromal Opacity. Cornea 2024; 43:609-626. [PMID: 38289027 PMCID: PMC10980177 DOI: 10.1097/ico.0000000000003475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 10/26/2023] [Accepted: 12/06/2023] [Indexed: 04/01/2024]
Abstract
PURPOSE The aims of this study were to construct a mesenchymal stem cell (MSC)-laden in situ-forming hydrogel and study its effects on preventing corneal stromal opacity. METHODS The native gellan gum was modified by high temperature and pressure, and the rabbit bone marrow MSCs were encapsulated before adding Ca 2+ to initiate cross-linking. The effects of the hydrogel on 3D culture and gene expression of the rabbit bone marrow MSCs were observed in vitro. Then, the MSC-hydrogel was used to repair corneal stromal injury in New Zealand white rabbits within 28 days postoperation. RESULTS The short-chain gellan gum solution has a very low viscosity (<0.1 Pa·s) that is ideal for encapsulating cells. Moreover, mRNA expressions of 3D-cultured MSCs coding for corneal stromal components (decorin, lumican, and keratocan) were upregulated (by 127.8, 165.5, and 25.4 times, respectively) ( P < 0.05) on day 21 in vitro and were verified by Western blotting results. For the in vivo study, the corneal densitometry of the experimental group was (20.73 ± 1.85) grayscale units which was lower than the other groups ( P < 0.05). The MSC-hydrogel downregulated mRNA expression coding for fibrosis markers (α-smooth muscle actin, vimentin, collagen type 5-α1, and collagen type 1-α1) in the rabbit corneal stroma. Furthermore, some of the 5-ethynyl-2'-deoxyuridine (EdU)-labeled MSCs integrated into the upper corneal stroma and expressed keratocyte-specific antigens on day 28 postoperation. CONCLUSIONS The short-chain gellan gum allows MSCs to slowly release to the corneal stromal defect and prevent corneal stromal opacity. Some of the implanted MSCs can integrate into the corneal stroma and differentiate into keratocytes.
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Affiliation(s)
- Yinan Liu
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China; and
- Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Beijing, China
| | - Jing Hong
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China; and
- Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Beijing, China
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15
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Epanomeritakis IE, Khan WS. Adipose-derived regenerative therapies for the treatment of knee osteoarthritis. World J Stem Cells 2024; 16:324-333. [PMID: 38690511 PMCID: PMC11056639 DOI: 10.4252/wjsc.v16.i4.324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 02/15/2024] [Accepted: 03/01/2024] [Indexed: 04/25/2024] Open
Abstract
Knee osteoarthritis is a degenerative condition with a significant disease burden and no disease-modifying therapy. Definitive treatment ultimately requires joint replacement. Therapies capable of regenerating cartilage could significantly reduce financial and clinical costs. The regenerative potential of mesenchymal stromal cells (MSCs) has been extensively studied in the context of knee osteoarthritis. This has yielded promising results in human studies, and is likely a product of immunomodulatory and chondroprotective biomolecules produced by MSCs in response to inflammation. Adipose-derived MSCs (ASCs) are becoming increasingly popular owing to their relative ease of isolation and high proliferative capacity. Stromal vascular fraction (SVF) and micro-fragmented adipose tissue (MFAT) are produced by the enzymatic and mechanical disruption of adipose tissue, respectively. This avoids expansion of isolated ASCs ex vivo and their composition of heterogeneous cell populations, including immune cells, may potentiate the reparative function of ASCs. In this editorial, we comment on a multicenter randomized trial regarding the efficacy of MFAT in treating knee osteoarthritis. We discuss the study's findings in the context of emerging evidence regarding adipose-derived regenerative therapies. An underlying mechanism of action of ASCs is proposed while drawing important distinctions between the properties of isolated ASCs, SVF, and MFAT.
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Affiliation(s)
- Ilias E Epanomeritakis
- Division of Trauma and Orthopaedic Surgery, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Wasim S Khan
- Division of Trauma and Orthopaedic Surgery, Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
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16
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Szűcs D, Monostori T, Miklós V, Páhi ZG, Póliska S, Kemény L, Veréb Z. Licensing effects of inflammatory factors and TLR ligands on the regenerative capacity of adipose-derived mesenchymal stem cells. Front Cell Dev Biol 2024; 12:1367242. [PMID: 38606318 PMCID: PMC11007080 DOI: 10.3389/fcell.2024.1367242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 03/15/2024] [Indexed: 04/13/2024] Open
Abstract
Introduction: Adipose tissue-derived mesenchymal stem cells are promising contributors to regenerative medicine, exhibiting the ability to regenerate tissues and modulate the immune system, which is particularly beneficial for addressing chronic inflammatory ulcers and wounds. Despite their inherent capabilities, research suggests that pretreatment amplifies therapeutic effectiveness. Methods: Our experimental design exposed adipose-derived mesenchymal stem cells to six inflammatory factors for 24 h. We subsequently evaluated gene expression and proteome profile alterations and observed the wound closure rate post-treatment. Results: Specific pretreatments, such as IL-1β, notably demonstrated an accelerated wound-healing process. Analysis of gene and protein expression profiles revealed alterations in pathways associated with tissue regeneration. Discussion: This suggests that licensed cells exhibit potentially higher therapeutic efficiency than untreated cells, shedding light on optimizing regenerative strategies using adipose tissue-derived stem cells.
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Affiliation(s)
- Diána Szűcs
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, Szeged, Hungary
| | - Tamás Monostori
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, Szeged, Hungary
| | | | - Zoltán G. Páhi
- Genome Integrity and DNA Repair Core Group, Hungarian Centre of Excellence for Molecular Medicine (HCEMM), University of Szeged, Szeged, Hungary
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Szilárd Póliska
- Genomic Medicine and Bioinformatics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Lajos Kemény
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, Szeged, Hungary
- Hungarian Centre of Excellence for Molecular Medicine-USz Skin Research Group, University of Szeged, Szeged, Hungary
| | - Zoltán Veréb
- Regenerative Medicine and Cellular Pharmacology Laboratory, Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
- Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, Szeged, Hungary
- Biobank, University of Szeged, Szeged, Hungary
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17
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Ruhl T, Nuptybayeva A, Kim BS, Beier JP. GPR55 inhibits the pro-adipogenic activity of anandamide in human adipose stromal cells. Exp Cell Res 2024; 435:113908. [PMID: 38163565 DOI: 10.1016/j.yexcr.2023.113908] [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: 11/03/2023] [Revised: 12/22/2023] [Accepted: 12/30/2023] [Indexed: 01/03/2024]
Abstract
The endocannabinoid anandamide (AEA) stimulates adipogenesis via the cannabinoid receptor CB1 in adipose stromal cells (ASCs). However, AEA interacts also with nonclassical cannabinoid receptors, including transient receptor potential cation channel (TRPV)1 and G protein-coupled receptor (GPR)55. Their roles in AEA mediated adipogenesis of human ASCs have not been investigated. We examined the receptor-expressions by immunostaining on human ASCs and tested their functionality by measuring the expression of immediate early genes (IEGs) related to the transcription factor-complex AP-1 upon exposition to receptor agonists. Cells were stimulated with increasing concentrations of specific ligands to investigate the effects on ASC viability (proliferation and metabolic activity), secretory activity, and AEA mediated differentiation. ASCs expressed both receptors, and their activation suppressed IEG expression. TRPV1 did not affect viability or cytokine secretion. GPR55 decreased proliferation, and it inhibited the release of hepatocyte growth factor. Blocking GPR55 increased the pro-adipogenic activity of AEA. These data suggest that GPR55 functions as negative regulator of cannabinoid mediated pro-adipogenic capacity in ASCs.
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Affiliation(s)
- Tim Ruhl
- Department of Plastic Surgery, Hand Surgery-Burn Center, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.
| | - Aigul Nuptybayeva
- Department of Plastic Surgery, Hand Surgery-Burn Center, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.
| | - Bong-Sung Kim
- Department of Plastic Surgery, Hand Surgery-Burn Center, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany; Department of Plastic and Hand Surgery, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.
| | - Justus P Beier
- Department of Plastic Surgery, Hand Surgery-Burn Center, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.
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18
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Hopkinson A, Notara M, Cursiefen C, Sidney LE. Increased Anti-Inflammatory Therapeutic Potential and Progenitor Marker Expression of Corneal Mesenchymal Stem Cells Cultured in an Optimized Propagation Medium. Cell Transplant 2024; 33:9636897241241992. [PMID: 38602231 PMCID: PMC11010753 DOI: 10.1177/09636897241241992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 02/19/2024] [Accepted: 03/05/2024] [Indexed: 04/12/2024] Open
Abstract
There is a huge unmet need for new treatment modalities for ocular surface inflammatory disorders (OSIDs) such as dry eye disease and meibomian gland dysfunction. Mesenchymal stem cell therapies may hold the answer due to their potent immunomodulatory properties, low immunogenicity, and ability to modulate both the innate and adaptive immune response. MSC-like cells that can be isolated from the corneal stroma (C-MSCs) offer a potential new treatment strategy; however, an optimized culture medium needs to be developed to produce the ideal phenotype for use in a cell therapy to treat OSIDs. The effects of in vitro expansion of human C-MSC in a medium of M199 containing fetal bovine serum (FBS) was compared to a stem cell medium (SCM) containing knockout serum replacement (KSR) with basic fibroblast growth factor (bFGF) and human leukemia inhibitory factor (LIF), investigating viability, protein, and gene expression. Isolating populations expressing CD34 or using siRNA knockdown of CD34 were investigated. Finally, the potential of C-MSC as a cell therapy was assessed using co-culture with an in vitro corneal epithelial cell injury model and the angiogenic effects of C-MSC conditioned medium were evaluated with blood and lymph endothelial cells. Both media supported proliferation of C-MSC, with SCM increasing expression of CD34, ABCG2, PAX6, NANOG, REX1, SOX2, and THY1, supported by increased associated protein expression. Isolating cell populations expressing CD34 protein made little difference to gene expression, however, knockdown of the CD34 gene led to decreased expression of progenitor genes. C-MSC increased viability of injured corneal epithelial cells whilst decreasing levels of cytotoxicity and interleukins-6 and -8. No pro-angiogenic effect of C-MSC was seen. Culture medium can significantly influence C-MSC phenotype and culture in SCM produced a cell phenotype more suitable for further consideration as an anti-inflammatory cell therapy. C-MSC show considerable potential for development as therapies for OSIDs, acting through anti-inflammatory action.
