|
1
|
Ma L, Fink J, Yao K, McDonald-Hyman C, Dougherty P, Koehn B, Blazar BR. Immunoregulatory iPSC-derived non-lymphoid progeny in autoimmunity and GVHD alloimmunity. Stem Cells 2025; 43:sxaf011. [PMID: 40103180 DOI: 10.1093/stmcls/sxaf011] [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: 12/19/2024] [Accepted: 02/19/2025] [Indexed: 03/20/2025]
Abstract
Non-lymphoid immunoregulatory cells, including mesenchymal stem cells (MSCs), myeloid-derived suppressor cells (MDSCs), regulatory macrophages (Mregs), and tolerogenic dendritic cells (Tol-DCs), play critical roles in maintaining immune homeostasis. However, their therapeutic application in autoimmune diseases and graft-versus-host disease (GVHD) has received comparatively less attention. Induced pluripotent stem cells (iPSCs) offer a promising platform for cell engineering, enabling superior quality control, scalable production, and large-scale in vitro expansion of iPSC-derived non-lymphoid immunoregulatory cells. These advances pave the way for their broader application in autoimmune disease and GVHD therapy. Recent innovations in iPSC differentiation protocols have facilitated the generation of these cell types with functional characteristics akin to their primary counterparts. This review explores the unique features and generation processes of iPSC-derived non-lymphoid immunoregulatory cells, their therapeutic potential in GVHD and autoimmune disease, and their progress toward clinical translation. It emphasizes the phenotypic and functional diversity within each cell type and their distinct effects on disease modulation. Despite these advancements, challenges persist in optimizing differentiation efficiency, ensuring functional stability, and bridging the gap to clinical application. By synthesizing current methodologies, preclinical findings, and translational efforts, this review underscores the transformative potential of iPSC-derived non-lymphoid immunoregulatory cells in advancing cell-based therapies for alloimmune and autoimmune diseases.
Collapse
Affiliation(s)
- Lie Ma
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
| | - Jordan Fink
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
| | - Ke Yao
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
| | - Cameron McDonald-Hyman
- Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, United States
| | - Phillip Dougherty
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
| | - Brent Koehn
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
| | - Bruce R Blazar
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
| |
Collapse
|
|
2
|
Xu W, Yi F, Liao H, Zhu C, Zou X, Dong Y, Zhou W, Sun Z, Yin J. The Potential and Challenges of Human Pluripotent Stem Cells in the Treatment of Diabetic Nephropathy. FRONT BIOSCI-LANDMRK 2025; 30:28283. [PMID: 40302328 DOI: 10.31083/fbl28283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/28/2024] [Accepted: 01/07/2025] [Indexed: 05/02/2025]
Abstract
Diabetic nephropathy (DN) is a prevalent complication of diabetes, with current treatment options offering limited effectiveness, particularly in advanced stages. Human pluripotent stem cells (hPSCs), particularly induced PSCs (iPSCs), show promising potential in the treatment of DN due to their pluripotency, capacity for differentiation into kidney-specific cells, and suitability for personalized therapies. iPSC-based personalized approaches can effectively mitigate immune rejection, a common challenge with allogeneic transplants, thus enhancing therapeutic outcomes. Clustered regularly interspaced short palindromic repeats (CRISPR) gene editing further enhances the potential of hPSCs by enabling the precise correction of disease-associated genetic defects, increasing both the safety and efficacy of therapeutic cells. In addition to direct treatment, hPSCs have proven valuable in disease modeling and drug screening, particularly for identifying and validating disease-specific targets. Kidney organoids derived from hPSCs replicate key features of DN pathology, making them useful platforms for validating therapeutic targets and assessing drug efficacy. Comparatively, both hPSCs and mesenchymal SCs (MSCs) have shown promise in improving renal function in preclinical models, with hPSCs offering broader differentiation capacity. Integration with tissue engineering technologies, such as three-dimensional bioprinting and bioengineered scaffolds, expands the regenerative potential of hPSCs by supporting the formation of functional renal structures and enhancing in vivo integration and regenerative capacity. Despite current challenges, such as tumorigenicity, genomic instability, and limited direct research, advances in gene editing, differentiation protocols, and tissue engineering promise to address these barriers. Continued optimization of these approaches will likely lead to successful clinical applications of hPSCs, potentially revolutionizing treatment options for DN.
Collapse
Affiliation(s)
- Wanyue Xu
- Nephrology Department, Hangzhou Hospital of Traditional Chinese Medicine, 310007 Hangzhou, Zhejiang, China
| | - Fangyu Yi
- Hangzhou Clinical College, Zhejiang Chinese Medical University, 310053 Hangzhou, Zhejiang, China
| | - Haiyang Liao
- Hangzhou Clinical College, Zhejiang Chinese Medical University, 310053 Hangzhou, Zhejiang, China
| | - Caifeng Zhu
- Nephrology Department, Hangzhou Hospital of Traditional Chinese Medicine, 310007 Hangzhou, Zhejiang, China
| | - Xiaodi Zou
- Department of Orthopedics, The Second Affiliated Hospital of Zhejiang Chinese Medical University, 310003 Hangzhou, Zhejiang, China
- Department of Orthopedics, The First Affiliated Hospital, Zhejiang University, 310000 Hangzhou, Zhejiang, China
| | - Yanzhao Dong
- Department of Orthopedics, The First Affiliated Hospital, Zhejiang University, 310000 Hangzhou, Zhejiang, China
| | - Weijie Zhou
- Department of Orthopedics, The First Affiliated Hospital, Zhejiang University, 310000 Hangzhou, Zhejiang, China
| | - Zexing Sun
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, 310053 Hangzhou, Zhejiang, China
| | - Jiazhen Yin
- Nephrology Department, Hangzhou Hospital of Traditional Chinese Medicine, 310007 Hangzhou, Zhejiang, China
| |
Collapse
|
|
3
|
Wei X, Mu H, Zhang Q, Zhang Z, Ru Y, Lai K, Ma Y, Lin Z, Tuxun R, Chen Z, Xiang AP, Li T. MSCs act as biopatches for blood-retinal barrier preservation to enhance functional recovery after retinal I/R. MOLECULAR THERAPY. NUCLEIC ACIDS 2025; 36:102445. [PMID: 39967853 PMCID: PMC11834101 DOI: 10.1016/j.omtn.2024.102445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 12/30/2024] [Indexed: 02/20/2025]
Abstract
Retinal ischemia/reperfusion (I/R) is one of the most common pathologies of many vision-threatening diseases and is caused by blood-retinal barrier (BRB) breakdown and the resulting inflammatory infiltration. Targeting BRB is promising for retinal I/R treatment. Mesenchymal stromal cells (MSCs) are emerging as novel therapeutic strategies. Although intravitreal injection targets the retina, the restricted number of injected cells still requires the precise biodistribution of MSCs near the injury site. Here, we found that retinal I/R led to BRB breakdown, which induced protein and cell leakage from the circulation. Retinal cell death and diminished visual function were subsequently detected. Moreover, the expression of the chemokine CCL5 increased after retinal I/R, and CCL5 colocalized with the BRB. We then overexpressed CCR5 in human induced pluripotent stem cell-derived MSCs (iMSCs). In vivo, intravitreal-injected iMSCCCR5 preferentially migrated and directly integrated into the BRB, which preferably restored BRB integrity and eventually promoted retinal function recovery after retinal I/R. In summary, our work suggested that iMSCs act as biopatches for BRB preservation and that iMSC-based therapy is a promising therapeutic approach for retinal diseases related to I/R.
Collapse
Affiliation(s)
- Xiaoyue Wei
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510230, China
| | - Hanyiqi Mu
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Qinmu Zhang
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Ziyuan Zhang
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Yifei Ru
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Kunbei Lai
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510230, China
| | - Yuan Ma
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510230, China
| | - Zhuangling Lin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510230, China
| | - Rebiya Tuxun
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510230, China
| | - Zitong Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510230, China
| | - Andy Peng Xiang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou 510080, China
| | - Tao Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510230, China
| |
Collapse
|
|
4
|
Kirkeby A, Main H, Carpenter M. Pluripotent stem-cell-derived therapies in clinical trial: A 2025 update. Cell Stem Cell 2025; 32:10-37. [PMID: 39753110 DOI: 10.1016/j.stem.2024.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 12/05/2024] [Accepted: 12/05/2024] [Indexed: 01/28/2025]
Abstract
Since the first derivation of human pluripotent stem cells (hPSCs) 27 years ago, technologies to control their differentiation and manufacturing have advanced immensely, enabling increasing numbers of clinical trials with hPSC-derived products. Here, we revew the landscape of interventional hPSC trials worldwide, highlighting available data on clinical safety and efficacy. As of December 2024, we identify 116 clinical trials with regulatory approval, testing 83 hPSC products. The majority of trials are targeting eye, central nervous system, and cancer. To date, more than 1,200 patients have been dosed with hPSC products, accumulating to >1011 clinically administered cells, so far showing no generalizable safety concerns.
Collapse
Affiliation(s)
- Agnete Kirkeby
- Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW) and Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Experimental Medical Sciences, Wallenberg Center for Molecular Medicine (WCMM) and Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden.
| | - Heather Main
- HOYA Consulting (ReGenMed Solutions), Stockholm, Sweden
| | | |
Collapse
|
|
5
|
Buitrago JC, Morris SL, Backhaus A, Kaltenecker G, Kaipa JM, Girard C, Schneider S, Gruber J. Unveiling the Immunomodulatory and regenerative potential of iPSC-derived mesenchymal stromal cells and their extracellular vesicles. Sci Rep 2024; 14:24098. [PMID: 39407038 PMCID: PMC11480492 DOI: 10.1038/s41598-024-75956-3] [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] [Received: 06/27/2024] [Accepted: 10/09/2024] [Indexed: 10/19/2024] Open
Abstract
Induced pluripotent stem cell (iPSC)-derived mesenchymal stromal cells (iMSCs) offer a promising alternative to primary mesenchymal stromal cells (MSCs) and their derivatives, particularly extracellular vesicles (EVs), for use in advanced therapy medicinal products. In this study we evaluated the immunomodulatory and regenerative potential of iMSCs as well as iMSC-EVs, alongside primary human umbilical cord-derived mesenchymal stromal cells (hUCMSCs). Our findings demonstrate that iMSCs exhibit comparable abilities to hUCMSCs in regulating lymphocyte proliferation and inducing an anti-inflammatory phenotype in monocytes. We also observed decreased TNFα levels and increased IL-10 induction, indicating a potential mechanism for their immunomodulatory effects. Furthermore, iMSC-EVs also showed effective immunomodulation by inhibiting T cell proliferation and inducing macrophage polarization similar to their parental cells. Additionally, iMSC-EVs exhibited pro-regenerative potential akin to hUCMSC-EVs in in vitro scratch assays. Notably, priming iMSCs with pro-inflammatory cytokines significantly enhanced the immunomodulatory potential of iMSC-EVs. These results underscore the considerable promise of iMSCs and iMSCs-EVs as an alternate source for MSC-derived therapeutics, given their potent immunomodulatory and regenerative properties.
Collapse
Affiliation(s)
- July Constanza Buitrago
- Curexsys GmbH, Göttingen, Germany.
- PhD Biomedical and Biological Sciences Program, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia.
- Life Science Factory, Curexsys GmbH, Annastraβe 27, Göttingen, Germany, D-37075.
| | | | | | | | | | | | | | - Jens Gruber
- Curexsys GmbH, Göttingen, Germany.
- Life Science Factory, Curexsys GmbH, Annastraβe 27, Göttingen, Germany, D-37075.
| |
Collapse
|
|
6
|
Chakraborty A, Wang C, Hodgson-Garms M, Broughton BRS, Frith JE, Kelly K, Samuel CS. Induced pluripotent stem cell-derived mesenchymal stem cells reverse bleomycin-induced pulmonary fibrosis and related lung stiffness. Biomed Pharmacother 2024; 178:117259. [PMID: 39116786 DOI: 10.1016/j.biopha.2024.117259] [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: 06/03/2024] [Revised: 07/23/2024] [Accepted: 08/02/2024] [Indexed: 08/10/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is characterised by lung scarring and stiffening, for which there is no effective cure. Based on the immunomodulatory and anti-fibrotic effects of induced pluripotent stem cell (iPSC) and mesenchymoangioblast-derived mesenchymal stem cells (iPSCs-MSCs), this study evaluated the therapeutic effects of iPSCs-MSCs in a bleomycin (BLM)-induced model of pulmonary fibrosis. Adult male C57BL/6 mice received a double administration of BLM (0.15 mg/day) 7-days apart and were then maintained for a further 28-days (until day-35), whilst control mice were administered saline 7-days apart and maintained for the same time-period. Sub-groups of BLM-injured mice were intravenously-injected with 1×106 iPSC-MSCs on day-21 alone or on day-21 and day-28 and left until day-35 post-injury. Measures of lung inflammation, fibrosis and compliance were then evaluated. BLM-injured mice presented with lung inflammation characterised by increased immune cell infiltration and increased pro-inflammatory cytokine expression, epithelial damage, lung transforming growth factor (TGF)-β1 activity, myofibroblast differentiation, interstitial collagen fibre deposition and topology (fibrosis), in conjunction with reduced matrix metalloproteinase (MMP)-to-tissue inhibitor of metalloproteinase (TIMP) ratios and dynamic lung compliance. All these measures were ameliorated by a single or once-weekly intravenous-administration of iPSC-MSCs, with the latter reducing dendritic cell infiltration and lung epithelial damage, whilst promoting anti-inflammatory interleukin (IL)-10 levels to a greater extent. Proteomic profiling of the conditioned media of cultured iPSC-MSCs that were stimulated with TNF-α and IFN-γ, revealed that these stem cells secreted protein levels of immunosuppressive factors that contributed to the anti-fibrotic and therapeutic potential of iPSCs-MSCs as a novel treatment option for IPF.