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Affiliation(s)
- Andrew Hopkinson
- Academic Ophthalmology, Mental Health and Clinical Neurosciences, University of Nottingham, Nottingham, UK
| | - Maria Notara
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Koln, Germany
| | - Claus Cursiefen
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Koln, Germany
| | - Laura E. Sidney
- Academic Ophthalmology, Mental Health and Clinical Neurosciences, University of Nottingham, Nottingham, UK
- Regenerating and Modelling Tissues, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK
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19
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da Silva MDV, Piva M, Martelossi-Cebinelli G, Stinglin Rosa Ribas M, Hoffmann Salles Bianchini B, K Heintz O, Casagrande R, Verri WA. Stem cells and pain. World J Stem Cells 2023; 15:1035-1062. [PMID: 38179216 PMCID: PMC10762525 DOI: 10.4252/wjsc.v15.i12.1035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 11/06/2023] [Accepted: 11/30/2023] [Indexed: 12/26/2023] Open
Abstract
Pain can be defined as an unpleasant sensory and emotional experience caused by either actual or potential tissue damage or even resemble that unpleasant experience. For years, science has sought to find treatment alternatives, with minimal side effects, to relieve pain. However, the currently available pharmacological options on the market show significant adverse events. Therefore, the search for a safer and highly efficient analgesic treatment has become a priority. Stem cells (SCs) are non-specialized cells with a high capacity for replication, self-renewal, and a wide range of differentiation possibilities. In this review, we provide evidence that the immune and neuromodulatory properties of SCs can be a valuable tool in the search for ideal treatment strategies for different types of pain. With the advantage of multiple administration routes and dosages, therapies based on SCs for pain relief have demonstrated meaningful results with few downsides. Nonetheless, there are still more questions than answers when it comes to the mechanisms and pathways of pain targeted by SCs. Thus, this is an evolving field that merits further investigation towards the development of SC-based analgesic therapies, and this review will approach all of these aspects.
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Affiliation(s)
- Matheus Deroco Veloso da Silva
- Department of Pathology, Laboratory of Pain, Inflammation, Neuropathy and Cancer, State University of Londrina, Londrina 86057-970, Paraná, Brazil
| | - Maiara Piva
- Department of Pathology, Laboratory of Pain, Inflammation, Neuropathy and Cancer, State University of Londrina, Londrina 86057-970, Paraná, Brazil
| | - Geovana Martelossi-Cebinelli
- Department of Pathology, Laboratory of Pain, Inflammation, Neuropathy and Cancer, State University of Londrina, Londrina 86057-970, Paraná, Brazil
| | - Mariana Stinglin Rosa Ribas
- Department of Pathology, Laboratory of Pain, Inflammation, Neuropathy and Cancer, State University of Londrina, Londrina 86057-970, Paraná, Brazil
| | - Beatriz Hoffmann Salles Bianchini
- Department of Pathology, Laboratory of Pain, Inflammation, Neuropathy and Cancer, State University of Londrina, Londrina 86057-970, Paraná, Brazil
| | - Olivia K Heintz
- Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA 01655, United States
| | - Rubia Casagrande
- Department of Pharmaceutical Sciences, Center of Health Science, State University of Londrina, Londrina 86038-440, Paraná, Brazil
| | - Waldiceu A Verri
- Department of Pathology, Laboratory of Pain, Inflammation, Neuropathy and Cancer, Center of Biological Sciences, State University of Londrina, Londrina 86057-970, Paraná, Brazil.
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20
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Bai X, Chen T, Li Y, Ge X, Qiu C, Gou H, Wei S, Liu T, Yang W, Yang L, Liang Y, Jia Z, Lv L, Li T. PD-L1 expression levels in mesenchymal stromal cells predict their therapeutic values for autoimmune hepatitis. Stem Cell Res Ther 2023; 14:370. [PMID: 38111045 PMCID: PMC10729378 DOI: 10.1186/s13287-023-03594-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 11/29/2023] [Indexed: 12/20/2023] Open
Abstract
BACKGROUND Autoimmune hepatitis is a chronic inflammatory hepatic disorder with no effective treatment. Mesenchymal stromal cells (MSCs) have emerged as a promising treatment owing to their unique advantages. However, their heterogeneity is hampering use in clinical applications. METHODS Wharton's jelly derived MSCs (WJ-MSCs) were isolated from 58 human donors using current good manufacturing practice conditions. Gene expression profiles of the WJ-MSCs were analyzed by transcriptome and single-cell RNA-sequencing (scRNA-seq), and subsequent functional differences were assessed. Expression levels of programmed death-ligand 1 (PD-L1) were used as an indicator to screen WJ-MSCs with varied immunomodulation activities and assessed their corresponding therapeutic effects in a mouse model of concanavalin A-induced autoimmune hepatitis. RESULTS The 58 different donor-derived WJ-MSCs were grouped into six gene expression profile clusters. The gene in different clusters displayed obvious variations in cell proliferation, differentiation bias, trophic factor secretion, and immunoregulation. Data of scRNA-seq revealed four distinct WJ-MSCs subpopulations. Notably, the different immunosuppression capacities of WJ-MSCs were positively correlated with PD-L1 expression. WJ-MSCs with high expression of PD-L1 were therapeutically superior to WJ-MSCs with low PD-L1 expression in treating autoimmune hepatitis. CONCLUSION PD-L1 expression levels of WJ-MSCs could be regarded as an indicator to choose optimal MSCs for treating autoimmune disease. These findings provided novel insights into the quality control of MSCs and will inform improvements in the therapeutic benefits of MSCs.
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Affiliation(s)
- Xilong Bai
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
- Xi'an ChaoYue Stem Cell Co., Ltd, Xi'an, 710100, Shaanxi, China
- Department of Hematology, Xi'an International Medical Center Hospital, Xi'an, 710100, Shaanxi, China
| | - Tingwei Chen
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Yuqi Li
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Xiaofan Ge
- Xi'an ChaoYue Stem Cell Co., Ltd, Xi'an, 710100, Shaanxi, China
| | - Caie Qiu
- Xi'an ChaoYue Stem Cell Co., Ltd, Xi'an, 710100, Shaanxi, China
| | - Huili Gou
- Xi'an ChaoYue Stem Cell Co., Ltd, Xi'an, 710100, Shaanxi, China
| | - Sili Wei
- Xi'an ChaoYue Stem Cell Co., Ltd, Xi'an, 710100, Shaanxi, China
| | - Tingting Liu
- Xi'an ChaoYue Stem Cell Co., Ltd, Xi'an, 710100, Shaanxi, China
| | - Wei Yang
- Xi'an ChaoYue Stem Cell Co., Ltd, Xi'an, 710100, Shaanxi, China
| | - Liting Yang
- Xi'an ChaoYue Stem Cell Co., Ltd, Xi'an, 710100, Shaanxi, China
| | - Yingmin Liang
- Department of Hematology, Xi'an International Medical Center Hospital, Xi'an, 710100, Shaanxi, China
| | - Zhansheng Jia
- Department of Infection and Liver Disease, Xi'an International Medical Center Hospital, Xi'an, 710100, Shaanxi, China
| | - Liangshan Lv
- Department of Minimally Invasive Interventional Radiology, Xi'an Gaoxin Hospital, Xi'an, , 710075, Shaanxi, China
| | - Tianqing Li
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China.
- Xi'an ChaoYue Stem Cell Co., Ltd, Xi'an, 710100, Shaanxi, China.
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21
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Hao T, Ji G, Qian M, Li QX, Huang H, Deng S, Liu P, Deng W, Wei Y, He J, Wang S, Gao W, Li T, Cheng J, Tian J, Pan L, Gao F, Li Z, Zhao Q. Intracellular delivery of nitric oxide enhances the therapeutic efficacy of mesenchymal stem cells for myocardial infarction. SCIENCE ADVANCES 2023; 9:eadi9967. [PMID: 38019911 PMCID: PMC10686553 DOI: 10.1126/sciadv.adi9967] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 10/27/2023] [Indexed: 12/01/2023]
Abstract
Cell therapy by autologous mesenchymal stem cells (MSCs) is a clinically acceptable strategy for treating various diseases. Unfortunately, the therapeutic efficacy is largely affected by the low quality of MSCs collected from patients. Here, we showed that the gene expression of MSCs from patients with diabetes was differentially regulated compared to that of MSCs from healthy controls. Then, MSCs were genetically engineered to catalyze an NO prodrug to release NO intracellularly. Compared to extracellular NO conversion, intracellular NO delivery effectively prolonged survival and enhanced the paracrine function of MSCs, as demonstrated by in vitro and in vivo assays. The enhanced therapeutic efficacy of engineered MSCs combined with intracellular NO delivery was further confirmed in mouse and rat models of myocardial infarction, and a clinically relevant cell administration paradigm through secondary thoracotomy has been attempted.
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Affiliation(s)
- Tian Hao
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Guangbo Ji
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Meng Qian
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Qiu Xuan Li
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Haoyan Huang
- Nankai University School of Medicine, Tianjin 300071, China
| | - Shiyu Deng
- The Key Laboratory of Weak-Light Nonlinear Photonics of Education Ministry, School of Physics and TEDA Institute of Applied Physics, Nankai University, Tianjin 300071, China
| | - Pei Liu
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Weiliang Deng
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Yongzhen Wei
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Ju He
- Department of Vascular Surgery, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
| | - Shusen Wang
- Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Wenqing Gao
- Department of Heart Center, The Third Central Hospital of Tianjin, Nankai University, Tianjin, China
| | - Tong Li
- Department of Heart Center, The Third Central Hospital of Tianjin, Nankai University, Tianjin, China
| | - Jiansong Cheng
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300353, China
| | - Jinwei Tian
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Leiting Pan
- The Key Laboratory of Weak-Light Nonlinear Photonics of Education Ministry, School of Physics and TEDA Institute of Applied Physics, Nankai University, Tianjin 300071, China
| | - Fei Gao
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Zongjin Li
- Nankai University School of Medicine, Tianjin 300071, China
| | - Qiang Zhao
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials (Ministry of Education), Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300071, China
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22
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Haghmorad D, Khaleghian A, Eslami M, Sadeghnejad A, Tarahomi M, Yousefi B. Bone marrow mesenchymal stem cells to ameliorate experimental autoimmune encephalomyelitis via modifying expression patterns of miRNAs. Mol Biol Rep 2023; 50:9971-9984. [PMID: 37897611 DOI: 10.1007/s11033-023-08843-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 09/25/2023] [Indexed: 10/30/2023]
Abstract
INTRODUCTION Clinical and experimental studies highlighted the significant therapeutic role of Mesenchymal stem cells (MSCs) in neurodegenerative diseases. MSCs possess potent immunomodulatory properties by releasing exosomes, which generate a suitable microenvironment. microRNAs (miRNAs), as one of several effective bioactive molecules of exosomes, influence cellular communication and activities in recipient cells. Recent studies revealed that miRNAs could control the progression of multiple sclerosis (MS) via differentiation and function of T helper cells (Th). METHODS Here, we investigated the therapeutic effects of syngeneic-derived BM-MSC in experimental autoimmune encephalomyelitis (EAE) mouse model of MS by evaluating expression profile of miRNAs, pro- and anti-inflammatory in serum and brain tissues. Three-time scheme groups (6th day, 6th & 12th days, and 12th day, of post-EAE induction) were applied to determine the therapeutic effects of intraperitoneally received 1*106 of BM-MSCs. RESULTS The expression levels of mature isoforms of miR-193, miR-146a, miR-155, miR-21, and miR-326 showed that BM-MSCs treatment attenuated the EAE clinical score and reduced clinical inflammation as well as demyelination. The improved neurological functional outcome associated with enhanced expression of miR-193 and miR-146a, but decreased expression levels of miR-155, miR-21, and miR-326 were followed by suppressing effects on Th1/Th17 immune responses (reduced levels of IFN-γand IL-17 cytokine expression) and induction of Treg cells, immunoregulatory responses (increase of IL-10, TGF-β, and IL-4) in treatment groups. CONCLUSION Our findings suggest that BM-MSCs administration might change expression patterns of miRNAs and downstream interactions followed by immune system modulation. However, there is a need to carry out future human clinical trials and complementary experiments.