Collapse
Affiliation(s)
- Amlan Chakraborty
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI) and Department of Pharmacology, Monash University, Clayton, Victoria, Australia; Division of Immunology, Immunity to Infection and Respiratory Medicine, The University of Manchester, Manchester, England, UK
| | - Chao Wang
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI) and Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | - Margeaux Hodgson-Garms
- Department of Materials Science and Engineering, Monash University, Clayton, Victoria, Australia
| | - Brad R S Broughton
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI) and Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | - Jessica E Frith
- Department of Materials Science and Engineering, Monash University, Clayton, Victoria, Australia
| | - Kilian Kelly
- Cynata Therapeutics Ltd, Cremorne, Victoria, Australia
| | - Chrishan S Samuel
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI) and Department of Pharmacology, Monash University, Clayton, Victoria, Australia; Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, Victoria, Australia.
| |
Collapse
|
|
7
|
Winston T, Song Y, Shi H, Yang J, Alsudais M, Kontaridis MI, Wu Y, Gaborski TR, Meng Q, Cooney RN, Ma Z. Lineage-Specific Mesenchymal Stromal Cells Derived from Human iPSCs Showed Distinct Patterns in Transcriptomic Profile and Extracellular Vesicle Production. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2308975. [PMID: 38757640 PMCID: PMC11267277 DOI: 10.1002/advs.202308975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 04/16/2024] [Indexed: 05/18/2024]
Abstract
Over the past decades, mesenchymal stromal cells (MSCs) have been extensively investigated as a potential therapeutic cell source for the treatment of various disorders. Differentiation of MSCs from human induced pluripotent stem cells (iMSCs) has provided a scalable approach for the biomanufacturing of MSCs and related biological products. Although iMSCs shared typical MSC markers and functions as primary MSCs (pMSCs), there is a lack of lineage specificity in many iMSC differentiation protocols. Here, a stepwise hiPSC-to-iMSC differentiation method is employed via intermediate cell stages of neural crest and cytotrophoblast to generate lineage-specific MSCs with varying differentiation efficiencies and gene expression. Through a comprehensive comparison between early developmental cell types (hiPSCs, neural crest, and cytotrophoblast), two lineage-specific iMSCs, and six source-specific pMSCs, are able to not only distinguish the transcriptomic differences between MSCs and early developmental cells, but also determine the transcriptomic similarities of iMSC subtypes to postnatal or perinatal pMSCs. Additionally, it is demonstrated that different iMSC subtypes and priming conditions affected EV production, exosomal protein expression, and cytokine cargo.
Collapse
Affiliation(s)
- Tackla Winston
- Department of Biomedical & Chemical EngineeringSyracuse University329 Link HallSyracuseNY13244USA
- BioInspired Institute for Materials and Living SystemsSyracuse University318 Bowne HallSyracuseNY13244USA
| | - Yuanhui Song
- Department of Biomedical & Chemical EngineeringSyracuse University329 Link HallSyracuseNY13244USA
- BioInspired Institute for Materials and Living SystemsSyracuse University318 Bowne HallSyracuseNY13244USA
| | - Huaiyu Shi
- Department of Biomedical & Chemical EngineeringSyracuse University329 Link HallSyracuseNY13244USA
- BioInspired Institute for Materials and Living SystemsSyracuse University318 Bowne HallSyracuseNY13244USA
| | - Junhui Yang
- Department of Biomedical & Chemical EngineeringSyracuse University329 Link HallSyracuseNY13244USA
- BioInspired Institute for Materials and Living SystemsSyracuse University318 Bowne HallSyracuseNY13244USA
| | - Munther Alsudais
- Departments of Biomedical and Chemical EngineeringRochester Institute of TechnologyOne Lomb Memorial DriveRochesterNY14623USA
| | - Maria I. Kontaridis
- Department of Biomedical Research and Translational MedicineMasonic Medical Research Institute2150 Bleecker StreetUticaNY13501USA
- Department of Medicine, Division of Cardiology, Beth Israel Deaconess Medical CenterHarvard Medical School330 Brookline AveBostonMA02215USA
- Department of Biological Chemistry and Molecular PharmacologyHarvard Medical SchoolBuilding C, 240 Longwood AveBostonMA02115USA
| | - Yaoying Wu
- Department of Biomedical & Chemical EngineeringSyracuse University329 Link HallSyracuseNY13244USA
- BioInspired Institute for Materials and Living SystemsSyracuse University318 Bowne HallSyracuseNY13244USA
- Department of Microbiology & ImmunologySUNY Upstate Medical University766 Irving AvenueSyracuseNY13210USA
| | - Thomas R. Gaborski
- Departments of Biomedical and Chemical EngineeringRochester Institute of TechnologyOne Lomb Memorial DriveRochesterNY14623USA
| | - Qinghe Meng
- Department of SurgeryState University of New York Upstate Medical University750 East Adams StreetSyracuseNY13210USA
- Sepsis Interdisciplinary Research CenterState University of New York Upstate Medical University766 Irving AvenueSyracuseNY13210USA
| | - Robert N. Cooney
- Department of SurgeryState University of New York Upstate Medical University750 East Adams StreetSyracuseNY13210USA
- Sepsis Interdisciplinary Research CenterState University of New York Upstate Medical University766 Irving AvenueSyracuseNY13210USA
| | - Zhen Ma
- Department of Biomedical & Chemical EngineeringSyracuse University329 Link HallSyracuseNY13244USA
- BioInspired Institute for Materials and Living SystemsSyracuse University318 Bowne HallSyracuseNY13244USA
- Department of BiologySyracuse University107 College PlSyracuseNY13210USA
| |
Collapse
|
|
8
|
Ma CY, Zhai Y, Li CT, Liu J, Xu X, Chen H, Tse HF, Lian Q. Translating mesenchymal stem cell and their exosome research into GMP compliant advanced therapy products: Promises, problems and prospects. Med Res Rev 2024; 44:919-938. [PMID: 38095832 DOI: 10.1002/med.22002] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 06/22/2023] [Accepted: 11/26/2023] [Indexed: 04/06/2024]
Abstract
Mesenchymal stem cells (MSCs) are one of the few stem cell types used in clinical practice as therapeutic agents for immunomodulation and ischemic tissue repair, due to their unique paracrine capacity, multiple differentiation potential, active components in exosomes, and effective mitochondria donation. At present, MSCs derived from tissues such as bone marrow and umbilical cord are widely applied in preclinical and clinical studies. Nevertheless, there remain challenges to the maintenance of consistently good quality MSCs derived from different donors or tissues, directly impacting their application as advanced therapy products. In this review, we discuss the promises, problems, and prospects associated with translation of MSC research into a pharmaceutical product. We review the hurdles encountered in translation of MSCs and MSC-exosomes from the research bench to an advanced therapy product compliant with good manufacturing practice (GMP). These difficulties include how to set up GMP-compliant protocols, what factors affect raw material selection, cell expansion to product formulation, establishment of quality control (QC) parameters, and quality assurance to comply with GMP standards. To avoid human error and reduce the risk of contamination, an automatic, closed system that allows real-time monitoring of QC should be considered. We also highlight potential advantages of pluripotent stem cells as an alternative source for MSC and exosomes generation and manufacture.
Collapse
Affiliation(s)
- Chui-Yan Ma
- Center for Translational Stem Cell Biology, Hong Kong, China
- Department of Medicine, HKUMed Laboratory of Cellular Therapeutics, University of Hong Kong, Hong Kong, China
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Yuqing Zhai
- Center for Translational Stem Cell Biology, Hong Kong, China
- Department of Medicine, HKUMed Laboratory of Cellular Therapeutics, University of Hong Kong, Hong Kong, China
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Chung Tony Li
- Center for Translational Stem Cell Biology, Hong Kong, China
- Department of Medicine, HKUMed Laboratory of Cellular Therapeutics, University of Hong Kong, Hong Kong, China
| | - Jie Liu
- Department of Medicine, HKUMed Laboratory of Cellular Therapeutics, University of Hong Kong, Hong Kong, China
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
| | - Xiang Xu
- Department of Stem Cell and Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
| | - Hao Chen
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Hung-Fat Tse
- Center for Translational Stem Cell Biology, Hong Kong, China
- Department of Medicine, HKUMed Laboratory of Cellular Therapeutics, University of Hong Kong, Hong Kong, China
- Department of Cardiology, Cardiac and Vascular Center, Shenzhen Hong Kong University Hospital, Shenzhen, China
- Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, The University of Hong Kong, Hong Kong, China
- Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China
| | - Qizhou Lian
- Center for Translational Stem Cell Biology, Hong Kong, China
- Department of Medicine, HKUMed Laboratory of Cellular Therapeutics, University of Hong Kong, Hong Kong, China
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China
| |
Collapse
|
|
9
|
Barrère-Lemaire S, Vincent A, Jorgensen C, Piot C, Nargeot J, Djouad F. Mesenchymal stromal cells for improvement of cardiac function following acute myocardial infarction: a matter of timing. Physiol Rev 2024; 104:659-725. [PMID: 37589393 DOI: 10.1152/physrev.00009.2023] [Citation(s) in RCA: 29] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 07/05/2023] [Accepted: 08/16/2023] [Indexed: 08/18/2023] Open
Abstract
Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery, i.e., reperfusion, is the only way to save the myocardium. However, the expected benefits of reducing infarct size are disappointing due to the reperfusion paradox, which also induces specific cell death. These ischemia-reperfusion (I/R) lesions can account for up to 50% of final infarct size, a major determinant for both mortality and the risk of heart failure (morbidity). In this review, we provide a detailed description of the cell death and inflammation mechanisms as features of I/R injury and cardioprotective strategies such as ischemic postconditioning as well as their underlying mechanisms. Due to their biological properties, the use of mesenchymal stromal/stem cells (MSCs) has been considered a potential therapeutic approach in AMI. Despite promising results and evidence of safety in preclinical studies using MSCs, the effects reported in clinical trials are not conclusive and even inconsistent. These discrepancies were attributed to many parameters such as donor age, in vitro culture, and storage time as well as injection time window after AMI, which alter MSC therapeutic properties. In the context of AMI, future directions will be to generate MSCs with enhanced properties to limit cell death in myocardial tissue and thereby reduce infarct size and improve the healing phase to increase postinfarct myocardial performance.
Collapse
Affiliation(s)
- Stéphanie Barrère-Lemaire
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Anne Vincent
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Christian Jorgensen
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
| | - Christophe Piot
- Département de Cardiologie Interventionnelle, Clinique du Millénaire, Montpellier, France
| | - Joël Nargeot
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Farida Djouad
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
| |
Collapse
|
|
10
|
Pirsadeghi A, Namakkoobi N, Behzadi MS, Pourzinolabedin H, Askari F, Shahabinejad E, Ghorbani S, Asadi F, Hosseini-Chegeni A, Yousefi-Ahmadipour A, Kamrani MH. Therapeutic approaches of cell therapy based on stem cells and terminally differentiated cells: Potential and effectiveness. Cells Dev 2024; 177:203904. [PMID: 38316293 DOI: 10.1016/j.cdev.2024.203904] [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: 06/10/2023] [Revised: 11/24/2023] [Accepted: 01/30/2024] [Indexed: 02/07/2024]
Abstract
Cell-based therapy, as a promising regenerative medicine approach, has been a promising and effective strategy to treat or even cure various kinds of diseases and conditions. Generally, two types of cells are used in cell therapy, the first is the stem cell, and the other is a fully differentiated cell. Initially, all cells in the body are derived from stem cells. Based on the capacity, potency and differentiation potential of stem cells, there are four types: totipotent (produces all somatic cells plus perinatal tissues), pluripotent (produces all somatic cells), multipotent (produces many types of cells), and unipotent (produces a particular type of cells). All non-totipotent stem cells can be used for cell therapy, depending on their potency and/or disease state/conditions. Adult fully differentiated cell is another cell type for cell therapy that is isolated from adult tissues or obtained following the differentiation of stem cells. The cells can then be transplanted back into the patient to replace damaged or malfunctioning cells, promote tissue repair, or enhance the targeted organ's overall function. With increasing science and knowledge in biology and medicine, different types of techniques have been developed to obtain efficient cells to use for therapeutic approaches. In this study, the potential and opportunity of use of all cell types, both stem cells and fully differentiated cells, are reviewed.
Collapse
Affiliation(s)
- Ali Pirsadeghi
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Negar Namakkoobi
- Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mahtab Sharifzadeh Behzadi
- Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Hanieh Pourzinolabedin
- Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Fatemeh Askari
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; USERN Office, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Erfan Shahabinejad
- Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; USERN Office, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Somayeh Ghorbani
- Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Fatemeh Asadi
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Cancer and Stem Cell Research Laboratory, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Ali Hosseini-Chegeni
- Cancer and Stem Cell Research Laboratory, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Aliakbar Yousefi-Ahmadipour
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Cancer and Stem Cell Research Laboratory, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
| | - Mohammad Hossein Kamrani
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| |
Collapse
|
|
11
|
Rasouli M, Naeimzadeh Y, Hashemi N, Hosseinzadeh S. Age-Related Alterations in Mesenchymal Stem Cell Function: Understanding Mechanisms and Seeking Opportunities to Bypass the Cellular Aging. Curr Stem Cell Res Ther 2024; 19:15-32. [PMID: 36642876 DOI: 10.2174/1574888x18666230113144016] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/28/2022] [Accepted: 11/23/2022] [Indexed: 01/17/2023]
Abstract
Undoubtedly, mesenchymal stem cells (MSCs) are the most common cell therapy candidates in clinical research and therapy. They not only exert considerable therapeutic effects to alleviate inflammation and promote regeneration, but also show low-immunogenicity properties, which ensure their safety following allogeneic transplantation. Thanks to the necessity of providing a sufficient number of MSCs to achieve clinically efficient outcomes, prolonged in vitro cultivation is indisputable. However, either following long-term in vitro expansion or aging in elderly individuals, MSCs face cellular senescence. Senescent MSCs undergo an impairment in their function and therapeutic capacities and secrete degenerative factors which negatively affect young MSCs. To this end, designing novel investigations to further elucidate cellular senescence and to pave the way toward finding new strategies to reverse senescence is highly demanded. In this review, we will concisely discuss current progress on the detailed mechanisms of MSC senescence and various inflicted changes following aging in MSC. We will also shed light on the examined strategies underlying monitoring and reversing senescence in MSCs to bypass the comprised therapeutic efficacy of the senescent MSCs.
Collapse
Affiliation(s)
- Mehdi Rasouli
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yasaman Naeimzadeh
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nader Hashemi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Simzar Hosseinzadeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
12
|
Kaewchuchuen J, Roamcharern N, Phuagkhaopong S, Bimbo LM, Seib FP. Microfibre-Functionalised Silk Hydrogels. Cells 2023; 13:10. [PMID: 38201214 PMCID: PMC10777932 DOI: 10.3390/cells13010010] [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: 11/15/2023] [Revised: 12/10/2023] [Accepted: 12/14/2023] [Indexed: 01/12/2024] Open
Abstract
Silk hydrogels have shown potential for tissue engineering applications, but several gaps and challenges, such as a restricted ability to form hydrogels with tuned mechanics and structural features, still limit their utilisation. Here, Bombyx mori and Antheraea mylitta (Tasar) silk microfibres were embedded within self-assembling B. mori silk hydrogels to modify the bulk hydrogel mechanical properties. This approach is particularly attractive because it creates structured silk hydrogels. First, B. mori and Tasar microfibres were prepared with lengths between 250 and 500 μm. Secondary structure analyses showed high beta-sheet contents of 61% and 63% for B. mori and Tasar microfibres, respectively. Mixing either microfibre type, at either 2% or 10% (w/v) concentrations, into 3% (w/v) silk solutions during the solution-gel transition increased the initial stiffness of the resulting silk hydrogels, with the 10% (w/v) addition giving a greater increase. Microfibre addition also altered hydrogel stress relaxation, with the fastest stress relaxation observed with a rank order of 2% (w/v) > 10% (w/v) > unmodified hydrogels for either fibre type, although B. mori fibres showed a greater effect. The resulting data sets are interesting because they suggest that the presence of microfibres provided potential 'flow points' within these hydrogels. Assessment of the biological responses by monitoring cell attachment onto these two-dimensional hydrogel substrates revealed greater numbers of human induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) attached to the hydrogels containing 10% (w/v) B. mori microfibres as well as 2% (w/v) and 10% (w/v) Tasar microfibres at 24 h after seeding. Cytoskeleton staining revealed a more elongated and stretched morphology for the cells growing on hydrogels containing Tasar microfibres. Overall, these findings illustrate that hydrogel stiffness, stress relaxation and the iPSC-MSC responses towards silk hydrogels can be tuned using microfibres.
Collapse
Affiliation(s)
- Jirada Kaewchuchuen
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK (L.M.B.)
| | - Napaporn Roamcharern
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK (L.M.B.)
| | - Suttinee Phuagkhaopong
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK (L.M.B.)
- Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Luis M. Bimbo
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK (L.M.B.)
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal
- CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal
| | - F. Philipp Seib
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK (L.M.B.)
- Fraunhofer Institute for Molecular Biology & Applied Ecology, Branch Bioresources, Ohlebergsweg 12, 35392 Giessen, Germany
- Institute of Pharmacy, Friedrich Schiller University Jena, Lessingstr. 8, 07743 Jena, Germany
| |
Collapse
|
|
13
|
Tsai ET, Peng SY, Wu YR, Lin TC, Chen CY, Liu YH, Tseng YH, Hsiao YJ, Tseng HC, Lai WY, Lin YY, Yang YP, Chiou SH, Chen SP, Chien Y. HLA-Homozygous iPSC-Derived Mesenchymal Stem Cells Rescue Rotenone-Induced Experimental Leber's Hereditary Optic Neuropathy-like Models In Vitro and In Vivo. Cells 2023; 12:2617. [PMID: 37998352 PMCID: PMC10670753 DOI: 10.3390/cells12222617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 11/02/2023] [Accepted: 11/07/2023] [Indexed: 11/25/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) hold promise for cell-based therapy, yet the sourcing, quality, and invasive methods of MSCs impede their mass production and quality control. Induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) can be infinitely expanded, providing advantages over conventional MSCs in terms of meeting unmet clinical demands. METHODS The potential of MSC therapy for Leber's hereditary optic neuropathy (LHON) remains uncertain. In this study, we used HLA-homozygous induced pluripotent stem cells to generate iMSCs using a defined protocol, and we examined their therapeutic potential in rotenone-induced LHON-like models in vitro and in vivo. RESULTS The iMSCs did not cause any tumorigenic incidence or inflammation-related lesions after intravitreal transplantation, and they remained viable for at least nine days in the mouse recipient's eyes. In addition, iMSCs exhibited significant efficacy in safeguarding retinal ganglion cells (RGCs) from rotenone-induced cytotoxicity in vitro, and they ameliorated CGL+IPL layer thinning and RGC loss in vivo. Optical coherence tomography (OCT) and an electroretinogram demonstrated that iMSCs not only prevented RGC loss and impairments to the retinal architecture, but they also improved retinal electrophysiology performance. CONCLUSION The generation of iMSCs via the HLA homozygosity of iPSCs offers a compelling avenue for overcoming the current limitations of MSC-based therapies. The results underscore the potential of iMSCs when addressing retinal disorders, and they highlight their clinical significance, offering renewed hope for individuals affected by LHON and other inherited retinal conditions.
Collapse
Affiliation(s)
- En-Tung Tsai
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (E.-T.T.)
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (S.-Y.P.); (Y.-R.W.); (Y.-H.L.); (Y.-J.H.); (Y.-Y.L.); (Y.-P.Y.)
| | - Shih-Yuan Peng
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (S.-Y.P.); (Y.-R.W.); (Y.-H.L.); (Y.-J.H.); (Y.-Y.L.); (Y.-P.Y.)
| | - You-Ren Wu
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (S.-Y.P.); (Y.-R.W.); (Y.-H.L.); (Y.-J.H.); (Y.-Y.L.); (Y.-P.Y.)
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
| | - Tai-Chi Lin
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (S.-Y.P.); (Y.-R.W.); (Y.-H.L.); (Y.-J.H.); (Y.-Y.L.); (Y.-P.Y.)
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
- Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112201, Taiwan
| | - Chih-Ying Chen
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (S.-Y.P.); (Y.-R.W.); (Y.-H.L.); (Y.-J.H.); (Y.-Y.L.); (Y.-P.Y.)
| | - Yu-Hao Liu
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (S.-Y.P.); (Y.-R.W.); (Y.-H.L.); (Y.-J.H.); (Y.-Y.L.); (Y.-P.Y.)
| | - Yu-Hsin Tseng
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (S.-Y.P.); (Y.-R.W.); (Y.-H.L.); (Y.-J.H.); (Y.-Y.L.); (Y.-P.Y.)
| | - Yu-Jer Hsiao
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (S.-Y.P.); (Y.-R.W.); (Y.-H.L.); (Y.-J.H.); (Y.-Y.L.); (Y.-P.Y.)
- Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112201, Taiwan
| | - Huan-Chin Tseng
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (S.-Y.P.); (Y.-R.W.); (Y.-H.L.); (Y.-J.H.); (Y.-Y.L.); (Y.-P.Y.)
| | - Wei-Yi Lai
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (S.-Y.P.); (Y.-R.W.); (Y.-H.L.); (Y.-J.H.); (Y.-Y.L.); (Y.-P.Y.)
| | - Yi-Ying Lin
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (S.-Y.P.); (Y.-R.W.); (Y.-H.L.); (Y.-J.H.); (Y.-Y.L.); (Y.-P.Y.)
| | - Yi-Ping Yang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (S.-Y.P.); (Y.-R.W.); (Y.-H.L.); (Y.-J.H.); (Y.-Y.L.); (Y.-P.Y.)
| | - Shih-Hwa Chiou
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (E.-T.T.)
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (S.-Y.P.); (Y.-R.W.); (Y.-H.L.); (Y.-J.H.); (Y.-Y.L.); (Y.-P.Y.)
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
- Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112201, Taiwan
- Genomic Research Center, Academia Sinica, Taipei 115024, Taiwan
| | - Shih-Pin Chen
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (E.-T.T.)
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (S.-Y.P.); (Y.-R.W.); (Y.-H.L.); (Y.-J.H.); (Y.-Y.L.); (Y.-P.Y.)
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei 112201, Taiwan
| | - Yueh Chien
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (S.-Y.P.); (Y.-R.W.); (Y.-H.L.); (Y.-J.H.); (Y.-Y.L.); (Y.-P.Y.)
| |
Collapse
|
|
14
|
Kim J, Lee SK, Jeong SY, You H, Han SD, Park S, Kim S, Kim TM. Multifaceted action of stem cell-derived extracellular vesicles for nonalcoholic steatohepatitis. J Control Release 2023; 364:S0168-3659(23)00706-X. [PMID: 39491172 DOI: 10.1016/j.jconrel.2023.10.045] [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: 06/22/2023] [Revised: 10/24/2023] [Accepted: 10/27/2023] [Indexed: 11/05/2024]
Abstract
Nonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with metabolic syndrome. Extracellular vesicles (EVs) are essential signaling mediators containing functional biomolecules. EVs are secreted from various cell types, and recent studies have shown that mesenchymal stem cell-derived EVs have therapeutic potential against immune and metabolic diseases. In this study, we investigated whether EVs from induced mesenchymal stem cells (iMSC-EVs) regulate AMPK signaling and lipid metabolism using cell-based studies and two different mouse models of NASH (methionine/choline-deficient diet-induced and ob/ob mice). Protein analysis revealed that iMSC-EVs carry cargo proteins with the potential to regulate lipid metabolism. iMSC-EVs inhibited free fatty acid release from adipose tissues by downregulating the activity of lipolytic genes in NASH. In addition, iMSC-EVs improved hepatic steatosis by modulating AMPK signaling, which plays essential role in metabolic homeostasis in the liver. Moreover, iMSC-EVs reduced CD36 expression, contributing to the blockade of free fatty acid transport to the liver of NASH mice. Finally, iMSC-EVs reduced inflammation, endoplasmic reticulum stress, and apoptosis while promoting hepatic regeneration of the NASH liver. In conclusion, iMSC-EVs can potentially serve as cell-free therapeutics for NASH owing to their multifaceted modality.
Collapse
Affiliation(s)
- Jimin Kim
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul 05855, South Korea
| | - Seul Ki Lee
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul 05855, South Korea
| | - Seon-Yeong Jeong
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul 05855, South Korea
| | - Haedeun You
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul 05855, South Korea
| | - Sang-Deok Han
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul 05855, South Korea
| | - Somi Park
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul 05855, South Korea
| | - Soo Kim
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul 05855, South Korea
| | - Tae Min Kim
- Graduate School of International Agricultural Technology, Seoul National University, Pyeongchang, Gangwon-do 25354, South Korea; Institutes of Green-Bio Science and Technology, Seoul National University, Pyeongchang, Gangwon-do 25354, South Korea.
| |
Collapse
|
|
15
|
Esteves F, Brito D, Rajado AT, Silva N, Apolónio J, Roberto VP, Araújo I, Nóbrega C, Castelo-Branco P, Bragança J. Reprogramming iPSCs to study age-related diseases: Models, therapeutics, and clinical trials. Mech Ageing Dev 2023; 214:111854. [PMID: 37579530 DOI: 10.1016/j.mad.2023.111854] [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: 06/09/2023] [Revised: 07/19/2023] [Accepted: 07/30/2023] [Indexed: 08/16/2023]
Abstract
The unprecedented rise in life expectancy observed in the last decades is leading to a global increase in the ageing population, and age-associated diseases became an increasing societal, economic, and medical burden. This has boosted major efforts in the scientific and medical research communities to develop and improve therapies to delay ageing and age-associated functional decline and diseases, and to expand health span. The establishment of induced pluripotent stem cells (iPSCs) by reprogramming human somatic cells has revolutionised the modelling and understanding of human diseases. iPSCs have a major advantage relative to other human pluripotent stem cells as their obtention does not require the destruction of embryos like embryonic stem cells do, and do not have a limited proliferation or differentiation potential as adult stem cells. Besides, iPSCs can be generated from somatic cells from healthy individuals or patients, which makes iPSC technology a promising approach to model and decipher the mechanisms underlying the ageing process and age-associated diseases, study drug effects, and develop new therapeutic approaches. This review discusses the advances made in the last decade using iPSC technology to study the most common age-associated diseases, including age-related macular degeneration (AMD), neurodegenerative and cardiovascular diseases, brain stroke, cancer, diabetes, and osteoarthritis.
Collapse
Affiliation(s)
- Filipa Esteves
- Algarve Biomedical Center Research Institute (ABC-RI), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal; Algarve Biomedical Center (ABC), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal
| | - David Brito
- Algarve Biomedical Center Research Institute (ABC-RI), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal; Algarve Biomedical Center (ABC), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal
| | - Ana Teresa Rajado
- Algarve Biomedical Center Research Institute (ABC-RI), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal; Algarve Biomedical Center (ABC), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal
| | - Nádia Silva
- Algarve Biomedical Center Research Institute (ABC-RI), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal; Algarve Biomedical Center (ABC), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal
| | - Joana Apolónio
- Algarve Biomedical Center Research Institute (ABC-RI), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal; Algarve Biomedical Center (ABC), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal
| | - Vânia Palma Roberto
- Algarve Biomedical Center Research Institute (ABC-RI), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal; Algarve Biomedical Center (ABC), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal; ABC Collaborative Laboratory, Association for Integrated Aging and Rejuvenation Solutions (ABC CoLAB), 8100-735 Loulé, Portugal
| | - Inês Araújo
- Algarve Biomedical Center Research Institute (ABC-RI), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal; Algarve Biomedical Center (ABC), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal; ABC Collaborative Laboratory, Association for Integrated Aging and Rejuvenation Solutions (ABC CoLAB), 8100-735 Loulé, Portugal; Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal; Champalimaud Research Program, Champalimaud Centre for the Unknown, Avenida Brasília, 1400-038 Lisbon, Portugal
| | - Clévio Nóbrega
- Algarve Biomedical Center Research Institute (ABC-RI), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal; Algarve Biomedical Center (ABC), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal; ABC Collaborative Laboratory, Association for Integrated Aging and Rejuvenation Solutions (ABC CoLAB), 8100-735 Loulé, Portugal; Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal; Champalimaud Research Program, Champalimaud Centre for the Unknown, Avenida Brasília, 1400-038 Lisbon, Portugal
| | - Pedro Castelo-Branco
- Algarve Biomedical Center Research Institute (ABC-RI), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal; Algarve Biomedical Center (ABC), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal; ABC Collaborative Laboratory, Association for Integrated Aging and Rejuvenation Solutions (ABC CoLAB), 8100-735 Loulé, Portugal; Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal; Champalimaud Research Program, Champalimaud Centre for the Unknown, Avenida Brasília, 1400-038 Lisbon, Portugal
| | - José Bragança
- Algarve Biomedical Center Research Institute (ABC-RI), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal; Algarve Biomedical Center (ABC), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal; ABC Collaborative Laboratory, Association for Integrated Aging and Rejuvenation Solutions (ABC CoLAB), 8100-735 Loulé, Portugal; Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal; Champalimaud Research Program, Champalimaud Centre for the Unknown, Avenida Brasília, 1400-038 Lisbon, Portugal.
| |
Collapse
|
|
16
|
Ouzin M, Kogler G. Mesenchymal Stromal Cells: Heterogeneity and Therapeutical Applications. Cells 2023; 12:2039. [PMID: 37626848 PMCID: PMC10453316 DOI: 10.3390/cells12162039] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/06/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
Mesenchymal stromal cells nowadays emerge as a major player in the field of regenerative medicine and translational research. They constitute, with their derived products, the most frequently used cell type in different therapies. However, their heterogeneity, including different subpopulations, the anatomic source of isolation, and high donor-to-donor variability, constitutes a major controversial issue that affects their use in clinical applications. Furthermore, the intrinsic and extrinsic molecular mechanisms underlying their self-renewal and fate specification are still not completely elucidated. This review dissects the different heterogeneity aspects of the tissue source associated with a distinct developmental origin that need to be considered when generating homogenous products before their usage for clinical applications.