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Affiliation(s)
- Dariush Haghmorad
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Ali Khaleghian
- Department of Biochemistry, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Majid Eslami
- Department of Bacteriology and Virology, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Mahdieh Tarahomi
- Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Bahman Yousefi
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran.
- Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran.
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23
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Finocchio L, Zeppieri M, Gabai A, Spadea L, Salati C. Recent Advances of Adipose-Tissue-Derived Mesenchymal Stem Cell-Based Therapy for Retinal Diseases. J Clin Med 2023; 12:7015. [PMID: 38002628 PMCID: PMC10672618 DOI: 10.3390/jcm12227015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 10/29/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open
Abstract
With the rapid development of stem cell research in modern times, stem cell-based therapy has opened a new era of tissue regeneration, becoming one of the most promising strategies for currently untreatable retinal diseases. Among the various sources of stem cells, adipose tissue-derived mesenchymal stem cells (ADSCs) have emerged as a promising therapeutic modality due to their characteristics and multiple functions, which include immunoregulation, anti-apoptosis of neurons, cytokine and growth factor secretion, and antioxidative activities. Studies have shown that ADSCs can facilitate the replacement of dying cells, promote tissue remodeling and regeneration, and support the survival and growth of retinal cells. Recent studies in this field have provided numerous experiments using different preclinical models. The aim of our review is to provide an overview of the therapeutic strategies, modern-day clinical trials, experimental models, and potential clinical use of this fascinating class of cells in addressing retinal disorders and diseases.
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Affiliation(s)
- Lucia Finocchio
- Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy; (L.F.)
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy; (L.F.)
| | - Andrea Gabai
- Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy; (L.F.)
| | - Leopoldo Spadea
- Eye Clinic, Policlinico Umberto I, La Sapienza University of Rome, 00142 Rome, Italy
| | - Carlo Salati
- Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy; (L.F.)
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24
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Bekhit AA, Beshay ON, Fawzy MA, Abdel-Hafez SMN, Batiha GES, Ataya FS, Fathy M. Curative Effect of AD-MSCs against Cisplatin-Induced Hepatotoxicity in Rats is Potentiated by Azilsartan: Targeting Oxidative Stress, MAPK, and Apoptosis Signaling Pathways. Stem Cells Int 2023; 2023:6767735. [PMID: 37908315 PMCID: PMC10615573 DOI: 10.1155/2023/6767735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 09/02/2023] [Accepted: 10/03/2023] [Indexed: 11/02/2023] Open
Abstract
Despite its clinical value, cisplatin (CISP) is complicated by marked hepatotoxicity via inducing oxidative stress, inflammatory, and apoptotic pathways. This study aims to explore the protective impact of azilsartan (AZIL), an antihypertensive drug, in addition to adipose tissue-derived mesenchymal stem cells (AD-MSCs) on CISP-induced hepatotoxicity. After characterization and labeling of AD-MSCs by PKH26 dye, 54 Wistar male albino rats were randomly divided into nine groups: I (CONT), II (AZIL.H), III (CISP), IV (CISP + AZIL.L), V (CISP + AZIL.H), VI (CISP + AD-MSCs), VII (CISP + AZIL.L + AD-MSCs), VIII (CISP + AZIL.H + AD-MSCs), and IX (CISP + VITA C). Serum alanine aminotransferase (ALT), alanine aminotransferase (AST), and albumin levels were determined. Assessment of reactive oxygen species, malondialdehyde, and glutathione contents, and superoxide dismutase activity and histopathological evaluations were done on hepatic tissue. Quantitative real-time PCR was utilized to estimate the expression of TNF-α and IL-6 genes. Cell homing of labeled AD-MSCs to the liver tissues was investigated. Hepatic expression of JNK1/2, ERK1/2, p38, Bax, Bcl-2, and cleaved caspase-3 proteins was investigated by western blot analysis. CISP elevated serum ALT and AST activities, reduced albumin level, and remarkably changed the hepatic architecture. It increased the expression TNF-α and IL-6 genes, raised the expression of JNK1/2, ERK1/2, p38, Bax, and cleaved caspase-3 proteins, and diminished the Bcl-2 protein. By contrast, treatment of animals with either AZIL or AD-MSCs dramatically reduced the effects of CISP injection. Moreover, treatment with combination therapy (AZIL.L or H + AD-MSCs) considerably mitigated all previously mentioned alterations superior to AZIL or AD-MSCs alone, which might be attributed to the AZIL-enhanced homing ability of AD-MSCs into the injured liver tissue. In conclusion, the present findings demonstrated that AZIL improves the hepatoprotective potential of AD-MSCs against CISP-induced hepatotoxicity by modulating oxidative stress, mitogen-activated protein kinase, and apoptotic pathways.
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Affiliation(s)
| | - Olivia N. Beshay
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt
| | - Michael A. Fawzy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt
| | | | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, AlBeheira 22511, Egypt
| | - Farid S. Ataya
- Department of Biochemistry, College of Science, King Saud University, P.O. Box, 2455, Riyadh 11451, Saudi Arabia
| | - Moustafa Fathy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt
- Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan
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25
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Chen J, Ye P, Gu R, Zhu H, He W, Mu X, Wu X, Pang H, Han F, Nie X. Neuropeptide substance P: A promising regulator of wound healing in diabetic foot ulcers. Biochem Pharmacol 2023; 215:115736. [PMID: 37549795 DOI: 10.1016/j.bcp.2023.115736] [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: 08/01/2023] [Accepted: 08/02/2023] [Indexed: 08/09/2023]
Abstract
In the past, neuropeptide substance P (SP) was predominantly recognized as a neuroinflammatory factor, while its potent healing activity was overlooked. This paper aims to review the regulatory characteristics of neuropeptide SP in both normal and diabetic wound healing. SP actively in the regulation of wound healing-related cells directly and indirectly, exhibiting robust inflammatory properties, promoting cell proliferation and migration and restoring the activity and paracrine ability of skin cells under diabetic conditions. Furthermore, SP not only regulates healing-related cells but also orchestrates the immune environment, thereby presenting unique and promising application prospects in wound intervention. As new SP-based preparations are being explored, SP-related drugs are poised to become an effective therapeutic intervention for diabetic foot ulcers (DFU).
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Affiliation(s)
- Jitao Chen
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China; Key Lab of the Basic Pharmacology of the Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Penghui Ye
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China; Key Lab of the Basic Pharmacology of the Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Rifang Gu
- University Medical Office, Zunyi Medical University, Zunyi 563000, China
| | - Huan Zhu
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China; Key Lab of the Basic Pharmacology of the Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Wenjie He
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China; Key Lab of the Basic Pharmacology of the Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Xingrui Mu
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China; Key Lab of the Basic Pharmacology of the Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Xingqian Wu
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China; Key Lab of the Basic Pharmacology of the Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Huiwen Pang
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Felicity Han
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Xuqiang Nie
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia; Key Lab of the Basic Pharmacology of the Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi 563000, China.
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26
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Teo KYW, Tan R, Wong KL, Hey DHW, Hui JHP, Toh WS. Small extracellular vesicles from mesenchymal stromal cells: the next therapeutic paradigm for musculoskeletal disorders. Cytotherapy 2023; 25:837-846. [PMID: 37191613 DOI: 10.1016/j.jcyt.2023.04.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 04/06/2023] [Accepted: 04/20/2023] [Indexed: 05/17/2023]
Abstract
Musculoskeletal disorders are one of the biggest contributors to morbidity and place an enormous burden on the health care system in an aging population. Owing to their immunomodulatory and regenerative properties, mesenchymal stromal/stem cells (MSCs) have demonstrated therapeutic efficacy for treatment of a wide variety of conditions, including musculoskeletal disorders. Although MSCs were originally thought to differentiate and replace injured/diseased tissues, it is now accepted that MSCs mediate tissue repair through secretion of trophic factors, particularly extracellular vesicles (EVs). Endowed with a diverse cargo of bioactive lipids, proteins, nucleic acids and metabolites, MSC-EVs have been shown to elicit diverse cellular responses and interact with many cell types needed in tissue repair. The present review aims to summarize the latest advances in the use of native MSC-EVs for musculoskeletal regeneration, examine the cargo molecules and mechanisms underlying their therapeutic effects, and discuss the progress and challenges in their translation to the clinic.
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Affiliation(s)
- Kristeen Ye Wen Teo
- Department of Orthopedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore; Faculty of Dentistry, National University of Singapore, Singapore, Republic of Singapore
| | - Rachel Tan
- Department of Orthopedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
| | - Keng Lin Wong
- Department of Orthopedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore; Department of Orthopedic Surgery, Sengkang General Hospital, Singapore Health Services, Singapore, Republic of Singapore
| | - Dennis Hwee Weng Hey
- Department of Orthopedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
| | - James Hoi Po Hui
- Department of Orthopedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore; Tissue Engineering Program, Life Sciences Institute, National University of Singapore, Singapore, Republic of Singapore
| | - Wei Seong Toh
- Department of Orthopedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore; Faculty of Dentistry, National University of Singapore, Singapore, Republic of Singapore; Tissue Engineering Program, Life Sciences Institute, National University of Singapore, Singapore, Republic of Singapore; Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore, Singapore, Republic of Singapore; Integrative Sciences and Engineering Program, NUS Graduate School, National University of Singapore, Singapore, Republic of Singapore.
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27
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Ong HS, Riau AK, Yam GHF, Yusoff NZBM, Han EJY, Goh TW, Lai RC, Lim SK, Mehta JS. Mesenchymal Stem Cell Exosomes as Immunomodulatory Therapy for Corneal Scarring. Int J Mol Sci 2023; 24:7456. [PMID: 37108619 PMCID: PMC10144287 DOI: 10.3390/ijms24087456] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 04/14/2023] [Accepted: 04/15/2023] [Indexed: 04/29/2023] Open
Abstract
Corneal scarring is a leading cause of worldwide blindness. Human mesenchymal stem cells (MSC) have been reported to promote corneal wound healing through secreted exosomes. This study investigated the wound healing and immunomodulatory effects of MSC-derived exosomes (MSC-exo) in corneal injury through an established rat model of corneal scarring. After induction of corneal scarring by irregular phototherapeutic keratectomy (irrPTK), MSC exosome preparations (MSC-exo) or PBS vehicle as controls were applied to the injured rat corneas for five days. The animals were assessed for corneal clarity using a validated slit-lamp haze grading score. Stromal haze intensity was quantified using in-vivo confocal microscopy imaging. Corneal vascularization, fibrosis, variations in macrophage phenotypes, and inflammatory cytokines were evaluated using immunohistochemistry techniques and enzyme-linked immunosorbent assays (ELISA) of the excised corneas. Compared to the PBS control group, MSC-exo treatment group had faster epithelial wound closure (0.041), lower corneal haze score (p = 0.002), and reduced haze intensity (p = 0.004) throughout the follow-up period. Attenuation of corneal vascularisation based on CD31 and LYVE-1 staining and reduced fibrosis as measured by fibronectin and collagen 3A1 staining was also observed in the MSC-exo group. MSC-exo treated corneas also displayed a regenerative immune phenotype characterized by a higher infiltration of CD163+, CD206+ M2 macrophages over CD80+, CD86+ M1 macrophages (p = 0.023), reduced levels of pro-inflammatory IL-1β, IL-8, and TNF-α, and increased levels of anti-inflammatory IL-10. In conclusion, topical MSC-exo could alleviate corneal insults by promoting wound closure and reducing scar development, possibly through anti-angiogenesis and immunomodulation towards a regenerative and anti-inflammatory phenotype.