Collapse
Affiliation(s)
- Meryem Ouzin
- Institute for Transplantation Diagnostics and Cell Therapeutics, University Hospital Düsseldorf, 40225 Düsseldorf, Germany;
| | | |
Collapse
|
|
17
|
Suzdaltseva Y, Kiselev SL. Mesodermal Derivatives of Pluripotent Stem Cells Route to Scarless Healing. Int J Mol Sci 2023; 24:11945. [PMID: 37569321 PMCID: PMC10418846 DOI: 10.3390/ijms241511945] [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: 06/16/2023] [Revised: 07/07/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Scar formation during normal tissue regeneration in adults may result in noticeable cosmetic and functional defects and have a significant impact on the quality of life. In contrast, fetal tissues in the mid-gestation period are known to be capable of complete regeneration with the restitution of the initial architecture, organization, and functional activity. Successful treatments that are targeted to minimize scarring can be realized by understanding the cellular and molecular mechanisms of fetal wound regeneration. However, such experiments are limited by the inaccessibility of fetal material for comparable studies. For this reason, the molecular mechanisms of fetal regeneration remain unknown. Mesenchymal stromal cells (MSCs) are central to tissue repair because the molecules they secrete are involved in the regulation of inflammation, angiogenesis, and remodeling of the extracellular matrix. The mesodermal differentiation of human pluripotent stem cells (hPSCs) recapitulates the sequential steps of embryogenesis in vitro and provides the opportunity to generate the isogenic cell models of MSCs corresponding to different stages of human development. Further investigation of the functional activity of cells from stromal differon in a pro-inflammatory microenvironment will procure the molecular tools to better understand the fundamental mechanisms of fetal tissue regeneration. Herein, we review recent advances in the generation of clonal precursors of primitive mesoderm cells and MSCs from hPSCs and discuss critical factors that determine the functional activity of MSCs-like cells in a pro-inflammatory microenvironment in order to identify therapeutic targets for minimizing scarring.
Collapse
Affiliation(s)
- Yulia Suzdaltseva
- Department of Epigenetics, Vavilov Institute of General Genetics of the Russian Academy of Sciences, 119333 Moscow, Russia;
| | | |
Collapse
|
|
18
|
Chiou SH, Ong HKA, Chou SJ, Aldoghachi AF, Loh JK, Verusingam ND, Yang YP, Chien Y. Current trends and promising clinical utility of IPSC-derived MSC (iMSC). PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 199:131-154. [PMID: 37678969 DOI: 10.1016/bs.pmbts.2023.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/09/2023]
Abstract
Mesenchymal stem cells (MSCs) differentiated from human induced pluripotent stem cells (iPSC) or induced MSC (iMSCs) are expected to address issues of scalability and safety as well as the difficulty in producing homogenous clinical grade MSCs as demonstrated by the promising outcomes from preclinical and clinical trials, currently ongoing. The assessment of iMSCs based in vitro and in vivo studies have thus far showed more superior performance as compared to that of the primary or native human MSCs, in terms of cell proliferation, expansion capacity, immunomodulation properties as well as the influence of paracrine signaling and exosomal influence in cell-cell interaction. In this chapter, an overview of current well-established methods in generating a sustainable source of iMSCs involving well defined culture media is discussed followed by the properties of iMSC as compared to that of MSC and its promising prospects for continuous development into potential clinical grade applications.
Collapse
Affiliation(s)
- Shih-Hwa Chiou
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Medical Research, Taipei Veteran General Hospital, Taipei, Taiwan
| | - Han Kiat Alan Ong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Shih-Jie Chou
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Medical Research, Taipei Veteran General Hospital, Taipei, Taiwan
| | - A F Aldoghachi
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Jit Kai Loh
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Nalini Devi Verusingam
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Yi-Ping Yang
- Department of Medical Research, Taipei Veteran General Hospital, Taipei, Taiwan.
| | - Yueh Chien
- Department of Medical Research, Taipei Veteran General Hospital, Taipei, Taiwan
| |
Collapse
|
|
19
|
Yang X, Li Q, Liu W, Zong C, Wei L, Shi Y, Han Z. Mesenchymal stromal cells in hepatic fibrosis/cirrhosis: from pathogenesis to treatment. Cell Mol Immunol 2023; 20:583-599. [PMID: 36823236 PMCID: PMC10229624 DOI: 10.1038/s41423-023-00983-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 01/29/2023] [Indexed: 02/25/2023] Open
Abstract
Hepatic fibrosis/cirrhosis is a significant health burden worldwide, resulting in liver failure or hepatocellular carcinoma (HCC) and accounting for many deaths each year. The pathogenesis of hepatic fibrosis/cirrhosis is very complex, which makes treatment challenging. Endogenous mesenchymal stromal cells (MSCs) have been shown to play pivotal roles in the pathogenesis of hepatic fibrosis. Paradoxically, exogenous MSCs have also been used in clinical trials for liver cirrhosis, and their effectiveness has been observed in most completed clinical trials. There are still many issues to be resolved to promote the use of MSCs in the clinic in the future. In this review, we will examine the controversial role of MSCs in the pathogenesis and treatment of hepatic fibrosis/cirrhosis. We also investigated the clinical trials involving MSCs in liver cirrhosis, summarized the parameters that need to be standardized, and discussed how to promote the use of MSCs from a clinical perspective.
Collapse
Affiliation(s)
- Xue Yang
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Key Laboratory of Stem Cells and Medical Biomaterials of Jiangsu Province, Medical College of Soochow University, Soochow University, Suzhou, 215000, China
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Qing Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Wenting Liu
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Chen Zong
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Lixin Wei
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Yufang Shi
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Key Laboratory of Stem Cells and Medical Biomaterials of Jiangsu Province, Medical College of Soochow University, Soochow University, Suzhou, 215000, China.
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy.
| | - Zhipeng Han
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China.
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China.
| |
Collapse
|
|
20
|
Zhang J, Liao JQ, Wen LR, Padhiar AA, Li Z, He ZY, Wu HC, Li JF, Zhang S, Zhou Y, Pan XH, Yang JH, Zhou GQ. Rps6ka2 enhances iMSC chondrogenic differentiation to attenuate knee osteoarthritis through articular cartilage regeneration in mice. Biochem Biophys Res Commun 2023; 663:61-70. [PMID: 37119767 DOI: 10.1016/j.bbrc.2023.04.049] [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: 02/26/2023] [Revised: 03/14/2023] [Accepted: 04/17/2023] [Indexed: 05/01/2023]
Abstract
Articular cartilage (AC) is most susceptible to degeneration in knee osteoarthritis (OA); however, the existing treatments for OA do not target the core link of the pathogenesis-"decreased tissue cell function activity and extracellular matrix (ECM) metabolic disorders" for effective intervention. iMSC hold lower heterogeneity and great promise in biological research and clinical applications. Rps6ka2 may play an important role in the iMSC to treat OA. In this study, the CRISPR/Cas9 gene editing Rps6ka2-/- iMSC were obtained. Effect of Rps6ka2 on iMSC proliferation and chondrogenic differentiation was evaluated in vitro. An OA model was constructed in mice by surgical destabilization of medial meniscus (DMM). The Rps6ka2-/- iMSC and iMSC were injected into the articular cavity twice-weekly for 8 weeks. In vitro experiments showed that Rps6ka2 could promote iMSC proliferation and chondrogenic differentiation. In vivo results further confirmed that Rps6ka2 could improve iMSC viability to promote ECM production to attenuate OA in mice.
Collapse
Affiliation(s)
- Juan Zhang
- Department of Medical Cell Biology and Genetics, Guangdong Key Laboratory of Genomic Stability and Disease Prevention, Shenzhen Key Laboratory of Anti-Aging and Regenerative Medicine, Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopaedic Diseases, Health Science Center, Shenzhen University, Shenzhen, 518107, China; The Affiliated Nanhua Hospital, Department of Endocrinology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
| | - Jin-Qi Liao
- Lungene Biotech Ltd., Longhua District, Shenzhen, 518107, China.
| | - Li-Ru Wen
- Department of Medical Cell Biology and Genetics, Guangdong Key Laboratory of Genomic Stability and Disease Prevention, Shenzhen Key Laboratory of Anti-Aging and Regenerative Medicine, Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopaedic Diseases, Health Science Center, Shenzhen University, Shenzhen, 518107, China.
| | - Arshad-Ahmed Padhiar
- Department of Medical Cell Biology and Genetics, Guangdong Key Laboratory of Genomic Stability and Disease Prevention, Shenzhen Key Laboratory of Anti-Aging and Regenerative Medicine, Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopaedic Diseases, Health Science Center, Shenzhen University, Shenzhen, 518107, China.
| | - Zhu Li
- Department of Medical Cell Biology and Genetics, Guangdong Key Laboratory of Genomic Stability and Disease Prevention, Shenzhen Key Laboratory of Anti-Aging and Regenerative Medicine, Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopaedic Diseases, Health Science Center, Shenzhen University, Shenzhen, 518107, China.
| | - Zhong-Yuan He
- Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopaedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
| | - Hua-Chuan Wu
- Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopaedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
| | - Jian-Feng Li
- Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopaedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
| | - Shuai Zhang
- Brain Research Centre and Department of Biology, Southern University of Science and Technology, Shenzhen, 518107, China.
| | - Yan Zhou
- Department of Medical Cell Biology and Genetics, Guangdong Key Laboratory of Genomic Stability and Disease Prevention, Shenzhen Key Laboratory of Anti-Aging and Regenerative Medicine, Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopaedic Diseases, Health Science Center, Shenzhen University, Shenzhen, 518107, China; Lungene Biotech Ltd., Longhua District, Shenzhen, 518107, China.
| | - Xiao-Hua Pan
- Department of Orthopaedics, The Second Affiliated Hospital of Shenzhen University, The Second School of Clinical Medicine, Southern Medical University, The Clinical Medical College of Guangdong Medical University, People's Hospital of Shenzhen Baoan District, Shenzhen, 518107, China.
| | - Jian-Hua Yang
- The Second Affiliated Hospital, The Chinese University of Hong Kong, Shenzhen & Longgang District People's Hospital of Shenzhen, Shenzhen, 518107, China.
| | - Guang-Qian Zhou
- Department of Medical Cell Biology and Genetics, Guangdong Key Laboratory of Genomic Stability and Disease Prevention, Shenzhen Key Laboratory of Anti-Aging and Regenerative Medicine, Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopaedic Diseases, Health Science Center, Shenzhen University, Shenzhen, 518107, China.
| |
Collapse
|
|
21
|
Kim J, Lee SK, Jung M, Jeong SY, You H, Won JY, Han SD, Cho HJ, Park S, Park J, Kim TM, Kim S. Extracellular vesicles from IFN-γ-primed mesenchymal stem cells repress atopic dermatitis in mice. J Nanobiotechnology 2022; 20:526. [PMID: 36496385 PMCID: PMC9741801 DOI: 10.1186/s12951-022-01728-8] [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: 09/02/2022] [Accepted: 11/28/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by immune dysregulation, pruritus, and abnormal epidermal barrier function. Compared with conventional mesenchymal stem cell (MSC), induced pluripotent stem cell (iPSC)-derived mesenchymal stem cell (iMSC) is recognized as a unique source for producing extracellular vesicles (EVs) because it can be obtained in a scalable manner with an enhanced homogeneity. Stimulation of iMSCs with inflammatory cytokines can improve the immune-regulatory, anti-inflammatory, and tissue-repairing potential of iMSC-derived EVs. RESULTS Proteome analysis showed that IFN-γ-iMSC-EVs are enriched with protein sets that are involved in regulating interferon responses and inflammatory pathways. In AD mice, expression of interleukin receptors for Th2 cytokines (IL-4Rα/13Rα1/31Rα) and activation of their corresponding intracellular signaling molecules was reduced. IFN-γ-iMSC-EVs decreased itching, which was supported by reduced inflammatory cell infiltration and mast cells in AD mouse skin; reduced IgE receptor expression and thymic stromal lymphopoietin and NF-kB activation; and recovered impaired skin barrier, as evidenced by upregulation of key genes of epidermal differentiation and lipid synthesis. CONCLUSIONS IFN-γ-iMSC-EVs inhibit Th2-induced immune responses, suppress inflammation, and facilitate skin barrier restoration, contributing to AD improvement.
Collapse
Affiliation(s)
- Jimin Kim
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Seul Ki Lee
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Minyoung Jung
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Seon-Yeong Jeong
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Haedeun You
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Ji-Yeon Won
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Sang-Deok Han
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Hye Jin Cho
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Somi Park
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Joonghoon Park
- grid.31501.360000 0004 0470 5905Graduate School of International Agricultural Technology, Seoul National University, Pyeongchang, Gangwon-do 25354 South Korea ,grid.31501.360000 0004 0470 5905Institutes of Green-Bio Science and Technology, Seoul National University, Pyeongchang, Gangwon-do 25354 South Korea
| | - Tae Min Kim
- grid.31501.360000 0004 0470 5905Graduate School of International Agricultural Technology, Seoul National University, Pyeongchang, Gangwon-do 25354 South Korea ,grid.31501.360000 0004 0470 5905Institutes of Green-Bio Science and Technology, Seoul National University, Pyeongchang, Gangwon-do 25354 South Korea
| | - Soo Kim
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| |
Collapse
|
|
22
|
Romanazzo S, Kopecky C, Jiang S, Doshi R, Mukund V, Srivastava P, Rnjak‐Kovacina J, Kelly K, Kilian KA. Biomaterials directed activation of a cryostable therapeutic secretome in induced pluripotent stem cell derived mesenchymal stromal cells. J Tissue Eng Regen Med 2022; 16:1008-1018. [PMID: 36017672 PMCID: PMC9804847 DOI: 10.1002/term.3347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 07/11/2022] [Accepted: 08/09/2022] [Indexed: 01/09/2023]
Abstract
Mesenchymal stem cell therapy has suffered from wide variability in clinical efficacy, largely due to heterogeneous starting cell populations and large-scale cell death during and after implantation. Optimizing the manufacturing process has led to reproducible cell populations that can be cryopreserved for clinical applications. Nevertheless, ensuring a reproducible cell state that persists after cryopreservation remains a significant challenge, and is necessary to ensure reproducible clinical outcomes. Here we demonstrate how matrix-conjugated hydrogel cell culture materials can normalize a population of induced pluripotent stem cell derived mesenchymal stem cells (iPSC-MSCs) to display a defined secretory profile that promotes enhanced neovascularization in vitro and in vivo. Using a protein-conjugated biomaterials screen we identified two conditions-1 kPa collagen and 10 kPa fibronectin coated polyacrylamide gels-that promote reproducible secretion of pro-angiogenic and immunomodulatory cytokines from iPSC-MSCs that enhance tubulogenesis of endothelial cells in Geltrex and neovascularization in chick chorioallantoic membranes. Using defined culture substrates alone, we demonstrate maintenance of secretory activity after cryopreservation for the first time. This advance provides a simple and scalable approach for cell engineering and subsequent manufacturing, toward normalizing and priming a desired cell activity for clinical regenerative medicine.
Collapse
Affiliation(s)
- Sara Romanazzo
- School of ChemistryAustralian Centre for NanoMedicineUniversity of New South WalesSydneyNew South WalesAustralia
| | - Chantal Kopecky
- School of ChemistryAustralian Centre for NanoMedicineUniversity of New South WalesSydneyNew South WalesAustralia
| | - Shouyuan Jiang
- Graduate School of Biomedical EngineeringUniversity of New South WalesSydneyNew South WalesAustralia
| | - Riddhesh Doshi
- School of ChemistryAustralian Centre for NanoMedicineUniversity of New South WalesSydneyNew South WalesAustralia
| | - Vipul Mukund
- School of ChemistryAustralian Centre for NanoMedicineUniversity of New South WalesSydneyNew South WalesAustralia
| | - Pallavi Srivastava
- School of ChemistryAustralian Centre for NanoMedicineUniversity of New South WalesSydneyNew South WalesAustralia,School of Medical SciencesUniversity of New South WalesSydneyNew South WalesAustralia
| | - Jelena Rnjak‐Kovacina
- Graduate School of Biomedical EngineeringUniversity of New South WalesSydneyNew South WalesAustralia
| | - Kilian Kelly
- Cynata Therapeutics LimitedCremorneVictoriaAustralia
| | - Kristopher A. Kilian
- School of ChemistryAustralian Centre for NanoMedicineUniversity of New South WalesSydneyNew South WalesAustralia,School of Materials Science and EngineeringUniversity of New South WalesSydneyNew South WalesAustralia
| |
Collapse
|
|
23
|
Recent Advances in Extracellular Vesicle-Based Therapies Using Induced Pluripotent Stem Cell-Derived Mesenchymal Stromal Cells. Biomedicines 2022; 10:biomedicines10092281. [PMID: 36140386 PMCID: PMC9496279 DOI: 10.3390/biomedicines10092281] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/09/2022] [Accepted: 09/11/2022] [Indexed: 11/26/2022] Open
Abstract
Extracellular vesicles (EVs) are being widely investigated as acellular therapeutics in regenerative medicine applications. EVs isolated from mesenchymal stromal cells (MSCs) are by far the most frequently used in preclinical models for diverse therapeutic applications, including inflammatory, degenerative, or acute diseases. Although they represent promising tools as cell-free therapeutic agents, one limitation to their use is related to the batch-to-batch unreliability that may arise from the heterogeneity between MSC donors. Isolating EVs from MSCs derived from induced pluripotent stem cells (iMSCs) might allow unlimited access to cells with a more stable phenotype and function. In the present review, we first present the latest findings regarding the functional aspects of EVs isolated from iMSCs and their interest in regenerative medicine for the treatment of various diseases. We will then discuss future directions for their translation to clinics with good manufacturing practice implementation.
Collapse
|
|
24
|
Gao S, Zhang Y, Liang K, Bi R, Du Y. Mesenchymal Stem Cells (MSCs): A Novel Therapy for Type 2 Diabetes. Stem Cells Int 2022; 2022:8637493. [PMID: 36045953 PMCID: PMC9424025 DOI: 10.1155/2022/8637493] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 02/15/2022] [Accepted: 07/05/2022] [Indexed: 11/25/2022] Open
Abstract
Although plenty of drugs are currently available for type 2 diabetes mellitus (T2DM), a subset of patients still failed to restore normoglycemia. Recent studies proved that symptoms of T2DM patients who are unresponsive to conventional medications could be relieved with mesenchymal stem/stromal cell (MSC) therapy. However, the lack of systematic summary and analysis for animal and clinical studies of T2DM has limited the establishment of standard guidelines in anti-T2DM MSC therapy. Besides, the therapeutic mechanisms of MSCs to combat T2DM have not been thoroughly understood. In this review, we present an overview of the current status of MSC therapy in treating T2DM for both animal studies and clinical studies. Potential mechanisms of MSC-based intervention on multiple pathological processes of T2DM, such as β-cell exhaustion, hepatic dysfunction, insulin resistance, and systemic inflammation, are also delineated. Moreover, we highlight the importance of understanding the pharmacokinetics (PK) of transplanted cells and discuss the hurdles in MSC-based T2DM therapy toward future clinical applications.
Collapse
Affiliation(s)
- Shuang Gao
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yuanyuan Zhang
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Kaini Liang
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Ran Bi
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yanan Du
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| |
Collapse
|
|
25
|
Wei Y, Wang B, Jia L, Huang W, Xiang AP, Fang C, Liang X, Li W. Lateral Mesoderm-Derived Mesenchymal Stem Cells With Robust Osteochondrogenic Potential and Hematopoiesis-Supporting Ability. Front Mol Biosci 2022; 9:767536. [PMID: 35573747 PMCID: PMC9095820 DOI: 10.3389/fmolb.2022.767536] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are among the most promising cell sources for the treatment of various diseases. Nonetheless, the therapeutic efficacy in clinical trials has been inconsistent due to the heterogeneity of MSCs, which may be partially attributed to their undefined developmental origins. The lateral mesoderm is also a developmental source of MSCs that constitute appendicular skeletal elements in the developing vertebrate embryo. However, it is difficult to isolate homogeneous lateral mesoderm (LM)-derived MSCs from bone tissues or bone marrow due to the lack of understanding of their characteristics. Herein, we successfully established an efficient differentiation protocol for the derivation of MSCs with a LM origin from human pluripotent stem cells (hPSCs) under specific conditions. LM-MSCs resembled bone marrow-derived MSCs (BMSCs) with regard to cell surface markers, global gene profiles, and immunoregulatory activity and showed a homeodomain transcription factor (HOX) gene expression pattern typical of skeletal MSCs in long bones. Moreover, we demonstrated that LM-MSCs had an increased osteogenic/chondrogenic differentiation capacity and hematopoietic support potential compared to BMSCs. These homogeneous LM-MSCs may serve as a powerful tool for elucidating their precise role in bone formation and hematopoiesis and could be a potentially ideal cell source for therapeutic applications.
Collapse
Affiliation(s)
- Yili Wei
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Bin Wang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Lei Jia
- Reproductive Medicine Research Center, Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Weijun Huang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Andy Peng Xiang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, China
| | - Cong Fang
- Reproductive Medicine Research Center, Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xiaoyan Liang
- Reproductive Medicine Research Center, Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- *Correspondence: Xiaoyan Liang, ; Weiqiang Li,
| | - Weiqiang Li
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, China
- *Correspondence: Xiaoyan Liang, ; Weiqiang Li,
| |
Collapse
|
|
26
|
Li Y, Hao J, Hu Z, Yang YG, Zhou Q, Sun L, Wu J. Current status of clinical trials assessing mesenchymal stem cell therapy for graft versus host disease: a systematic review. Stem Cell Res Ther 2022; 13:93. [PMID: 35246235 PMCID: PMC8895864 DOI: 10.1186/s13287-022-02751-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 01/31/2022] [Indexed: 12/11/2022] Open
Abstract
Background Graft-versus-host disease (GVHD) is a common fatal complication of hematopoietic stem cell transplantation (HSCT), where steroids are used as a treatment option. However, there are currently no second-line treatments for patients that develop steroid-resistance (SR). Mesenchymal stem cells (MSCs) have immunomodulatory functions and can exert immunosuppressive effects on the inflammatory microenvironment. A large number of in vitro experiments have confirmed that MSCs can significantly inhibit the proliferation or activation of innate and adaptive immune cells. In a mouse model of GVHD, MSCs improved weight loss and increased survival rate. Therefore, there is great promise for the clinical translation of MSCs for the prevention or treatment of GVHD, and several clinical trials have already been conducted to date. Main body In this study, we searched multiple databases and found 79 clinical trials involving the use of MSCs to prevent or treat GVHD and summarized the characteristics of these clinical trials, including study design, phase, status, and locations. We analyzed the results of these clinical trials, including the response and survival rates, to enable researchers to obtain a comprehensive understanding of the field’s progress, challenges, limitations, and future development trends. Additionally, factors that might result in inconsistencies in clinical trial results were discussed. Conclusion In this study, we attempted to analyze the clinical trials for MSCs in GVHD, identify the most suitable group of patients for MSC therapy, and provide a new perspective for the design of such trials in the future. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02751-0.
Collapse
Affiliation(s)
- Ying Li
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China.,Department of Gastroenterology, The First Hospital, Jilin University, Changchun, 130021, China
| | - Jie Hao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China
| | - Zheng Hu
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China.,International Center of Future Science, Jilin University, Changchun, 130021, China
| | - Qi Zhou
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. .,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Liguang Sun
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China. .,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China.
| | - Jun Wu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. .,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China.
| |
Collapse
|
|
27
|
Liu TM. Application of mesenchymal stem cells derived from human pluripotent stem cells in regenerative medicine. World J Stem Cells 2021; 13:1826-1844. [PMID: 35069985 PMCID: PMC8727229 DOI: 10.4252/wjsc.v13.i12.1826] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/29/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) represent the most clinically used stem cells in regenerative medicine. However, due to the disadvantages with primary MSCs, such as limited cell proliferative capacity and rarity in the tissues leading to limited MSCs, gradual loss of differentiation during in vitro expansion reducing the efficacy of MSC application, and variation among donors increasing the uncertainty of MSC efficacy, the clinical application of MSCs has been greatly hampered. MSCs derived from human pluripotent stem cells (hPSC-MSCs) can circumvent these problems associated with primary MSCs. Due to the infinite self-renewal of hPSCs and their differentiation potential towards MSCs, hPSC-MSCs are emerging as an attractive alternative for regenerative medicine. This review summarizes the progress on derivation of MSCs from human pluripotent stem cells, disease modelling and drug screening using hPSC-MSCs, and various applications of hPSC-MSCs in regenerative medicine. In the end, the challenges and concerns with hPSC-MSC applications are also discussed.
Collapse
Affiliation(s)
- Tong-Ming Liu
- Agency for Science, Technology and Research, Institute of Molecular and Cell Biology, Singapore 138648, Singapore.
| |
Collapse
|
|
28
|
Liu X, Robbins S, Wang X, Virk S, Schuck K, Deveza LA, Oo WM, Carmichael K, Antony B, Eckstein F, Wirth W, Little C, Linklater J, Harris A, Humphries D, O'Connell R, Heller G, Buttel T, Lohmander S, Ding C, Hunter DJ. Efficacy and cost-effectiveness of Stem Cell injections for symptomatic relief and strUctural improvement in people with Tibiofemoral knee OsteoaRthritis: protocol for a randomised placebo-controlled trial (the SCUlpTOR trial). BMJ Open 2021; 11:e056382. [PMID: 34845081 PMCID: PMC8633994 DOI: 10.1136/bmjopen-2021-056382] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION Knee osteoarthritis (KOA) is a highly prevalent disabling joint disease. Intra-articular stem cell therapy is increasingly being used for treating KOA with little high-quality evidence to support its use. The aim of this study is to investigate the efficacy, safety and cost-effectiveness of allogeneic mesenchymal stem cells (Cymerus MSCs) for treating symptomatic tibiofemoral KOA and improving knee structure over 24 months. METHODS AND ANALYSIS The Stem Cell injections for symptomatic relief and strUctural improvement in people with Tibiofemoral knee OsteoaRthritis study is a phase III, multi-centre, parallel, superiority, randomised, double-blind, placebo-controlled trial, which will be conducted in Sydney and Hobart, Australia. 440 participants (220 per arm) aged over 40 years with painful KOA and mild to moderate structural change on X-ray (Kellgren and Lawrence grade 2 or 3) with medial minimum joint space width between 1 and 4 mm in the study knee will be recruited from the community and randomly allocated to receive either intra-articular MSCs or saline at baseline, week 3 and week 52. The coprimary outcomes will be the proportion of participants achieving patient-acceptable symptom state for knee pain at 24 months and quantitative central medial femorotibial compartment cartilage thickness change from baseline to 24 months. Main secondary outcomes include change in knee pain, Patient Global Assessment, physical function, quality of life and other structural changes. Additional data for cost-effectiveness analysis will also be recorded. Adverse events will be monitored throughout the study. The primary analysis will be conducted using modified intention-to-treat. ETHICS AND DISSEMINATION This protocol has been approved by The University of Sydney (USYD) Human Research Ethics Committee (HREC) #: 2020/119 and The University of Tasmania (UTAS) HREC #: H0021868. All participants will be required to provide informed consent. Dissemination will occur through conferences, social media, and scientific publications. TRIAL REGISTRATION NUMBERS Australian New Zealand Clinical Trials Registry (ACTRN12620000870954); U1111-1234-4897.
Collapse
Affiliation(s)
- Xiaoqian Liu
- Department of Rheumatology, Royal North Shore Hospital, Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Institute of Bone and Joint Research, Kolling Institute of Medical Research, The University of Sydney, Sydney, New South Wales, Australia
| | - Sarah Robbins
- Department of Rheumatology, Royal North Shore Hospital, Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Institute of Bone and Joint Research, Kolling Institute of Medical Research, The University of Sydney, Sydney, New South Wales, Australia
| | - Xia Wang
- Department of Rheumatology, Royal North Shore Hospital, Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Institute of Bone and Joint Research, Kolling Institute of Medical Research, The University of Sydney, Sydney, New South Wales, Australia
| | - Sonika Virk
- Department of Rheumatology, Royal North Shore Hospital, Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Institute of Bone and Joint Research, Kolling Institute of Medical Research, The University of Sydney, Sydney, New South Wales, Australia
| | - Karen Schuck
- Department of Rheumatology, Royal North Shore Hospital, Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Institute of Bone and Joint Research, Kolling Institute of Medical Research, The University of Sydney, Sydney, New South Wales, Australia
| | - Leticia A Deveza
- Department of Rheumatology, Royal North Shore Hospital, Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Institute of Bone and Joint Research, Kolling Institute of Medical Research, The University of Sydney, Sydney, New South Wales, Australia
| | - Win Min Oo
- Department of Rheumatology, Royal North Shore Hospital, Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Institute of Bone and Joint Research, Kolling Institute of Medical Research, The University of Sydney, Sydney, New South Wales, Australia
| | - Kirsty Carmichael
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
| | - Benny Antony
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
| | - Felix Eckstein
- Institute of Anatomy and Cell Biology and Ludwig Boltzmann Institute for Arthritis and Rehabilitation, Paracelsus Medical University Salzburg, Salzburg, Austria
- Chondrometrics GmbH, Freilassing, Germany
| | - Wolfgang Wirth
- Institute of Anatomy and Cell Biology and Ludwig Boltzmann Institute for Arthritis and Rehabilitation, Paracelsus Medical University Salzburg, Salzburg, Austria
- Chondrometrics GmbH, Freilassing, Germany
| | - Christopher Little
- Raymond Purves Bone and Joint Research Labs, Kolling Institute of Medical Research, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - James Linklater
- Castlereagh Imaging, St Leonards, Sydney, New South Wales, Australia
| | - Anthony Harris
- Centre for Health Economics, Monash University, Clayton, Victoria, Australia
| | - David Humphries
- School of Medicine, College of Health and Medicine, University of Tasmania Faculty of Health, Hobart, Tasmania, Australia
| | - R O'Connell
- NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - Gillian Heller
- NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - Thomas Buttel
- Representative of People with Knee Osteoarthritis, Sydney, New South Wales, Australia
| | - Stefan Lohmander
- Department of Clinical Sciences Lund, Orthopaedics, Lund University, Lund, Sweden
| | - Changhai Ding
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - David J Hunter
- Department of Rheumatology, Royal North Shore Hospital, Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Institute of Bone and Joint Research, Kolling Institute of Medical Research, The University of Sydney, Sydney, New South Wales, Australia
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| |
Collapse
|
|
29
|
Kelly K, Rasko JEJ. Mesenchymal Stromal Cells for the Treatment of Graft Versus Host Disease. Front Immunol 2021; 12:761616. [PMID: 34764962 PMCID: PMC8577186 DOI: 10.3389/fimmu.2021.761616] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/07/2021] [Indexed: 12/28/2022] Open
Abstract
Graft versus host disease (GvHD) is a life-threating complication of allogeneic hematopoietic stem cell transplantation, which is initially treated with high dose corticosteroids. Approximately 50% of acute GvHD cases are resistant to steroid treatment, and two-year mortality rates in those steroid-resistant patients exceed 80%. Chronic GvHD necessitates prolonged corticosteroid use, which is typically associated with limited efficacy and troublesome adverse effects. No agent has yet been established as an optimal second line therapy for either acute or chronic GvHD, but mesenchymal stromal cells (MSCs) have shown substantial promise. MSCs promote an immunosuppressive and immunoregulatory environment via multifactorial mechanisms, including: secretion of proteins/peptides/hormones; transfer of mitochondria; and transfer of exosomes or microvesicles containing RNA and other molecules. A large number of clinical studies have investigated MSCs from various sources as a treatment for acute and/or chronic GvHD. MSCs are generally safe and well tolerated, and most clinical studies have generated encouraging efficacy results, but response rates have varied. Confounding factors include variability in MSC donor types, production methodology and dose regimens, as well as variations in study design. It is well-established that extensive culture expansion of primary donor-derived MSCs leads to marked changes in functionality, and that there is a high level of inter-donor variability in MSC properties. However, recent manufacturing innovations may be capable of overcoming these problems. Further adequately powered prospective studies are required to confirm efficacy and establish the place of MSC therapy in the treatment of this condition.