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Affiliation(s)
- Hon Shing Ong
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore 169856, Singapore
- Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore 169857, Singapore
- Corneal and External Diseases Department, Singapore National Eye Centre, Singapore 168751, Singapore
| | - Andri K. Riau
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore 169856, Singapore
- Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Gary Hin-Fai Yam
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore 169856, Singapore
- Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | | | - Evelina J. Y. Han
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore 169856, Singapore
| | - Tze-Wei Goh
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore 169856, Singapore
| | - Ruenn Chai Lai
- Institute of Medical Biology & Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
| | - Sai Kiang Lim
- Institute of Medical Biology & Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
| | - Jodhbir S. Mehta
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore 169856, Singapore
- Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore 169857, Singapore
- Corneal and External Diseases Department, Singapore National Eye Centre, Singapore 168751, Singapore
- School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798, Singapore
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28
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García-Bonilla M, Ojeda-Pérez B, Shumilov K, Rodríguez-Pérez LM, Domínguez-Pinos D, Vitorica J, Jiménez S, Ramírez-Lorca R, Echevarría M, Cárdenas-García C, Iglesias T, Gutiérrez A, McAllister JP, Limbrick DD, Páez-González P, Jiménez AJ. Generation of Periventricular Reactive Astrocytes Overexpressing Aquaporin 4 Is Stimulated by Mesenchymal Stem Cell Therapy. Int J Mol Sci 2023; 24:5640. [PMID: 36982724 PMCID: PMC10057840 DOI: 10.3390/ijms24065640] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/09/2023] [Accepted: 03/11/2023] [Indexed: 03/18/2023] Open
Abstract
Aquaporin-4 (AQP4) plays a crucial role in brain water circulation and is considered a therapeutic target in hydrocephalus. Congenital hydrocephalus is associated with a reaction of astrocytes in the periventricular white matter both in experimental models and human cases. A previous report showed that bone marrow-derived mesenchymal stem cells (BM-MSCs) transplanted into the lateral ventricles of hyh mice exhibiting severe congenital hydrocephalus are attracted by the periventricular astrocyte reaction, and the cerebral tissue displays recovery. The present investigation aimed to test the effect of BM-MSC treatment on astrocyte reaction formation. BM-MSCs were injected into the lateral ventricles of four-day-old hyh mice, and the periventricular reaction was detected two weeks later. A protein expression analysis of the cerebral tissue differentiated the BM-MSC-treated mice from the controls and revealed effects on neural development. In in vivo and in vitro experiments, BM-MSCs stimulated the generation of periventricular reactive astrocytes overexpressing AQP4 and its regulatory protein kinase D-interacting substrate of 220 kDa (Kidins220). In the cerebral tissue, mRNA overexpression of nerve growth factor (NGF), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 (HIF1α), and transforming growth factor beta 1 (TGFβ1) could be related to the regulation of the astrocyte reaction and AQP4 expression. In conclusion, BM-MSC treatment in hydrocephalus can stimulate a key developmental process such as the periventricular astrocyte reaction, where AQP4 overexpression could be implicated in tissue recovery.
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Affiliation(s)
- María García-Bonilla
- Department of Cell Biology, Genetics and Physiology, University of Malaga, 29010 Malaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Malaga, Spain
| | - Betsaida Ojeda-Pérez
- Department of Cell Biology, Genetics and Physiology, University of Malaga, 29010 Malaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Malaga, Spain
| | - Kirill Shumilov
- Department of Cell Biology, Genetics and Physiology, University of Malaga, 29010 Malaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Malaga, Spain
- Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA
| | - Luis-Manuel Rodríguez-Pérez
- Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Malaga, Spain
- Departamento de Fisiología Humana, Histología Humana, Anatomía Patológica y Educación Física y Deportiva, University of Malaga, 29010 Malaga, Spain
| | | | - Javier Vitorica
- Department of Molecular Biology and Biochemistry, University of Seville, 41013 Sevilla, Spain
- Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, (HUVR)/Spanish National Research Council (CSIC)/University of Seville, 41013 Seville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos II, 28029 Madrid, Spain
| | - Sebastián Jiménez
- Department of Molecular Biology and Biochemistry, University of Seville, 41013 Sevilla, Spain
- Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, (HUVR)/Spanish National Research Council (CSIC)/University of Seville, 41013 Seville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos II, 28029 Madrid, Spain
| | - Reposo Ramírez-Lorca
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos II, 28029 Madrid, Spain
- Department of Physiology and Biophysics, University of Seville, 41009 Seville, Spain
| | - Miriam Echevarría
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos II, 28029 Madrid, Spain
- Department of Physiology and Biophysics, University of Seville, 41009 Seville, Spain
| | - Casimiro Cárdenas-García
- Servicios Centrales de Apoyo a la Investigación (SCAI), University of Malaga, 29010 Malaga, Spain
| | - Teresa Iglesias
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos II, 28029 Madrid, Spain
- Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28029 Madrid, Spain
| | - Antonia Gutiérrez
- Department of Cell Biology, Genetics and Physiology, University of Malaga, 29010 Malaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Malaga, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos II, 28029 Madrid, Spain
| | - James P. McAllister
- Department of Neurosurgery, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA
| | - David D. Limbrick
- Department of Neurosurgery, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA
| | - Patricia Páez-González
- Department of Cell Biology, Genetics and Physiology, University of Malaga, 29010 Malaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Malaga, Spain
| | - Antonio J. Jiménez
- Department of Cell Biology, Genetics and Physiology, University of Malaga, 29010 Malaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Malaga, Spain
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Classical monocyte-derived macrophages as therapeutic targets of umbilical cord mesenchymal stem cells: comparison of intratracheal and intravenous administration in a mouse model of pulmonary fibrosis. Respir Res 2023; 24:68. [PMID: 36870972 PMCID: PMC9985859 DOI: 10.1186/s12931-023-02357-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 02/01/2023] [Indexed: 03/06/2023] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that has no cure. Although mesenchymal stem cells (MSCs) have been reported to ameliorate lung inflammation and fibrosis in mouse models, their mechanisms of action remain unknown. Therefore, we aimed to determine the changes in various immune cells, especially macrophages and monocytes, involved in the effects of MSC treatment on pulmonary fibrosis. METHODS We collected and analyzed explanted lung tissues and blood from patients with IPF who underwent lung transplantation. After establishing a pulmonary fibrosis model via the intratracheal administration of bleomycin (BLM) to 8-week-old mice, MSCs derived from human umbilical cords were administered intravenously or intratracheally on day 10 and the lungs were immunologically analyzed on days 14 and 21. Flow cytometry was performed to analyze the immune cell characteristics, and gene expression levels were examined using quantitative reverse transcription-polymerase chain reaction. RESULTS In the histological analysis of explanted human lung tissues, the terminally fibrotic areas contained a larger number of macrophages and monocytes than the early fibrotic areas of the lungs. When human monocyte-derived macrophages (MoMs) were stimulated with interleukin-13 in vitro, the expression of type 2 macrophage (M2) markers was more prominent in MoMs from the classical monocyte subset than in those from intermediate or non-classical monocyte subsets, and MSCs suppressed M2 marker expression independent of MoM subsets. In the mouse model, the increased number of inflammatory cells in the bronchoalveolar lavage fluid and the degree of lung fibrosis observed in BLM-treated mice were significantly reduced by MSC treatment, which tended to be more prominent with intravenous administration than intratracheal administration. Both M1 and M2 MoMs were upregulated in BLM-treated mice. The M2c subset of M2 MoMs was significantly reduced by MSC treatment. Among M2 MoMs, M2 MoMs derived from Ly6C+ monocytes were most effectively regulated by the intravenous administration, not intratracheal administration, of MSCs. CONCLUSIONS Inflammatory classical monocytes may play a role in lung fibrosis in human IPF and BLM-induced pulmonary fibrosis. Intravenous rather than intratracheal administration of MSCs may ameliorate pulmonary fibrosis by inhibiting monocyte differentiation into M2 macrophages.
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Small RNA sequencing of small extracellular vesicles secreted by umbilical cord mesenchymal stem cells following replicative senescence. Genes Genomics 2023; 45:347-358. [PMID: 35917089 DOI: 10.1007/s13258-022-01297-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 07/20/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND Umbilical cord mesenchymal stem cells (UCMSC) are subsets of multipotent stem cells involved in immune modulation, tissue regeneration, and antimicrobial defense. Cellular senescence is associated with the onset of aging-related diseases and small extracellular vesicles (sEVs) are important mediators of senescence and aging. OBJECTIVE However, little is known about the role and function of microRNAs (miRNAs) carried by UCMSC-derived sEVs. To analyze the expression profiles of miRNAs secreted by senescent UCMSC, small RNA sequencing of the miRNAs within the sEVs was performed in this study. METHODS UCMSC cultures underwent serial passaging beyond passage number 20 to achieve replicative senescence, which was confirmed by various methods, including increased senescence-associated β-gal staining and cytokine secretion levels. sEVs derived from non-senescent and senescent UCMSC were isolated and characterized by nanoparticle tracking analysis, transmission electron microscopy, and immunoblot analysis. RESULTS Small RNA sequencing of the miRNAs within the sEVs revealed senescence-associated differences in the miRNA composition, as shown by the upregulation of miR-122-5p and miR-146a-5p, and downregulation of miR-125b-5p and miR-29-3p. In addition, total RNA sequencing analysis showed that PENK, ITGA8, and TSIX were upregulated, whereas AKR1B10, UNC13D, and IL21R were downregulated by replicative senescence in UCMSC. In sEVs, upregulated genes were linked to downregulated miRNAs, and vice versa. In the gene-concept network analysis, five gynecologic terms were retrieved. CONCLUSIONS The study provides an insight into the cellular characteristics of UCMSC following replicative senescence and emphasizes the importance of monitoring passage numbers of UCMSC for further therapeutic use.
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Jo SY, Cho HJ, Kim TM. Fenoldopam Mesylate Enhances the Survival of Mesenchymal Stem Cells Under Oxidative Stress and Increases the Therapeutic Function in Acute Kidney Injury. Cell Transplant 2023; 32:9636897221147920. [PMID: 36594258 PMCID: PMC9830573 DOI: 10.1177/09636897221147920] [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] [Indexed: 01/04/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have gained interest as an alternative therapeutic option for renal diseases, including acute kidney injury (AKI). However, their use is often limited owing to low survival rates in vivo. Fenoldopam mesylate (FD) is a selective dopamine D1 receptor agonist with antioxidative and anti-apoptotic roles. Herein, we investigated whether FD can enhance the survival of MSCs undergoing oxidative stress in vitro. In addition, the therapeutic effect of MSCs and FD-treated MSCs (FD-MSCs) was compared in a mouse model of AKI induced by cisplatin. The survival of MSCs under oxidative stress was augmented by FD treatment. FD induced the phosphorylation of cAMP response element-binding protein and AKT, contributing to enhanced growth compared with untreated MSCs. The expression of nuclear factor erythroid-2-related factor 2 (NRF2) and heme oxygenase-1 was increased by FD treatment, and nuclear translocation of NRF2 was found exclusively in FD-MSCs. FD downregulated BAX expression, increased the mitochondrial membrane potential, reduced reactive oxygen species generation, and decreased the apoptotic death of MSCs induced by oxidative stress. Moreover, renal function and tubular injury were improved in FD-MSCs compared with non-treated MSCs. Furthermore, tubular injury, apoptosis, and macrophage infiltration, as well as the serum level of tumor necrosis factor-α were reduced, while tubular cell proliferation was markedly increased in FD-MSCs compared with MSCs. Our study demonstrated that FD increases the survivability of MSCs in an oxidative environment, and its use may be effective in preparing robust therapeutic MSCs.
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Affiliation(s)
- Seo Yeon Jo
- Graduate School of International Agricultural Technology, Seoul National University, Pyeongchang, South Korea
| | - Hye Jin Cho
- Graduate School of International Agricultural Technology, Seoul National University, Pyeongchang, South Korea
| | - Tae Min Kim
- Graduate School of International Agricultural Technology, Seoul National University, Pyeongchang, South Korea,Institutes of Green Bio Science & Technology, Seoul National University, Pyeongchang, South Korea,Tae Min Kim, Graduate School of International Agricultural Technology and Institutes of Green Bio Science & Technology, Seoul National University, Pyeongchang Daero 1447, Pyeongchang 25354, Gangwon-do, South Korea.
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Skoloudik L, Chrobok V, Laco J, Dedkova J, Diaz Garcia D, Filip S. An Effect of Cyclosporin A in a Treatment of Temporal Bone Defect Using hBM-MSCs. Biomedicines 2022; 10:biomedicines10112918. [PMID: 36428486 PMCID: PMC9687466 DOI: 10.3390/biomedicines10112918] [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: 10/11/2022] [Revised: 11/02/2022] [Accepted: 11/10/2022] [Indexed: 11/16/2022] Open
Abstract
Background. The treatment of middle ear cholesteatoma requires surgical treatment and the reconstruction of the temporal bone, which represents an ongoing problem. Otologists have focused on the research of materials allowing an airy middle ear and the preservation of hearing function to reconstruct the temporal bone. Methods. This study evaluated the effect of cyclosporin A (CsA) and a combined biomaterial in the healing process of postoperative temporal bone defects in an animal model. Cultured human Bone Marrow Mesenchymal Stromal Cells (hBM-MSCs) were mixed with hydroxyapatite (Cem-Ostetic®), and subsequently applied as a bone substitute after middle ear surgery, showing that the therapeutic potential of hBM-MSCs associated with bone regeneration and replacement is directly influenced by CsA, confirming that it promotes the survival of MSCs in vivo. Results. The therapeutic efficacy of the combination of MSCs with CsA is greater than the sole application of MSCs in a hydroxyapatite carrier. Conclusion. The reconstruction of a temporal bone defect using hBM-MSCs requires an immunosuppressant to improve the results of treatment.
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Affiliation(s)
- Lukas Skoloudik
- Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital Hradec Kralove, Faculty of Medicine in Hradec Kralove, Charles University, 500 03 Hradec Králové, Czech Republic
| | - Viktor Chrobok
- Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital Hradec Kralove, Faculty of Medicine in Hradec Kralove, Charles University, 500 03 Hradec Králové, Czech Republic
| | - Jan Laco
- The Fingerland Department of Pathology, University Hospital Hradec Kralove, Faculty of Medicine in Hradec Kralove, Charles University, 500 03 Hradec Králové, Czech Republic
| | - Jana Dedkova
- Department of Radiology, University Hospital Hradec Kralove, 500 05 Hradec Králové, Czech Republic
| | - Daniel Diaz Garcia
- Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, 500 03 Hradec Králové, Czech Republic
| | - Stanislav Filip
- Department of Oncology and Radiotherapy, Faculty of Medicine Hradec Kralove, Charles University, 500 03 Hradec Králové, Czech Republic
- Correspondence: ; Tel.: +420-495-834-618
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Lufkin L, Samanta A, Baker D, Lufkin S, Schulze J, Ellis B, Rose J, Lufkin T, Kraus P. Glis1 and oxaloacetate in nucleus pulposus stromal cell somatic reprogramming and survival. Front Mol Biosci 2022; 9:1009402. [PMID: 36406265 PMCID: PMC9671658 DOI: 10.3389/fmolb.2022.1009402] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 10/10/2022] [Indexed: 12/04/2022] Open
Abstract
Regenerative medicine aims to repair degenerate tissue through cell refurbishment with minimally invasive procedures. Adipose tissue (FAT)-derived stem or stromal cells are a convenient autologous choice for many regenerative cell therapy approaches. The intervertebral disc (IVD) is a suitable target. Comprised of an inner nucleus pulposus (NP) and an outer annulus fibrosus (AF), the degeneration of the IVD through trauma or aging presents a substantial socio-economic burden worldwide. The avascular nature of the mature NP forces cells to reside in a unique environment with increased lactate levels, conditions that pose a challenge to cell-based therapies. We assessed adipose and IVD tissue-derived stromal cells through in vitro transcriptome analysis in 2D and 3D culture and suggested that the transcription factor Glis1 and metabolite oxaloacetic acid (OAA) could provide NP cells with survival tools for the harsh niche conditions in the IVD.
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Affiliation(s)
- Leon Lufkin
- Department of Statistics and Data Science, Yale University, New Haven, CT, United States,The Clarkson School, Clarkson University, Potsdam, NY, United States
| | - Ankita Samanta
- Department of Biology, Clarkson University, Potsdam, NY, United States
| | - DeVaun Baker
- The Clarkson School, Clarkson University, Potsdam, NY, United States,Department of Biology, Clarkson University, Potsdam, NY, United States
| | - Sina Lufkin
- The Clarkson School, Clarkson University, Potsdam, NY, United States,Department of Biology, Clarkson University, Potsdam, NY, United States
| | | | - Benjamin Ellis
- Department of Biology, Clarkson University, Potsdam, NY, United States
| | - Jillian Rose
- Department of Biology, Clarkson University, Potsdam, NY, United States
| | - Thomas Lufkin
- Department of Biology, Clarkson University, Potsdam, NY, United States
| | - Petra Kraus
- Department of Biology, Clarkson University, Potsdam, NY, United States,*Correspondence: Petra Kraus,
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Pezzanite LM, Chow L, Phillips J, Griffenhagen GM, Moore AR, Schaer TP, Engiles JB, Werpy N, Gilbertie J, Schnabel LV, Antczak D, Miller D, Dow S, Goodrich LR. TLR-activated mesenchymal stromal cell therapy and antibiotics to treat multi-drug resistant Staphylococcal septic arthritis in an equine model. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:1157. [PMID: 36467344 PMCID: PMC9708491 DOI: 10.21037/atm-22-1746] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 09/23/2022] [Indexed: 01/29/2024]
Abstract
BACKGROUND Rapid development of antibiotic resistance necessitates advancement of novel therapeutic strategies to treat infection. Mesenchymal stromal cells (MSC) possess antimicrobial and immunomodulatory properties, mediated through antimicrobial peptide secretion and recruitment of innate immune cells including neutrophils and monocytes. TLR-3 activation of human, canine and equine MSC has been shown to enhance bacterial killing and clearance in vitro, in rodent Staphylococcal biofilm infection models and dogs with spontaneous multi-drug-resistant infections. The objective of this study was to determine if intra-articular (IA) TLR-3-activated MSC with antibiotics improved clinical parameters and reduced bacterial counts and inflammatory cytokine concentrations in synovial fluid (SF) of horses with induced septic arthritis. METHODS Eight horses were inoculated in one tarsocrural joint with multidrug-resistant Staphylococcus aureus (S. aureus). Bone marrow-derived MSC from three unrelated donors were activated with TLR-3 agonist polyinosinic, polycytidylic acid (pIC). Recipient horses received MSC plus vancomycin (TLR-MSC-VAN), or vancomycin (VAN) alone, on days 1, 4, 7 post-inoculation and systemic gentamicin. Pain scores, quantitative bacterial counts (SF, synovium), SF analyses, complete blood counts, cytokine concentrations (SF, plasma), imaging changes (MRI, ultrasound, radiographs), macroscopic joint scores and histologic changes were assessed. Results were reported as mean ± SEM. RESULTS Pain scores (d7, P=0.01, 15.2±0.2 vs. 17.9±0.5), ultrasound (d7, P=0.03, 9.0±0.6 vs. 11.8±0.5), quantitative bacterial counts (SF d7, P=0.02, 0±0 vs. 3.4±0.4; synovium P=0.003, 0.4±0.4 vs. 162.7±18.4), systemic neutrophil (d4, P=0.03, 4.6±0.6 vs. 7.8±0.6) and serum amyloid A (SAA) (d4, P=0.01, 1,106.0±659.0 vs. 2,858.8±141.3; d7, P=0.02, 761.8±746.2 vs. 2,357.3±304.3), and SF lactate (d7, P<0.0001, 5.4±0.2 vs. 15.0±0.3), SAA (endterm, P=0.01, 0.0 vs. 2,094.0±601.6), IL-6 (P=0.03, 313.0±119.2 vs. 1,328.2±208.9), and IL-18 (P=0.02, 11.1±0.5 vs. 13.3±3.8) were improved in TLR-MSC-VAN vs. VAN horses. Study limitations include the small horse sample size, short study duration, and lack of additional control groups. CONCLUSIONS Combined TLR-activated MSC with antibiotic therapy may be a promising approach to manage joint infections with drug resistant bacteria.
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Affiliation(s)
- Lynn M. Pezzanite
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
| | - Lyndah Chow
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
| | - Jennifer Phillips
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
| | - Gregg M. Griffenhagen
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
| | - A. Russell Moore
- Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
| | - Thomas P. Schaer
- Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, USA
| | - Julie B. Engiles
- Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, USA
- Department of Pathobiology, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, USA
| | | | - Jessica Gilbertie
- Department of Microbiology and Immunology, Edward Via College of Osteopathic Medicine, Blacksburg, VA, USA
| | - Lauren V. Schnabel
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, North Carolina State University, Raleigh, NC, USA
| | - Doug Antczak
- Baker Institute, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Donald Miller
- Baker Institute, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Steven Dow
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
- Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
| | - Laurie R. Goodrich
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
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Gilazieva Z, Chulpanova D, Ponomarev A, Filin I, Garanina E, Rizvanov A, Solovyeva V. Comparative Analysis of Natural and Cytochalasin B-Induced Membrane Vesicles from Tumor Cells and Mesenchymal Stem Cells. Curr Issues Mol Biol 2022; 44:5363-5378. [PMID: 36354675 PMCID: PMC9688684 DOI: 10.3390/cimb44110363] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 04/15/2025] Open
Abstract
To date, there are numerous protocols for the isolation of extracellular vesicles (EVs). Depending on the isolation method, it is possible to obtain vesicles with different characteristics, enriched with specific groups of proteins, DNA and RNA, which affect similar types of cells in the opposite way. Therefore, it is important to study and compare methods of vesicle isolation. Moreover, the differences between the EVs derived from tumor and mesenchymal stem cells are still poorly understood. This article compares EVs from human glioblastoma cells and mesenchymal stem cells (MSCs) obtained by two different methods, ultracentrifugation and cytochalasin B-mediated induction. The size of the vesicles, the presence of the main EV markers, the presence of nuclear and mitochondrial components, and the molecular composition of the vesicles were determined. It has been shown that EVs obtained by both ultracentrifugation and cytochalasin B treatment have similar features, contain particles of endogenous and membrane origin and can interact with monolayer cultures of tumor cells.