Collapse
Affiliation(s)
- Kilian Kelly
- Cynata Therapeutics Limited, Cremorne, VIC, Australia
| | - John E J Rasko
- Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Gene and Stem Cell Therapy Program Centenary Institute, University of Sydney, Sydney, NSW, Australia.,Central Clinical School, Faculty of Medicine & Health, University of Sydney, Sydney, NSW, Australia
| |
Collapse
|
|
30
|
Induced pluripotency in the context of stem cell expansion bioprocess development, optimization, and manufacturing: a roadmap to the clinic. NPJ Regen Med 2021; 6:72. [PMID: 34725374 PMCID: PMC8560749 DOI: 10.1038/s41536-021-00183-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 10/07/2021] [Indexed: 11/09/2022] Open
Abstract
The translation of laboratory-scale bioprocess protocols and technologies to industrial scales and the application of human induced pluripotent stem cell (hiPSC) derivatives in clinical trials globally presents optimism for the future of stem-cell products to impact healthcare. However, while many promising therapeutic approaches are being tested in pre-clinical studies, hiPSC-derived products currently account for a small fraction of active clinical trials. The complexity and volatility of hiPSCs present several bioprocessing challenges, where the goal is to generate a sufficiently large, high-quality, homogeneous population for downstream differentiation-the derivatives of which must retain functional efficacy and meet regulatory safety criteria in application. It is argued herein that one of the major challenges currently faced in improving the robustness of routine stem-cell biomanufacturing is in utilizing continuous, meaningful assessments of molecular and cellular characteristics from process to application. This includes integrating process data with biological characteristic and functional assessment data to model the interplay between variables in the search for global optimization strategies. Coupling complete datasets with relevant computational methods will contribute significantly to model development and automation in achieving process robustness. This overarching approach is thus crucially important in realizing the potential of hiPSC biomanufacturing for transformation of regenerative medicine and the healthcare industry.
Collapse
|
|
31
|
Zhang J, Chen M, Liao J, Chang C, Liu Y, Padhiar AA, Zhou Y, Zhou G. Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Hold Lower Heterogeneity and Great Promise in Biological Research and Clinical Applications. Front Cell Dev Biol 2021; 9:716907. [PMID: 34660579 PMCID: PMC8514743 DOI: 10.3389/fcell.2021.716907] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 09/03/2021] [Indexed: 01/14/2023] Open
Abstract
Mesenchymal stem cells (MSC) isolated from different tissue sources exhibit multiple biological effects and have shown promising therapeutic effects in a broad range of diseases. In order to fulfill their clinical applications in context of precision medicine, however, more detailed molecular characterization of diverse subgroups and standardized scalable production of certain functional subgroups would be highly desired. Thus far, the generation of induced pluripotent stem cell (iPSC)-derived MSC (iMSC) seems to provide the unique opportunity to solve most obstacles that currently exist to prevent the broad application of MSC as an advanced medicinal product. The features of iMSC include their single cell clone origins, and defined and controllable cultural conditions for their derivation and proliferation. Still, comprehensive research of the molecular and functional heterogeneity of iMSC, just like MSC from any other tissue types, would be required. Furthered on previous efforts on iMSC differentiation and expansion platform and transcriptomic studies, advantages of single cell multi-omics analysis and other up-to-dated technologies would be taken in order to elucidate the molecular origin and regulation of heterogeneity and to obtain iMSC subgroups homogeneous enough for particular clinical conditions. In this perspective, the current obstacles in MSC applications, the advantages of iMSC over MSC and their implications for biological research and clinical applications will be discussed.
Collapse
Affiliation(s)
- Juan Zhang
- Guangdong Key Laboratory of Genomic Stability and Disease Prevention, Shenzhen Key Laboratory of Anti-Aging and Regenerative Medicine, Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases, Department of Medical Cell Biology and Genetics, Health Science Center, Shenzhen University, Shenzhen, China.,Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, China
| | - Mingzhuang Chen
- Guangdong Key Laboratory of Genomic Stability and Disease Prevention, Shenzhen Key Laboratory of Anti-Aging and Regenerative Medicine, Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases, Department of Medical Cell Biology and Genetics, Health Science Center, Shenzhen University, Shenzhen, China.,Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, China.,Shenzhen University General Hospital, Shenzhen, China
| | | | | | - Yuqing Liu
- Cheerland Danlun Biopharma Co., Ltd., Shenzhen, China
| | | | - Yan Zhou
- Lungene Biotech Ltd., Shenzhen, China
| | - Guangqian Zhou
- Guangdong Key Laboratory of Genomic Stability and Disease Prevention, Shenzhen Key Laboratory of Anti-Aging and Regenerative Medicine, Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases, Department of Medical Cell Biology and Genetics, Health Science Center, Shenzhen University, Shenzhen, China.,Senotherapeutics Ltd., Hangzhou, China.,Central Laboratory, Longgang District People's Hospital of Shenzhen and The Third Affiliated Hospital (Provisional) of The Chinese University of Hong Kong, Shenzhen, China
| |
Collapse
|
|
32
|
Wruck W, Graffmann N, Spitzhorn LS, Adjaye J. Human Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Acquire Rejuvenation and Reduced Heterogeneity. Front Cell Dev Biol 2021; 9:717772. [PMID: 34604216 PMCID: PMC8481886 DOI: 10.3389/fcell.2021.717772] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/17/2021] [Indexed: 12/20/2022] Open
Abstract
Despite the uniform selection criteria for the isolation of human mesenchymal stem cells (MSCs), considerable heterogeneity exists which reflects the distinct tissue origins and differences between individuals with respect to their genetic background and age. This heterogeneity is manifested by the variabilities seen in the transcriptomes, proteomes, secretomes, and epigenomes of tissue-specific MSCs. Here, we review literature on different aspects of MSC heterogeneity including the role of epigenetics and the impact of MSC heterogeneity on therapies. We then combine this with a meta-analysis of transcriptome data from distinct MSC subpopulations derived from bone marrow, adipose tissue, cruciate, tonsil, kidney, umbilical cord, fetus, and induced pluripotent stem cells derived MSCs (iMSCs). Beyond that, we investigate transcriptome differences between tissue-specific MSCs and pluripotent stem cells. Our meta-analysis of numerous MSC-related data sets revealed markers and associated biological processes characterizing the heterogeneity and the common features of MSCs from various tissues. We found that this heterogeneity is mainly related to the origin of the MSCs and infer that microenvironment and epigenetics are key drivers. The epigenomes of MSCs alter with age and this has a profound impact on their differentiation capabilities. Epigenetic modifications of MSCs are propagated during cell divisions and manifest in differentiated cells, thus contributing to diseased or healthy phenotypes of the respective tissue. An approach used to reduce heterogeneity caused by age- and tissue-related epigenetic and microenvironmental patterns is the iMSC concept: iMSCs are MSCs generated from induced pluripotent stem cells (iPSCs). During iMSC generation epigenetic and chromatin remodeling result in a gene expression pattern associated with rejuvenation thus allowing to overcome age-related shortcomings (e.g., limited differentiation and proliferation capacity). The importance of the iMSC concept is underlined by multiple clinical trials. In conclusion, we propose the use of rejuvenated iMSCs to bypass tissue- and age-related heterogeneity which are associated with native MSCs.
Collapse
Affiliation(s)
- Wasco Wruck
- Medical Faculty, Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Nina Graffmann
- Medical Faculty, Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Lucas-Sebastian Spitzhorn
- Medical Faculty, Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - James Adjaye
- Medical Faculty, Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| |
Collapse
|
|
33
|
Karimi-Shahri M, Javid H, Sharbaf Mashhad A, Yazdani S, Hashemy SI. Mesenchymal stem cells in cancer therapy; the art of harnessing a foe to a friend. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:1307-1323. [PMID: 35096289 PMCID: PMC8769515 DOI: 10.22038/ijbms.2021.58227.12934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 08/04/2021] [Indexed: 12/09/2022]
Abstract
For a long time, mesenchymal stem cells (MSCs) were discussed only as stem cells which could give rise to different types of cells. However, when it became clear that their presence in the tumor microenvironment (TME) was like a green light for tumorigenesis, they emerged from the ashes. This review was arranged to provide a comprehensive and precise description of MSCs' role in regulating tumorigenesis and to discuss the dark and the bright sides of cancer treatment strategies using MSCs. To gather the details about MSCs, we made an intensive literature review using keywords, including MSCs, tumor microenvironment, tumorigenesis, and targeted therapy. Through transferring cytokines, growth factors, and microRNAs, MSCs maintain the cancer stem cell population, increase angiogenesis, provide a facility for cancer metastasis, and shut down the anti-tumor activity of the immune system. Although MSCs progress tumorigenesis, there is a consensus that these cells could be used as a vehicle to transfer anti-cancer agents into the tumor milieu. This feature opened a new chapter in MSCs biology, this time from the therapeutic perspective. Although the data are not sufficient, the advent of new genetic engineering methods might make it possible to engage these cells as Trojan horses to eliminate the malignant population. So many years of investigation showed that MSCs are an important group of cells, residing in the TME, studying the function of which not only could add a delicate series of information to the process of tumorigenesis but also could revolutionize cancer treatment strategies.
Collapse
Affiliation(s)
- Mehdi Karimi-Shahri
- Department of Pathology, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
- Department of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Javid
- Department of Medical Laboratory Sciences, Varastegan Institute for Medical Sciences, Mashhad, Iran
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Sharbaf Mashhad
- Department of Medical Laboratory Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shaghayegh Yazdani
- Department of Medical Laboratory Sciences, Ilam Institute for Medical Sciences, Ilam, Iran
| | - Seyed Isaac Hashemy
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
34
|
Pluripotent stem cell-derived mesenchymal stromal cells improve cardiac function and vascularity after myocardial infarction. Cytotherapy 2021; 23:1074-1084. [PMID: 34588150 DOI: 10.1016/j.jcyt.2021.07.016] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 07/27/2021] [Accepted: 07/28/2021] [Indexed: 01/10/2023]
Abstract
BACKGROUND AIMS Mesenchymal stromal cells (MSCs) have been shown to improve cardiac function after injury and are the subject of ongoing clinical trials. In this study, the authors tested the cardiac regenerative potential of an induced pluripotent stem cell-derived MSC (iPSC-MSC) population (Cymerus MSCs) in a rat model of myocardial ischemia-reperfusion (I/R). Furthermore, the authors compared this efficacy with bone marrow-derived MSCs (BM-MSCs), which are the predominant cell type in clinical trials. METHODS Four days after myocardial I/R injury, rats were randomly assigned to (i) a Cymerus MSC group (n = 15), (ii) a BM-MSC group (n = 15) or (iii) a vehicle control group (n = 14). For cell-treated animals, a total of 5 × 106 cells were injected at three sites within the infarcted left ventricular (LV) wall. RESULTS One month after cell transplantation, Cymerus MSCs improved LV function (assessed by echocardiography) compared with vehicle and BM-MSCs. Interestingly, Cymerus MSCs enhanced angiogenesis without sustained engraftment or significant impact on infarct scar size. Suggesting safety, Cymerus MSCs had no effect on inducible tachycardia or the ventricular scar heterogeneity that provides a substrate for cardiac re-entrant circuits. CONCLUSIONS The authors here demonstrate that intra-myocardial administration of iPSC-MSCs (Cymerus MSCs) provide better therapeutic effects compared with conventional BM-MSCs in a rodent model of myocardial I/R. Because of its manufacturing scalability, iPSC-MSC therapy offers an exciting opportunity for an "off-the-shelf" stem cell therapy for cardiac repair.
Collapse
|
|
35
|
Kim JY, Nam Y, Rim YA, Ju JH. Review of the Current Trends in Clinical Trials Involving Induced Pluripotent Stem Cells. Stem Cell Rev Rep 2021; 18:142-154. [PMID: 34532844 PMCID: PMC8445612 DOI: 10.1007/s12015-021-10262-3] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2021] [Indexed: 01/25/2023]
Abstract
In 2006, the induced pluripotent stem cell (iPSC) was presented to the world, paving the way for the development of a magnitude of novel therapeutic alternatives, addressing a diverse range of diseases. However, despite the immense cell therapy potential, relatively few clinical trials evaluating iPSC-technology have actually translated into interventional, clinically applied treatment regimens. Herein, our aim was to determine trends in globally conducted clinical trials involving iPSCs. Data were derived both from well-known registries recording clinical trials from across the globe, and databases from individual countries. Comparisons were firstly drawn between observational and interventional studies before the latter was further analyzed in terms of therapeutic and nontherapeutic trials. Our main observations included global distribution, purpose, target size, and types of disorder relevant to evaluated trials. In terms of nontherapeutic trials, the USA conducted the majority, a large average number of participants-187-was included in the trials, and studies on circulatory system disorders comprised a slightly higher proportion of total studies. Conversely, Japan was the frontrunner in terms of conducting therapeutic trials, and the average number of participants was much lower, at roughly 29. Disorders of the circulatory, as well as nervous and visual systems, were all studied in equal measure. This review highlights the impact that iPSC-based cell therapies can have, should development thereof gain more traction. We lastly considered a few companies that are actively utilizing iPSCs in the development of therapies for various diseases, for whom the global trends in clinical trials could become increasingly important.