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Affiliation(s)
| | | | | | | | | | | | - Valeriya Solovyeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
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36
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Yan L, Zheng H, Zhang H, Dai L, Zhang Q. Is mesenchymal stem cell effective for allergic rhinitis? A protocol for a systematic review and meta-analysis. BMJ Open 2022; 12:e062435. [PMID: 36270760 PMCID: PMC9594526 DOI: 10.1136/bmjopen-2022-062435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
INTRODUCTION Allergic rhinitis (AR) is a kind of widespread but unrecognised inflammatory disorder of nasal mucosa, characterised by itching, sneezing, runny nose and nasal congestion. The efficacy of mesenchymal stem cells (MSCs) in the treatment of AR remains controversial. This protocol describes a systematic review and meta-analysis approach to assess the efficacy and safety of MSCs in the treatment of AR. METHODS AND ANALYSIS Eight databases (PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, VIP and Wanfang) will be searched from the database inception to 1 December 2023. All randomised controlled trials related to MSCs for AR will be included. The primary outcomes will be therapeutic effect, serum IgE index and Visual Analogue Scale score for nasal symptoms. Risk of bias will be assessed using the Cochrane Collaboration's tool for assessing risk of bias. Article selection, data extraction and risk of bias assessment will be performed in duplicate by two independent reviewers. ETHICS AND DISSEMINATION Ethics approval is not required because individual patient data are not included. This protocol was registered in the international Prospective Register of Systematic Reviews on 22 January 2022. The systematic review and meta-analysis will be submitted for publication in a peer-reviewed journal. The findings will also be disseminated through conference presentations. PROSPERO REGISTRATION NUMBER CRD42022303146.
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Affiliation(s)
- Le Yan
- School of Medical and Life Sciences, Chengdu College of Traditional Chinese Medicine, Chengdu, China
| | - Hanxue Zheng
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese, Chengdu, Sichuan, China
| | - Huiping Zhang
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lintong Dai
- Panzhihua City Hospital of Integrated Traditional Chinese and Western Medicine, Panzhihua, Sichuan, China
| | - Qinxiu Zhang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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Koivunotko E, Snirvi J, Merivaara A, Harjumäki R, Rautiainen S, Kelloniemi M, Kuismanen K, Miettinen S, Yliperttula M, Koivuniemi R. Angiogenic Potential of Human Adipose-Derived Mesenchymal Stromal Cells in Nanofibrillated Cellulose Hydrogel. Biomedicines 2022; 10:2584. [PMID: 36289846 PMCID: PMC9599553 DOI: 10.3390/biomedicines10102584] [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: 07/11/2022] [Revised: 10/05/2022] [Accepted: 10/13/2022] [Indexed: 11/16/2022] Open
Abstract
Adipose-derived mesenchymal stromal cells (ASCs) hold great potential for cellular therapies by having immunomodulatory behavior and tissue regenerative properties. Due to the capability of ASCs to differentiate into endothelial cells (ECs) and other angiogenic cell types, such as pericytes, ASCs are a highly valuable source for stimulating angiogenesis. However, cellular therapies in tissue engineering have faced challenges in poor survival of the cells after transplantation, which is why a protective biomaterial scaffold is required. In this work, we studied the potential of nanofibrillated cellulose (NFC) hydrogel to be utilized as a suitable matrix for three-dimensional (3D) cell culturing of human-derived ASCs (hASCs) and studied their angiogenic properties and differentiation potential in ECs and pericytes. In addition, we tested the effect of hASC-conditioned medium and stimulation with angiopoietin-1 (Ang-1) on human umbilical vein endothelial cells (HUVECs) to induce blood vessel-type tube formation in NFC hydrogel. The hASCs were successfully 3D cell cultured in NFC hydrogel as they formed spheroids and had high cell viability with angiogenic features. Most importantly, they showed angiogenic potential by having pericyte-like characteristics when differentiated in EC medium, and their conditioned medium improved HUVEC viability and tube formation, which recalls the active paracrine properties. This study recommends NFC hydrogel for future use as an animal-free biomaterial scaffold for hASCs in therapeutic angiogenesis and other cell therapy purposes.
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Affiliation(s)
- Elle Koivunotko
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, 00790 Helsinki, Finland
| | - Jasmi Snirvi
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, 00790 Helsinki, Finland
| | - Arto Merivaara
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, 00790 Helsinki, Finland
| | - Riina Harjumäki
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, 00790 Helsinki, Finland
| | - Swarna Rautiainen
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, 00790 Helsinki, Finland
| | - Minna Kelloniemi
- Department of Plastic and Reconstructive Surgery, Tampere University Hospital, 33520 Tampere, Finland
| | - Kirsi Kuismanen
- Department of Obstetrics and Gynecology, Tampere University Hospital, 33520 Tampere, Finland
| | - Susanna Miettinen
- Faculty of Medicine and Health Technologies, University of Tampere, 33520 Tampere, Finland
- Research, Development and Innovation Centre, Tampere University Hospital, 33520 Tampere, Finland
| | - Marjo Yliperttula
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, 00790 Helsinki, Finland
| | - Raili Koivuniemi
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, 00790 Helsinki, Finland
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Sharma K, Zhang Y, Paudel KR, Kachelmeier A, Hansbro PM, Shi X. The Emerging Role of Pericyte-Derived Extracellular Vesicles in Vascular and Neurological Health. Cells 2022; 11:cells11193108. [PMID: 36231071 PMCID: PMC9563036 DOI: 10.3390/cells11193108] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/27/2022] [Accepted: 09/30/2022] [Indexed: 12/02/2022] Open
Abstract
Pericytes (PCs), as a central component of the neurovascular unit, contribute to the regenerative potential of the central nervous system (CNS) and peripheral nervous system (PNS) by virtue of their role in blood flow regulation, angiogenesis, maintenance of the BBB, neurogenesis, and neuroprotection. Emerging evidence indicates that PCs also have a role in mediating cell-to-cell communication through the secretion of extracellular vesicles (EVs). Extracellular vesicles are cell-derived, micro- to nano-sized vesicles that transport cell constituents such as proteins, nucleic acids, and lipids from a parent originating cell to a recipient cell. PC-derived EVs (PC-EVs) play a crucial homeostatic role in neurovascular disease, as they promote angiogenesis, maintain the integrity of the blood-tissue barrier, and provide neuroprotection. The cargo carried by PC-EVs includes growth factors such as endothelial growth factor (VEGF), connecting tissue growth factors (CTGFs), fibroblast growth factors, angiopoietin 1, and neurotrophic growth factors such as brain-derived neurotrophic growth factor (BDNF), neuron growth factor (NGF), and glial-derived neurotrophic factor (GDNF), as well as cytokines such as interleukin (IL)-6, IL-8, IL-10, and MCP-1. The PC-EVs also carry miRNA and circular RNA linked to neurovascular health and the progression of several vascular and neuronal diseases. Therapeutic strategies employing PC-EVs have potential in the treatment of vascular and neurodegenerative diseases. This review discusses current research on the characteristic features of EVs secreted by PCs and their role in neuronal and vascular health and disease.
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Affiliation(s)
- Kushal Sharma
- Oregon Hearing Research Center, Department of Otolaryngology/Head & Neck Surgery, Oregon Health & Science University, Portland, OR 97239, USA
| | - Yunpei Zhang
- Oregon Hearing Research Center, Department of Otolaryngology/Head & Neck Surgery, Oregon Health & Science University, Portland, OR 97239, USA
| | - Keshav Raj Paudel
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW 2007, Australia
| | - Allan Kachelmeier
- Oregon Hearing Research Center, Department of Otolaryngology/Head & Neck Surgery, Oregon Health & Science University, Portland, OR 97239, USA
| | - Philip M. Hansbro
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW 2007, Australia
| | - Xiaorui Shi
- Oregon Hearing Research Center, Department of Otolaryngology/Head & Neck Surgery, Oregon Health & Science University, Portland, OR 97239, USA
- Correspondence: ; Tel.: +1-503-494-2997
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Dadgar N, Altemus J, Li Y, Lightner AL. Effect of Crohn's disease mesenteric mesenchymal stem cells and their extracellular vesicles on T-cell immunosuppressive capacity. J Cell Mol Med 2022; 26:4924-4939. [PMID: 36047483 PMCID: PMC9549497 DOI: 10.1111/jcmm.17483] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 06/07/2022] [Accepted: 06/26/2022] [Indexed: 11/27/2022] Open
Abstract
Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal intestinal tract and has characteristic hypertrophic adipose changes observed in the mesentery. To better understand the role of the mesentery in the pathophysiology of Crohn's disease (CD), we evaluated the immunomodulatory potential of mesenchymal stem cells (MSCs) and their secreted extracellular vesicles (EVs) derived from Crohn's patients. MSCs and EVs were isolated from the mesentery and subcutaneous tissues of CD patients and healthy individuals subcutaneous tissues, and were analysed for differentiation, cytokine expression, self‐renewal and proliferation. The varying capacity of these tissue‐derived MSCs and EVs to attenuate T‐cell activation was measured in in vitro and an in vivo murine model. RNA sequencing of inflamed Crohn's disease mesentery tissue revealed an enrichment of T‐cell activation compared to non‐inflamed subcutaneous tissue. MSCs and MSC‐derived EVs isolated from Crohn's mesentery lose their ability to attenuate DSS‐induced colitis compared to subcutaneous tissue‐derived cell or EV therapy. We found that treatment with subcutaneous isolated MSCs and their EV product compared to Crohn's mesentery MSCs or EVs, the inhibition of T‐cell proliferation and IFN‐γ, IL‐17a production increased, suggesting a non‐inflamed microenvironment allows for T‐cell inhibition by MSCs/EVs. Our results demonstrate that Crohn's patient‐derived diseased mesentery tissue MSCs lose their immunosuppressive capacity in the treatment of colitis by distinct regulation of pathogenic T‐cell responses and/or T‐cell infiltration into the colon.
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Affiliation(s)
- Neda Dadgar
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland, Ohio, USA.,Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, Ohio, USA
| | - Jessica Altemus
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, Ohio, USA
| | - Yan Li
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland, Ohio, USA
| | - Amy L Lightner
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland, Ohio, USA.,Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, Ohio, USA
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40
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Lam J, Lee B, Yu J, Kwee BJ, Kim Y, Kim J, Choi Y, Yoon JS, Kim Y, Baek K, Jeon NL, Sung KE. A microphysiological system-based potency bioassay for the functional quality assessment of mesenchymal stromal cells targeting vasculogenesis. Biomaterials 2022; 290:121826. [DOI: 10.1016/j.biomaterials.2022.121826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 09/20/2022] [Accepted: 09/24/2022] [Indexed: 11/02/2022]
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Jantalika T, Manochantr S, Kheolamai P, Tantikanlayaporn D, Saijuntha W, Pinlaor S, Chairoungdua A, Paraoan L, Tantrawatpan C. Human chorion-derived mesenchymal stem cells suppress JAK2/STAT3 signaling and induce apoptosis of cholangiocarcinoma cell lines. Sci Rep 2022; 12:11341. [PMID: 35790790 PMCID: PMC9256624 DOI: 10.1038/s41598-022-15298-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 06/22/2022] [Indexed: 11/09/2022] Open
Abstract
Cholangiocarcinoma (CCA) is an aggressive malignancy arising from the damaged epithelial cells of the biliary tract. Previous studies have reported that the multi-potent mesenchymal stem cells (MSCs) activate a series of tumor signaling pathways by releasing several cytokines to influence tumor cell development. However, the roles and mechanisms of human chorion-derived MSCs (CH-MSCs) in cholangiocarcinoma progression have not been fully addressed. This present study aims to examine the effects of conditioned media derived from CH-MSCs (CH-CM) on CCA cell lines and investigate the respective underlying mechanism of action. For this purpose, MSCs were isolated from chorion tissue, and three cholangiocarcinoma cell lines, namely KKU100, KKU213A, and KKU213B, were used. MTT assay, annexin V/PI analysis, and JC-1 staining were used to assess the effects of CH-CM on proliferation and apoptosis of CCA cells, respectively. Moreover, the effect of CH-CM on caspase-dependent apoptotic pathways was also evaluated. The western blotting assay was also used for measuring the expression of JAK2/STAT3 signaling pathway-associated proteins. The results showed that CH-CM suppressed proliferation and promoted apoptosis of CCA cell lines. CH-CM treatment-induced loss of mitochondrial membrane potential (∆Ψm) in CCA cell lines. The factors presented in the CH-CM also inhibited JAK2/STAT3 signaling, reduced the expression of BCL-2, and increased BAX expression in CCA cells. In conclusion, our study suggests that the CH-CM has a potent anti-cancer effect on cholangiocarcinoma cells and thus provides opportunities for use in alternative cell therapy or in combination with a conventional chemotherapeutic drug to increase the efficiency of CCA treatment.
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Affiliation(s)
- Tanachapa Jantalika
- Division of Cell Biology, Department of Preclinical Sciences, Faculty of Medicine, Thammasat University, Pathumthani, 12120, Thailand.,Center of Excellence in Stem Cell Research, Thammasat University, Pathumthani, 12120, Thailand
| | - Sirikul Manochantr
- Division of Cell Biology, Department of Preclinical Sciences, Faculty of Medicine, Thammasat University, Pathumthani, 12120, Thailand.,Center of Excellence in Stem Cell Research, Thammasat University, Pathumthani, 12120, Thailand
| | - Pakpoom Kheolamai
- Division of Cell Biology, Department of Preclinical Sciences, Faculty of Medicine, Thammasat University, Pathumthani, 12120, Thailand.,Center of Excellence in Stem Cell Research, Thammasat University, Pathumthani, 12120, Thailand
| | - Duangrat Tantikanlayaporn
- Division of Cell Biology, Department of Preclinical Sciences, Faculty of Medicine, Thammasat University, Pathumthani, 12120, Thailand.,Center of Excellence in Stem Cell Research, Thammasat University, Pathumthani, 12120, Thailand
| | - Weerachai Saijuntha
- Biodiversity and Conservation Research Unit, Walai Rukhavej Botanical Research Institute (WRBRI), Mahasarakham University, Maha Sarakham, 44150, Thailand
| | - Somchai Pinlaor
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Arthit Chairoungdua
- Department of Physiology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand
| | - Luminita Paraoan
- Department of Biology, Faculty of Arts and Sciences, Edge Hill University, BioSciences Building, St Helens Road, Ormskirk, L39 4QP, UK.
| | - Chairat Tantrawatpan
- Division of Cell Biology, Department of Preclinical Sciences, Faculty of Medicine, Thammasat University, Pathumthani, 12120, Thailand. .,Center of Excellence in Stem Cell Research, Thammasat University, Pathumthani, 12120, Thailand.
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Bahmani L, Ullah M. Different Sourced Extracellular Vesicles and Their Potential Applications in Clinical Treatments. Cells 2022; 11:1989. [PMID: 35805074 PMCID: PMC9265969 DOI: 10.3390/cells11131989] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/19/2022] [Accepted: 06/20/2022] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) include a heterogeneous group of natural cell-derived nanostructures that are increasingly regarded as promising biotherapeutic agents and drug delivery vehicles in human medicine. Desirable intrinsic properties of EVs including the ability to bypass natural membranous barriers and to deliver their unique biomolecular cargo to specific cell populations position them as fiercely competitive alternatives for currently available cell therapies and artificial drug delivery platforms. EVs with distinct characteristics can be released from various cell types into the extracellular environment as a means of transmitting bioactive components and altering the status of the target cell. Despite the existence of a large number of preclinical studies confirming the therapeutic efficacy of different originated EVs for treating several pathological conditions, in this review, we first provide a brief overview of EV biophysical properties with an emphasis on their intrinsic therapeutic benefits over cell-based therapies and synthetic delivery systems. Next, we describe in detail different EVs derived from distinct cell sources, compare their advantages and disadvantages, and recapitulate their therapeutic effects on various human disorders to highlight the progress made in harnessing EVs for clinical applications. Finally, knowledge gaps and concrete hurdles that currently hinder the clinical translation of EV therapies are debated with a futuristic perspective.
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Affiliation(s)
- Leila Bahmani
- Institute for Immunity and Transplantation, Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Palo Alto, CA 94304, USA;
- Molecular Medicine Department of Medicine, Stanford University, Palo Alto, CA 94304, USA
| | - Mujib Ullah
- Institute for Immunity and Transplantation, Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Palo Alto, CA 94304, USA;
- Molecular Medicine Department of Medicine, Stanford University, Palo Alto, CA 94304, USA
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Edwards SD, Hou S, Brown JM, Boudreau RD, Lee Y, Kim YJ, Jeong KJ. Fast-Curing Injectable Microporous Hydrogel for In Situ Cell Encapsulation. ACS APPLIED BIO MATERIALS 2022; 5:2786-2794. [PMID: 35576622 DOI: 10.1021/acsabm.2c00214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Seth D. Edwards
- Department of Chemical Engineering, University of New Hampshire, Durham, New Hampshire 03824, United States
| | - Shujie Hou
- Department of Chemical Engineering, University of New Hampshire, Durham, New Hampshire 03824, United States
| | - Jason M. Brown
- Department of Chemical Engineering, University of New Hampshire, Durham, New Hampshire 03824, United States
| | - Ryann D. Boudreau
- Department of Chemical Engineering, University of New Hampshire, Durham, New Hampshire 03824, United States
| | - Yuhan Lee
- Engineering in Medicine, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Young Jo Kim
- Department of Chemical Engineering, University of New Hampshire, Durham, New Hampshire 03824, United States
| | - Kyung Jae Jeong
- Department of Chemical Engineering, University of New Hampshire, Durham, New Hampshire 03824, United States
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Sarvar DP, Effatpanah H, Akbarzadehlaleh P, Shamsasenjan K. Mesenchymal stromal cell-derived extracellular vesicles: novel approach in hematopoietic stem cell transplantation. Stem Cell Res Ther 2022; 13:202. [PMID: 35578300 PMCID: PMC9109321 DOI: 10.1186/s13287-022-02875-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 12/24/2021] [Indexed: 11/24/2022] Open
Abstract
Bone marrow mesenchymal stromal cells (MSCs) play a crucial role in the regulation of hematopoiesis. These cells affect the process through direct cell–cell contact, as well as releasing various trophic factors and extracellular vehicles (EVs) into the bone marrow microenvironment. MSC-derived EVs (MSC-EVs) are prominent intercellular communication tolls enriched with broad-spectrum bioactive factors such as proteins, cytokines, lipids, miRNAs, and siRNAs. They mimic some effects of MSCs by direct fusion with hematopoietic stem cells (HSC) membranes in the bone marrow (BM), thereby affecting HSC fate. MSC-EVs are attractive scope in cell-free therapy because of their unique capacity to repair BM tissue and regulate proliferation and differentiation of HSCs. These vesicles modulate the immune system responses and inhibit graft-versus-host disease following hematopoietic stem cell transplantation (HSCT). Recent studies have demonstrated that MSC-EVs play an influential role in the BM niches because of their unprecedented capacity to regulate HSC fate. Therefore, the existing paper intends to speculate upon the preconditioned MSC-EVs as a novel approach in HSCT.
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Affiliation(s)
| | | | - Parvin Akbarzadehlaleh
- Department of Pharmaceutical Biotechnology, Tabriz University of Medical Science, Tabriz, Iran
| | - Karim Shamsasenjan
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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45
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He X, Li C, Yin H, Tan X, Yi J, Tian S, Wang Y, Liu J. Mesenchymal stem cells inhibited the apoptosis of alveolar epithelial cells caused by ARDS through CXCL12/CXCR4 axis. Bioengineered 2022; 13:9060-9070. [PMID: 35301927 PMCID: PMC9161978 DOI: 10.1080/21655979.2022.2052652] [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] [Indexed: 11/07/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have a wide range of anti-inflammatory and immunomodulatory effects and have been observed to have potential therapeutic potential in the clinical treatment of various diseases. We pretreated lung cancer cells A549 with tumor necrosis factor (TNF-α), knocked down the key chemokine receptor CXCR4 on MSCs using lentivirus, and induced acute respiratory distress syndrome (ARDS) mouse model using lipopolysaccharide (LPS) and CXCL12 expression in vivo by adeno-associated virus (AAV-rh10) infection in mice. By co-culturing the MSCs with A549 and in vivo experiments, we observed the effects of MSCs on cell biological functions after inflammatory stimulation, oxidative stress, and the amelioration of lung injury in ARDS mice. TNF-α inhibited A549 proliferation and promoted apoptosis, scorch death-related factor activity, and oxidative stress factor were increased and CXCL12 levels in the cell supernatant were decreased. The co-culture of MSCs was able to increase cell activity and decrease oxidative stress factor levels, and this effect was not present after the knockdown of CXCR4 in MSCs. In vivo transplantation of MSCs significantly attenuated lung injury in ARDS, inhibited serum pro-inflammatory factors in mice, and down-regulated expression of apoptotic and focal factors in lung tissues while blocking CXCR4 or CXCL12 lost the repairing effect of MSCs on ARDS lung tissues. After the co-culture of MSC and lung cancer cells, the expression of CXCR4 on the surface of lung cancer cells was significantly increased, and more CXCR4 and CXCL12 acted together to activate more pro-survival pathways and inhibit apoptosis induced by TNF-α.