Collapse
Affiliation(s)
- Jennifer Yejean Kim
- Department of Biology, Georgetown University, Washington, DC, USA
- CiSTEM Laboratory, Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yoojun Nam
- CiSTEM Laboratory, Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yeri Alice Rim
- CiSTEM Laboratory, Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ji Hyeon Ju
- CiSTEM Laboratory, Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
- Division of Rheumatology, Department of Internal Medicine, St. Mary's Hospital, Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Korea.
| |
Collapse
|
|
36
|
Johnson J, Shojaee M, Mitchell Crow J, Khanabdali R. From Mesenchymal Stromal Cells to Engineered Extracellular Vesicles: A New Therapeutic Paradigm. Front Cell Dev Biol 2021; 9:705676. [PMID: 34409037 PMCID: PMC8366519 DOI: 10.3389/fcell.2021.705676] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 06/29/2021] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are multipotent cells obtained from many tissues including bone marrow, adipose tissue, umbilical cord, amniotic fluid, and placenta. MSCs are the leading cell source for stem cell therapy due to their regenerative and immunomodulatory properties, their low risk of tumorigenesis and lack of ethical constraints. However, clinical applications of MSCs remain limited. MSC therapeutic development continues to pose challenges in terms of preparation, purity, consistency, efficiency, reproducibility, processing time and scalability. Additionally, there are issues with their poor engraftment and survival in sites of disease or damage that limit their capacity to directly replace damaged cells. A key recent development in MSC research, however, is the now widely accepted view that MSCs primarily exert therapeutic effects via paracrine factor secretion. One of the major paracrine effectors are extracellular vesicles (EVs). EVs represent a potential cell-free alternative to stem cell therapy but are also rapidly emerging as a novel therapeutic platform in their own right, particularly in the form of engineered EVs (EEVs) tailored to target a broad range of clinical indications. However, the development of EVs and EEVs for therapeutic application still faces a number of hurdles, including the establishment of a consistent, scalable cell source, and the development of robust GMP-compliant upstream and downstream manufacturing processes. In this review we will highlight the clinical challenges of MSC therapeutic development and discuss how EVs and EEVs can overcome the challenges faced in the clinical application of MSCs.
Collapse
Affiliation(s)
- Jancy Johnson
- Exopharm Ltd., Melbourne, VIC, Australia.,Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, VIC, Australia
| | | | | | | |
Collapse
|
|
37
|
Borziak K, Parvanova I, Finkelstein J. ReMeDy: a platform for integrating and sharing published stem cell research data with a focus on iPSC trials. Database (Oxford) 2021; 2021:baab038. [PMID: 34156448 PMCID: PMC8218701 DOI: 10.1093/database/baab038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 05/25/2021] [Accepted: 05/28/2021] [Indexed: 12/28/2022]
Abstract
ABSTRACT Recent regenerative medicine studies have emphasized the need for increased standardization, harmonization and sharing of information related to stem cell product characterization, to help drive these innovative interventions toward public availability and to increase collaboration in the scientific community. Although numerous attempts and numerous databases have been made to manage these data, a platform that incorporates all the heterogeneous data collected from stem cell projects into a harmonized project-based framework is still lacking. The aim of the database, which is described in this study, is to provide an intelligent informatics solution that integrates comprehensive characterization of diverse stem cell product characteristics with research subject and project outcome information. In the resulting platform, heterogeneous data are validated using predefined ontologies and stored in a relational database, to ensure data quality and ease of access. Testing was performed using 51 published, publically available induced pluripotent stem cell projects conducted in clinical, preclinical and in-vitro evaluations. Future aims of this project include further increasing the database size to include all published stem cell trials and develop additional data visualization tools to improve usability. Our testing demonstrated the robustness of the proposed platform, by seamlessly harmonizing diverse common data elements, and the potential of this platform for driving knowledge generation from the aggregation and harmonization of these diverse data. DATABASE URL https://remedy.mssm.edu/.
Collapse
Affiliation(s)
- Kirill Borziak
- Center for Biomedical and Population Health Informatics, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Icahn L2-36, New York, NY 10029, USA
| | - Irena Parvanova
- Center for Biomedical and Population Health Informatics, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Icahn L2-36, New York, NY 10029, USA
| | - Joseph Finkelstein
- Center for Biomedical and Population Health Informatics, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Icahn L2-36, New York, NY 10029, USA
| |
Collapse
|
|
38
|
Spellicy SE, Hess DC. The Immunomodulatory Capacity of Induced Pluripotent Stem Cells in the Post-stroke Environment. Front Cell Dev Biol 2021; 9:647415. [PMID: 33796535 PMCID: PMC8007866 DOI: 10.3389/fcell.2021.647415] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 02/25/2021] [Indexed: 11/13/2022] Open
Abstract
Inflammation has proven to be a key contributing factor to the pathogenesis of ischemic and hemorrhagic stroke. This sequential and progressive response, marked by proliferation of resident immune cells and recruitment of peripheral immune populations, results in increased oxidative stress, and neuronal cell death. Therapeutics aimed at quelling various stages of this post-stroke inflammatory response have shown promise recently, one of which being differentiated induced pluripotent stem cells (iPSCs). While direct repopulation of damaged tissues and enhanced neurogenesis are hypothesized to encompass some of the therapeutic potential of iPSCs, recent evidence has demonstrated a substantial paracrine effect on neuroinflammation. Specifically, investigation of iPSCs, iPSC-neural progenitor cells (iPSC-NPCs), and iPSC-neuroepithelial like stem cells (iPSC-lt-NESC) has demonstrated significant immunomodulation of proinflammatory signaling and endogenous inflammatory cell populations, such as microglia. This review aims to examine the mechanisms by which iPSCs mediate neuroinflammation in the post-stroke environment, as well as delineate avenues for further investigation.
Collapse
Affiliation(s)
- Samantha E Spellicy
- MD-Ph.D. Program, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - David C Hess
- Dean's Office, Medical College of Georgia at Augusta University, Augusta, GA, United States
| |
Collapse
|
|
39
|
Nozaki T, Takahashi M, Ishikawa T, Haino A, Seki M, Kikuchi H, Yuan B, Nashimoto M. The heptamer sgRNA targeting the human OCT4 mRNA can upregulate the OCT4 expression. Biochem Biophys Rep 2021; 26:100918. [PMID: 33553691 PMCID: PMC7859166 DOI: 10.1016/j.bbrep.2021.100918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 12/24/2020] [Accepted: 01/07/2021] [Indexed: 11/17/2022] Open
Abstract
TRUE gene silencing is one of the gene suppression technologies. This technology exploits the enzymatic property of the tRNA 3' processing endoribonuclease tRNase ZL, which is that it can cleave a target RNA under the direction of a small guide RNA (sgRNA). We have been working on the development of therapeutic sgRNAs for hematological malignancies. In the course of an experiment to examine the ability of the heptamer-type sgRNA H15792 targeting the OCT4 mRNA to differentiate human amnion stem cells, we observed unexpectedly that the amnion cells exhibited a morphology resembling initialized cells. Here we investigated the effect of H15792 on human HL60 leukemia cells, and found that H15792 can upregulate the OCT4 expression and the expression of alkaline phosphatase in the cells.
Collapse
Affiliation(s)
- Tadasuke Nozaki
- Department of Clinical Molecular Genetics, Faculty of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Horinouchi 1432-1, Hachioji, Tokyo, 192-0392, Japan
| | - Masayuki Takahashi
- Research Institute for Healthy Living, Niigata University of Pharmacy and Applied Life Sciences, Higashijima 265-1, Akihaku, Niigata, Niigata, 956-8603, Japan
| | - Tatsuya Ishikawa
- Research Institute for Healthy Living, Niigata University of Pharmacy and Applied Life Sciences, Higashijima 265-1, Akihaku, Niigata, Niigata, 956-8603, Japan
| | - Arisa Haino
- Research Institute for Healthy Living, Niigata University of Pharmacy and Applied Life Sciences, Higashijima 265-1, Akihaku, Niigata, Niigata, 956-8603, Japan
| | - Mineaki Seki
- Research Institute for Healthy Living, Niigata University of Pharmacy and Applied Life Sciences, Higashijima 265-1, Akihaku, Niigata, Niigata, 956-8603, Japan
| | - Hidetomo Kikuchi
- Department of Clinical Molecular Genetics, Faculty of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Horinouchi 1432-1, Hachioji, Tokyo, 192-0392, Japan
| | - Bo Yuan
- Department of Clinical Molecular Genetics, Faculty of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Horinouchi 1432-1, Hachioji, Tokyo, 192-0392, Japan
| | - Masayuki Nashimoto
- Research Institute for Healthy Living, Niigata University of Pharmacy and Applied Life Sciences, Higashijima 265-1, Akihaku, Niigata, Niigata, 956-8603, Japan
| |
Collapse
|
|
40
|
Lin Y, Ren X, Chen Y, Chen D. Interaction Between Mesenchymal Stem Cells and Retinal Degenerative Microenvironment. Front Neurosci 2021; 14:617377. [PMID: 33551729 PMCID: PMC7859517 DOI: 10.3389/fnins.2020.617377] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 12/17/2020] [Indexed: 02/06/2023] Open
Abstract
Retinal degenerative diseases (RDDs) are a group of diseases contributing to irreversible vision loss with yet limited therapies. Stem cell-based therapy is a promising novel therapeutic approach in RDD treatment. Mesenchymal stromal/stem cells (MSCs) have emerged as a leading cell source due to their neurotrophic and immunomodulatory capabilities, limited ethical concerns, and low risk of tumor formation. Several pre-clinical studies have shown that MSCs have the potential to delay retinal degeneration, and recent clinical trials have demonstrated promising safety profiles for the application of MSCs in retinal disease. However, some of the clinical-stage MSC therapies have been unable to meet primary efficacy end points, and severe side effects were reported in some retinal “stem cell” clinics. In this review, we provide an update of the interaction between MSCs and the RDD microenvironment and discuss how to balance the therapeutic potential and safety concerns of MSCs' ocular application.
Collapse
Affiliation(s)
- Yu Lin
- The Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,The Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiang Ren
- The Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,The Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
| | - Yongjiang Chen
- The School of Optometry and Vision Science, University of Waterloo, Waterloo, ON, Canada
| | - Danian Chen
- The Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,The Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
41
|
Burnham AJ, Foppiani EM, Horwitz EM. Key Metabolic Pathways in MSC-Mediated Immunomodulation: Implications for the Prophylaxis and Treatment of Graft Versus Host Disease. Front Immunol 2020; 11:609277. [PMID: 33365034 PMCID: PMC7750397 DOI: 10.3389/fimmu.2020.609277] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 11/10/2020] [Indexed: 01/18/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are spindle-shaped, plastic-adherent cells in vitro with potent immunosuppressive activity both in vitro and in vivo. MSCs have been employed as a cellular immunotherapy in diverse preclinical models and clinical trials, but most commonly as agents for the prophylaxis or therapy of graft versus host disease after hematopoietic cell transplantation. In addition to the oft studied secreted cytokines, several metabolic pathways intrinsic to MSCs, notably indoleamine 2,3-dioxygenase, prostaglandin E2, hypoxia-inducible factor 1 α, heme oxygenase-1, as well as energy-generating metabolism, have been shown to play roles in the immunomodulatory activity of MSCs. In this review, we discuss these key metabolic pathways in MSCs which have been reported to contribute to MSC therapeutic effects in the setting of hematopoietic cell transplantation and graft versus host disease. Understanding the contribution of MSC metabolism to immunomodulatory activity may substantially inform the development of future clinical applications of MSCs.
Collapse
Affiliation(s)
- Andre J Burnham
- Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, United States.,Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
| | - Elisabetta Manuela Foppiani
- Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, United States.,Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
| | - Edwin M Horwitz
- Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, United States.,Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
| |
Collapse
|
|
42
|
Ji W, Hou B, Lin W, Wang L, Zheng W, Li W, Zheng J, Wen X, He P. 3D Bioprinting a human iPSC-derived MSC-loaded scaffold for repair of the uterine endometrium. Acta Biomater 2020; 116:268-284. [PMID: 32911103 DOI: 10.1016/j.actbio.2020.09.012] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 08/29/2020] [Accepted: 09/01/2020] [Indexed: 12/31/2022]
Abstract
Common events in the clinic, such as uterine curettage or inflammation, may lead to irreversible endometrial damage, often resulting in infertility in women of childbearing age. Currently, tissue engineering has the potential to achieve tissue manipulation, regeneration, and growth, but personalization and precision remain challenges. The application of "3D cell printing" is more in line with the clinical requirements of tissue repair. In this study, a porous grid-type human induced pluripotent stem cell-derived mesenchymal stem cell (hiMSC)-loaded hydrogel scaffold was constructed using a 3D bioprinting device. The 3D-printed hydrogel scaffold provided a permissive in vitro living environment for hiMSCs and significantly increased the survival duration of transplanted hiMSCs when compared with hiMSCs administered locally in vivo. Using an endometrial injury model, we found that hiMSC transplantation can cause early host immune responses (the serological immune response continued for more than 1 month, and the local immune response continued for approximately 1 week). Compared with the sham group, although the regenerative endometrium failed to show full restoration of the normal structure and function of the lining, implantation of the 3D-printed hiMSC-loaded scaffold not only promoted the recovery of the endometrial histomorphology (endometrial tissue and gland regeneration) and the regeneration of endometrial cells (stromal cells and epithelial cells) and endothelial cells but also improved endometrial receptivity functional indicators, namely, pinopode formation and leukemia inhibitory factor and αvβ3 expression, which partly restored the embryo implantation and pregnancy maintenance functions of the injured endometrium. These indicators were significantly better in the 3D-printed hiMSC-loaded scaffold group than in the unrepaired (empty) group, the hiMSCs alone group and the 3D scaffold group, and the empty group showed the worst repair results. Our study confirm that the 3D-printed hiMSC-loaded hydrogel scaffold may be a promising material for endometrial repair.
Collapse
Affiliation(s)
- Wanqing Ji
- Department of Obstetrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong Province, 510623, China
| | - Bo Hou
- Departments of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, 510630, China
| | - Weige Lin
- Department of Obstetrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong Province, 510623, China
| | - Linli Wang
- Guangzhou Regenerative Medicine Research Center, Future Homo sapiens Research Institute Co., Ltd., China
| | - Wenhan Zheng
- Departments of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, 510630, China
| | - Weidong Li
- Department of Maternal and Child Health Information, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Jie Zheng
- Department of Obstetrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong Province, 510623, China
| | - Xuejun Wen
- Department of Chemical and Life Science Engineering, Virginia Commonwealth University, 601 West Main Street, Richmond, VA 23220, USA.
| | - Ping He
- Department of Obstetrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong Province, 510623, China.
| |
Collapse
|
|
43
|
Abstract
Regenerative therapies, including both gene and cellular therapies, aim to induce regeneration of cells, tissues and organs and restore their functions. In this short Spotlight, we summarize the latest advances in cellular therapies using pluripotent stem cells (PSCs), highlighting the current status of clinical trials using induced (i)PSC-derived cells. We also discuss the different cellular products that might be used in clinical studies, and consider safety issues and other challenges in iPSC-based cell therapy.