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Affiliation(s)
| | | | | | | | - Jun Yi
- Xiangtan Central Hospital
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Henriques-Pons A, Beghini DG, Silva VDS, Iwao Horita S, da Silva FAB. Pulmonary Mesenchymal Stem Cells in Mild Cases of COVID-19 Are Dedicated to Proliferation; In Severe Cases, They Control Inflammation, Make Cell Dispersion, and Tissue Regeneration. Front Immunol 2022; 12:780900. [PMID: 35095855 PMCID: PMC8793136 DOI: 10.3389/fimmu.2021.780900] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/17/2021] [Indexed: 12/29/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have potent self-renewal capacity and differentiate into multiple cell types. For many reasons, these cells are a promising therapeutic alternative to treat patients with severe COVID-19 and pulmonary post-COVID sequelae. These cells are not only essential for tissue regeneration; they can also alter the pulmonary environment through the paracrine secretion of several mediators. They can control or promote inflammation, induce other stem cells differentiation, restrain the virus load, and much more. In this work, we performed single-cell RNA-seq data analysis of MSCs in bronchoalveolar lavage samples from control individuals and COVID-19 patients with mild and severe clinical conditions. When we compared samples from mild cases with control individuals, most genes transcriptionally upregulated in COVID-19 were involved in cell proliferation. However, a new set of genes with distinct biological functions was upregulated when we compared severely affected with mild COVID-19 patients. In this analysis, the cells upregulated genes related to cell dispersion/migration and induced the γ-activated sequence (GAS) genes, probably triggered by IFNGR1 and IFNGR2. Then, IRF-1 was upregulated, one of the GAS target genes, leading to the interferon-stimulated response (ISR) and the overexpression of many signature target genes. The MSCs also upregulated genes involved in the mesenchymal-epithelial transition, virus control, cell chemotaxis, and used the cytoplasmic RNA danger sensors RIG-1, MDA5, and PKR. In a non-comparative analysis, we observed that MSCs from severe cases do not express many NF-κB upstream receptors, such as Toll-like (TLRs) TLR-3, -7, and -8; tumor necrosis factor (TNFR1 or TNFR2), RANK, CD40, and IL-1R1. Indeed, many NF-κB inhibitors were upregulated, including PPP2CB, OPTN, NFKBIA, and FHL2, suggesting that MSCs do not play a role in the "cytokine storm" observed. Therefore, lung MSCs in COVID-19 sense immune danger and act protectively in concert with the pulmonary environment, confirming their therapeutic potential in cell-based therapy for COVID-19. The transcription of MSCs senescence markers is discussed.
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Affiliation(s)
- Andrea Henriques-Pons
- Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Rio de Janeiro, Brazil
| | - Daniela Gois Beghini
- Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Rio de Janeiro, Brazil
| | | | - Samuel Iwao Horita
- Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Rio de Janeiro, Brazil
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Characteristics of Pooled Wharton's Jelly Mesenchymal Stromal Cells (WJ-MSCs) and their Potential Role in Rheumatoid Arthritis Treatment. Stem Cell Rev Rep 2022; 18:1851-1864. [PMID: 35113368 DOI: 10.1007/s12015-022-10344-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2022] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Mesenchymal stromal cells (MSC) from Wharton's jelly of umbilical cord is primitive and serve as an inexhaustible source of stem cells with greater potential in clinics. The existence of heterogeneity among the donor MSCs makes it difficult to predict the properties and clinical outcome of WJ-MSCs. We developed a strategy to minimize the donor to donor heterogeneity and produce consistency in biological properties by pooling three individual donors WJ-MSCs. Further, evaluated the effectiveness of the pooled MSCs in regulating the disease severity of Rheumatoid arthritis (RA) in animal models. METHODS WJ-MSCs were isolated from umbilical cord obtained from different donors, characterised and pooled based on the gender of baby. The biological properties of the pooled WJ-MSCs were compared to the individual WJ-MSCs. Further, the pooled WJ-MSCs were analysed for their safety profile in both in vitro and in vivo settings. The efficiency of pooled WJ-MSCs in regulating RA pathogenesis was also analysed in mice models of Collagen induced arthritis (CIA). RESULTS We identified differences in proliferation capacity, pro inflammatory gene expression levels among individual WJ-MSCs isolated from different donors and the variation is also attributed to gender difference. WJ-MSCs pooled and cultured from different donor's exhibit all the MSC characteristics and exhibited superior immunosuppressive capabilities. In the in vivo toxicity study, pooled MSCs are found to be safe, and further in the RA preclinical studies, they were found to decrease the disease severity in these animals. CONCLUSIONS Pooled WJ-MSCs reduces heterogeneity of individual donors and have superior immunosuppressive property. It is also effective in reducing the disease severity in the experimental animal models of RA.
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Muthu S, Mir AA, Kumar R, Yadav V, Jeyaraman M, Khanna M. What is the clinically significant ideal mesenchymal stromal cell count in the management of osteoarthritis of the knee? - Meta-analysis of randomized controlled trials. J Clin Orthop Trauma 2022; 25:101744. [PMID: 35004170 PMCID: PMC8719017 DOI: 10.1016/j.jcot.2021.101744] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 12/17/2021] [Indexed: 02/08/2023] Open
Abstract
STUDY DESIGN Meta-analysis. OBJECTIVES We aim to identify the clinically significant ideal Mesenchymal Stem Cell (MSC) count in the management of osteoarthritis of knee from Randomized Controlled Trials (RCTs) available in the literature. MATERIALS AND METHODS We conducted independent and duplicate electronic database searches including PubMed, Embase, Web of Science, and Cochrane Library till August 2021 for RCTs conducted in the management of knee osteoarthritis using MSC therapy specifying the quantity of MSCs delivered. We categorized the studies based on the MSC count utilized in them into four groups namely <1 × 107 MSCs (Group I), 1-5x107 MSCs (Group II), 5-10 × 107 MSCs (Group III), and >10 × 107 MSCs (Group IV). Visual Analog Score (VAS) for Pain, Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), Lysholm score, Knee Osteoarthritis Outcome Score (KOOS), and adverse events were the outcomes analyzed. Analysis was performed in R-platform using OpenMeta [Analyst] software. RESULTS 14 studies involving 564 patients were included for analysis. We noted incremental decrease in the VAS with increasing dosage of MSCs at 12 months [Group I,WMD = 2.641(p = 0.854); Group II, WMD = -4.853(p = 0.379); Group III, WMD = -12.154 (p = 0.316); Group IV, WMD = -15.935(p = 0.116)], and 24 months [Group I,WMD = -6(p = 0.001); Group II, WMD = -15(p = 0.001); Group IV, WMD = -20(p = 0.001)]. We also noted incremental improvement in the WOMAC, KOOS with increasing dosage of MSCs at 12 months [Group I, WMD = 7(p = 0.001); Group II, WMD = 28(p = 0.001); Group IV, WMD = 30(p = 0.001)] and [Group II, WMD = -2.562(p = 0.676); Group III, WMD = 7.670(p = 0.099); Group IV, WMD = 13.475(p = 0.261)] respectively. However, we noted significant reduction in the Lysholm score in Group IV, compared to the others at 12 months (WMD = -12.5, 95%CI[-25.883,0.883]) and 24 months (WMD = -6.6, 95%CI[-23.596,10.396]). We did not find any significant increase in the adverse events with incremental dosage of MSCs in any of the groups compared. CONCLUSION Compared to the four dosage groups of MSCs analyzed, Group III showed consistent significant improvement in pain and functional outcomes analyzed compared to the other groups. Hence, we recommend a cell volume of 5-10 × 107 cells to be delivered to the target site to obtain superior benefits out of the procedure. However, we urge future trials of sufficient quality to validate our findings to arrive at a consensus on the ideal count of MSCs to be delivered in the cellular therapy for knee osteoarthritis.
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Affiliation(s)
- Sathish Muthu
- Department of Orthopaedics, Government Medical College and Hospital, Dindigul, Tamil Nadu, India
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, India
| | - Ayaz Ali Mir
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, India
- Fellow in Orthopaedic Rheumatology, Dr. RML National Law University, Lucknow, Uttar Pradesh, India
| | - Rakesh Kumar
- Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Vijendra Yadav
- Department of Orthopaedics, Sanjay Gandhi Institute of Trauma & Orthopaedics, Bengaluru, Karnataka, India
| | - Madhan Jeyaraman
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, India
- Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Manish Khanna
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, India
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Mesenchymal stem cell (MSC)-derived exosomes as novel vehicles for delivery of miRNAs in cancer therapy. Cancer Gene Ther 2022; 29:1105-1116. [PMID: 35082400 DOI: 10.1038/s41417-022-00427-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 12/11/2021] [Accepted: 01/14/2022] [Indexed: 12/15/2022]
Abstract
Mesenchymal stem cells (MSCs) are known as promising sources for cancer therapy and can be utilized as vehicles in cancer gene therapy. MSC-derived exosomes are central mediators in the therapeutic functions of MSCs, known as the novel cell-free alternatives to MSC-based cell therapy. MSC-derived exosomes show advantages including higher safety as well as more stability and convenience for storage, transport and administration compared to MSCs transplant therapy. Unmodified MSC-derived exosomes can promote or inhibit tumors while modified MSC-derived exosomes are involved in the suppression of cancer development and progression via the delivery of several therapeutics molecules including chemotherapeutic drugs, miRNAs, anti-miRNAs, specific siRNAs, and suicide gene mRNAs. In most malignancies, dysregulation of miRNAs not only occurs as a consequence of cancer progression but also is directly involved during tumor initiation and development due to their roles as oncogenes (oncomiRs) or tumor suppressors (TS-miRNAs). MiRNA restoration is usually achieved by overexpression of TS-miRNAs using synthetic miRNA mimics and viral vectors or even downregulation of oncomiRs using anti-miRNAs. Similar to other therapeutic molecules, the efficacy of miRNAs restoration in cancer therapy depends on the effectiveness of the delivery system. In the present review, we first provided an overview of the properties and potentials of MSCs in cancer therapy as well as the application of MSC-derived exosomes in cancer therapy. Finally, we specifically focused on harnessing the MSC-derived exosomes for the aim of miRNA delivery in cancer therapy.
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50
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Anders S, Grifka J. [Surgical treatment of focal cartilage defects in the knee : Indications, techniques, modifications and results]. DER ORTHOPADE 2022; 51:151-164. [PMID: 35076725 DOI: 10.1007/s00132-022-04220-1] [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: 11/26/2022]
Abstract
The treatment strategies for focal cartilage damage in the knee are multifarious. For established procedures, such as microfracturing (MFX), autologous matrix-induced chondrogenesis (AMIC), osteochondral transplantation (OCT) and autologous chondrocyte transplantation (ACT), well-founded, partly comparative long-term studies and overlapping size-dependent differential indications are available. Innovative cell sources, the utilization of biological scaffolds as well as biologic agents and various combinations, have recently become the focus of scientific attention; however, high regulatory demands are restricting their use in Germany. The success of every procedure is dependent on the appropriate indications, the treatment of comorbidities, such as axis deviations or ligamentous instability, the surgeon's experience and an adequate follow-up treatment.
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Affiliation(s)
- S Anders
- Orthopädische Klinik für die Universität Regensburg, Asklepios Klinikum Bad Abbach, Kaiser-Karl V.-Allee 3, 93077, Bad Abbach, Deutschland.
| | - J Grifka
- Orthopädische Klinik für die Universität Regensburg, Asklepios Klinikum Bad Abbach, Kaiser-Karl V.-Allee 3, 93077, Bad Abbach, Deutschland
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