Collapse
Affiliation(s)
- Hideyuki Okano
- Keio University School of Medicine, Department of Physiology, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan .,Keio University Global Research Institute, 2-15-45 Mita, Minato-ku, Tokyo 108-8345, Japan
| | - Doug Sipp
- Keio University School of Medicine, Department of Physiology, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.,Keio University Global Research Institute, 2-15-45 Mita, Minato-ku, Tokyo 108-8345, Japan.,RIKEN Center for Developmental Biology, 2-2-3 Minatojima Minamimachi, Chuo-ku, Kobe 650-0047, Japan.,RIKEN Center for Advanced Intelligence Project, Nihonbashi 1-chome Mitsui Building, 15th floor, 1-4-1 Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan
| |
Collapse
|
|
44
|
Production, safety and efficacy of iPSC-derived mesenchymal stromal cells in acute steroid-resistant graft versus host disease: a phase I, multicenter, open-label, dose-escalation study. Nat Med 2020; 26:1720-1725. [PMID: 32929265 DOI: 10.1038/s41591-020-1050-x] [Citation(s) in RCA: 204] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 08/03/2020] [Indexed: 02/07/2023]
Abstract
The therapeutic potential of donor-derived mesenchymal stromal cells (MSCs) has been investigated in diverse diseases1, including steroid-resistant acute graft versus host disease (SR-aGvHD)2. However, conventional manufacturing approaches are hampered by challenges with scalability and interdonor variability, and clinical trials have shown inconsistent outcomes3,4. Induced pluripotent stem cells (iPSCs) have the potential to overcome these challenges, due to their capacity for multilineage differentiation and indefinite proliferation5,6. Nonetheless, human clinical trials of iPSC-derived cells have not previously been completed. CYP-001 (iPSC-derived MSCs) is produced using an optimized, good manufacturing practice (GMP)-compliant manufacturing process. We conducted a phase 1, open-label clinical trial (no. NCT02923375) in subjects with SR-aGvHD. Sixteen subjects were screened and sequentially assigned to cohort A or cohort B (n = 8 per group). One subject in cohort B withdrew before receiving CYP-001 and was excluded from analysis. All other subjects received intravenous infusions of CYP-001 on days 0 and 7, at a dose level of either 1 × 106 cells per kg body weight, to a maximum of 1 × 108 cells per infusion (cohort A), or 2 × 106 cells per kg body weight, to a maximum dose of 2 × 108 cells per infusion (cohort B). The primary objective was to assess the safety and tolerability of CYP-001, while the secondary objectives were to evaluate efficacy based on the proportion of participants who showed a complete response (CR), overall response (OR) and overall survival (OS) by days 28/100. CYP-001 was safe and well tolerated. No serious adverse events were assessed as related to CYP-001. OR, CR and OS rates by day 100 were 86.7, 53.3 and 86.7%, respectively. The therapeutic application of iPSC-derived MSCs may now be explored in diverse inflammatory and immune-mediated diseases.
Collapse
|
|
45
|
Levy O, Kuai R, Siren EMJ, Bhere D, Milton Y, Nissar N, De Biasio M, Heinelt M, Reeve B, Abdi R, Alturki M, Fallatah M, Almalik A, Alhasan AH, Shah K, Karp JM. Shattering barriers toward clinically meaningful MSC therapies. SCIENCE ADVANCES 2020; 6:eaba6884. [PMID: 32832666 PMCID: PMC7439491 DOI: 10.1126/sciadv.aba6884] [Citation(s) in RCA: 405] [Impact Index Per Article: 81.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 06/05/2020] [Indexed: 05/11/2023]
Abstract
More than 1050 clinical trials are registered at FDA.gov that explore multipotent mesenchymal stromal cells (MSCs) for nearly every clinical application imaginable, including neurodegenerative and cardiac disorders, perianal fistulas, graft-versus-host disease, COVID-19, and cancer. Several companies have or are in the process of commercializing MSC-based therapies. However, most of the clinical-stage MSC therapies have been unable to meet primary efficacy end points. The innate therapeutic functions of MSCs administered to humans are not as robust as demonstrated in preclinical studies, and in general, the translation of cell-based therapy is impaired by a myriad of steps that introduce heterogeneity. In this review, we discuss the major clinical challenges with MSC therapies, the details of these challenges, and the potential bioengineering approaches that leverage the unique biology of MSCs to overcome the challenges and achieve more potent and versatile therapies.
Collapse
Affiliation(s)
- Oren Levy
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
| | - Rui Kuai
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
- BWH Center of Excellence for Biomedicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Erika M. J. Siren
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
| | - Deepak Bhere
- BWH Center of Excellence for Biomedicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Center for Stem Cell Therapeutics and Imaging, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Yuka Milton
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
| | - Nabeel Nissar
- Center for Stem Cell Therapeutics and Imaging, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Michael De Biasio
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
| | - Martina Heinelt
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
| | - Brock Reeve
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
| | - Reza Abdi
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Meshael Alturki
- National Center of Pharmaceutical Technology, Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
- KACST Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
| | - Mohanad Fallatah
- KACST Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
| | - Abdulaziz Almalik
- National Center of Pharmaceutical Technology, Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
- KACST Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
| | - Ali H. Alhasan
- National Center of Pharmaceutical Technology, Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
- KACST Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
| | - Khalid Shah
- BWH Center of Excellence for Biomedicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Center for Stem Cell Therapeutics and Imaging, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
| | - Jeffrey M. Karp
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
- BWH Center of Excellence for Biomedicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| |
Collapse
|
|
46
|
De la Torre-Tarazona HE, Jiménez R, Bueno P, Camarero S, Román L, Fernández-García JL, Beltrán M, Nothias LF, Cachet X, Paolini J, Litaudon M, Alcami J, Bedoya LM. 4-Deoxyphorbol inhibits HIV-1 infection in synergism with antiretroviral drugs and reactivates viral reservoirs through PKC/MEK activation synergizing with vorinostat. Biochem Pharmacol 2020; 177:113937. [PMID: 32224142 DOI: 10.1016/j.bcp.2020.113937] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 03/24/2020] [Indexed: 01/06/2023]
Abstract
Latent HIV reservoirs are the main obstacle to eradicate HIV infection. One strategy proposes to eliminate these viral reservoirs by pharmacologically reactivating the latently infected T cells. We show here that a 4-deoxyphorbol ester derivative isolated from Euphorbia amygdaloides ssp. semiperfoliata, 4β-dPE A, reactivates HIV-1 from latency and could potentially contribute to decrease the viral reservoir. 4β-dPE A shows two effects in the HIV replication cycle, infection inhibition and HIV transactivation, similarly to other phorboids PKC agonists such PMA and prostratin and to other diterpene esters such SJ23B. Our data suggest 4β-dPE A is non-tumorigenic, unlike the related compound PMA. As the compounds are highly similar, the lack of tumorigenicity by 4β-dPE A could be due to the lack of a long side lipophilic chain that is present in PMA. 4β-dPE activates HIV transcription at nanomolar concentrations, lower than the concentration needed by other latency reversing agents (LRAs) such as prostratin and similar to bryostatin. PKCθ/MEK activation is required for the transcriptional activity, and thus, anti-latency activity of 4β-dPE A. However, CD4, CXCR4 and CCR5 receptors down-regulation effect seems to be independent of PCK/MEK, suggesting the existence of at least two different targets for 4β-dPE A. Furthermore, NF-κb transcription factor is involved in 4β-dPE HIV reactivation, as previously shown for other PKCs agonists. We also studied the effects of 4β-dPE A in combination with other LRAs. When 4β-dPE A was combined with another PKC agonists such as prostratin an antagonic effect was achieved, while, when combined with an HDAC inhibitor such as vorinostat, a strong synergistic effect was obtained. Interestingly, the latency reversing effect of the combination was synergistically diminishing the EC50 value but also increasing the efficacy showed by the drugs alone. In addition, combinations of 4β-dPE A with antiretroviral drugs as CCR5 antagonist, NRTIs, NNRTIs and PIs, showed a consistent synergistic effect, suggesting that the combination would not interefer with antiretroviral therapy (ART). Finally, 4β-dPE A induced latent HIV reactivation in CD4 + T cells of infected patients under ART at similar levels than the tumorigenic phorbol derivative PMA, showing a clear reactivation effect. In summary, we describe here the mechanism of action of a new potent deoxyphorbol derivative as a latency reversing agent candidate to decrease the size of HIV reservoirs.
Collapse
Affiliation(s)
- H E De la Torre-Tarazona
- AIDS Immunopathology Department, National Centre of Microbiology, Instituto de Salud Carlos III. Ctra. Pozuelo Km. 2. Majadahonda, 28224 Madrid, Spain
| | - R Jiménez
- AIDS Immunopathology Department, National Centre of Microbiology, Instituto de Salud Carlos III. Ctra. Pozuelo Km. 2. Majadahonda, 28224 Madrid, Spain
| | - P Bueno
- AIDS Immunopathology Department, National Centre of Microbiology, Instituto de Salud Carlos III. Ctra. Pozuelo Km. 2. Majadahonda, 28224 Madrid, Spain
| | - S Camarero
- AIDS Immunopathology Department, National Centre of Microbiology, Instituto de Salud Carlos III. Ctra. Pozuelo Km. 2. Majadahonda, 28224 Madrid, Spain
| | - L Román
- AIDS Immunopathology Department, National Centre of Microbiology, Instituto de Salud Carlos III. Ctra. Pozuelo Km. 2. Majadahonda, 28224 Madrid, Spain
| | - J L Fernández-García
- AIDS Immunopathology Department, National Centre of Microbiology, Instituto de Salud Carlos III. Ctra. Pozuelo Km. 2. Majadahonda, 28224 Madrid, Spain; Pharmacology Department, Pharmacy Faculty, Universidad Complutense de Madrid, Pz. Ramón Y Cajal s/n, 28040 Madrid, Spain
| | - M Beltrán
- AIDS Immunopathology Department, National Centre of Microbiology, Instituto de Salud Carlos III. Ctra. Pozuelo Km. 2. Majadahonda, 28224 Madrid, Spain
| | - L F Nothias
- Institut de Chimie des Substances Naturelles, CNRS UPR 2301, University of Paris-Saclay, 91198 Gif-sur-Yvette, France
| | - X Cachet
- Institut de Chimie des Substances Naturelles, CNRS UPR 2301, University of Paris-Saclay, 91198 Gif-sur-Yvette, France; CiTCoM Laboratory, UMR 8038 CNRS-University of Paris, Faculty of Pharmacy, University of Paris, 75006 Paris, France
| | - J Paolini
- Laboratoire de Chimie des Produits Naturels, CNRS, UMR SPE 6134, University of Corsica, 20250 Corte, France
| | - M Litaudon
- Institut de Chimie des Substances Naturelles, CNRS UPR 2301, University of Paris-Saclay, 91198 Gif-sur-Yvette, France
| | - J Alcami
- AIDS Immunopathology Department, National Centre of Microbiology, Instituto de Salud Carlos III. Ctra. Pozuelo Km. 2. Majadahonda, 28224 Madrid, Spain; Infectious Diseases Unit, IBIDAPS, Hospital Clínic, University of Barcelona, Spain.
| | - L M Bedoya
- AIDS Immunopathology Department, National Centre of Microbiology, Instituto de Salud Carlos III. Ctra. Pozuelo Km. 2. Majadahonda, 28224 Madrid, Spain; Pharmacology Department, Pharmacy Faculty, Universidad Complutense de Madrid, Pz. Ramón Y Cajal s/n, 28040 Madrid, Spain.
| |
Collapse
|
|
47
|
Targeting cell plasticity for regeneration: From in vitro to in vivo reprogramming. Adv Drug Deliv Rev 2020; 161-162:124-144. [PMID: 32822682 DOI: 10.1016/j.addr.2020.08.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 08/13/2020] [Accepted: 08/14/2020] [Indexed: 12/14/2022]
Abstract
The discovery of induced pluripotent stem cells (iPSCs), reprogrammed to pluripotency from somatic cells, has transformed the landscape of regenerative medicine, disease modelling and drug discovery pipelines. Since the first generation of iPSCs in 2006, there has been enormous effort to develop new methods that increase reprogramming efficiency, and obviate the need for viral vectors. In parallel to this, the promise of in vivo reprogramming to convert cells into a desired cell type to repair damage in the body, constitutes a new paradigm in approaches for tissue regeneration. This review article explores the current state of reprogramming techniques for iPSC generation with a specific focus on alternative methods that use biophysical and biochemical stimuli to reduce or eliminate exogenous factors, thereby overcoming the epigenetic barrier towards vector-free approaches with improved clinical viability. We then focus on application of iPSC for therapeutic approaches, by giving an overview of ongoing clinical trials using iPSCs for a variety of health conditions and discuss future scope for using materials and reagents to reprogram cells in the body.
Collapse
|
|
48
|
Ortuño-Costela MDC, Cerrada V, García-López M, Gallardo ME. The Challenge of Bringing iPSCs to the Patient. Int J Mol Sci 2019; 20:E6305. [PMID: 31847153 PMCID: PMC6940848 DOI: 10.3390/ijms20246305] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 12/10/2019] [Accepted: 12/11/2019] [Indexed: 12/13/2022] Open
Abstract
The implementation of induced pluripotent stem cells (iPSCs) in biomedical research more than a decade ago, resulted in a huge leap forward in the highly promising area of personalized medicine. Nowadays, we are even closer to the patient than ever. To date, there are multiple examples of iPSCs applications in clinical trials and drug screening. However, there are still many obstacles to overcome. In this review, we will focus our attention on the advantages of implementing induced pluripotent stem cells technology into the clinics but also commenting on all the current drawbacks that could hinder this promising path towards the patient.
Collapse
Affiliation(s)
- María del Carmen Ortuño-Costela
- Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain. Instituto de Investigaciones Biomédicas “Alberto Sols”, (UAM-CSIC), 28029 Madrid, Spain;
- Grupo de Investigación Traslacional con células iPS, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), 28041 Madrid, Spain; (V.C.); (M.G.-L.)
| | - Victoria Cerrada
- Grupo de Investigación Traslacional con células iPS, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), 28041 Madrid, Spain; (V.C.); (M.G.-L.)
| | - Marta García-López
- Grupo de Investigación Traslacional con células iPS, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), 28041 Madrid, Spain; (V.C.); (M.G.-L.)
| | - M. Esther Gallardo
- Grupo de Investigación Traslacional con células iPS, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), 28041 Madrid, Spain; (V.C.); (M.G.-L.)
- Centro de Investigación Biomédica en Red (CIBERER), 28029 Madrid, Spain
| |
Collapse
|