Reference Citation Analysis: Find an Article, Find a Category, Find a Journal, Find a Scholar

For: Sun YQ, Zhang Y, Li X, Deng MX, Gao WX, Yao Y, Chiu SM, Liang X, Gao F, Chan CW, Tse HF, Shi J, Fu QL, Lian Q. Insensitivity of Human iPS Cells-Derived Mesenchymal Stem Cells to Interferon-γ-induced HLA Expression Potentiates Repair Efficiency of Hind Limb Ischemia in Immune Humanized NOD Scid Gamma Mice. Stem Cells 2015;33:3452-67. [PMID: 26175298 DOI: 10.1002/stem.2094] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [What about the content of this article? (0)] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 06/06/2015] [Indexed: 12/11/2022]

For:	Sun YQ, Zhang Y, Li X, Deng MX, Gao WX, Yao Y, Chiu SM, Liang X, Gao F, Chan CW, Tse HF, Shi J, Fu QL, Lian Q. Insensitivity of Human iPS Cells-Derived Mesenchymal Stem Cells to Interferon-γ-induced HLA Expression Potentiates Repair Efficiency of Hind Limb Ischemia in Immune Humanized NOD Scid Gamma Mice. Stem Cells 2015;33:3452-67. [PMID: 26175298 DOI: 10.1002/stem.2094] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [What about the content of this article? (0)] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 06/06/2015] [Indexed: 12/11/2022]

Number

Cited by Other Article(s)

Lee S, Kim B, Lee MJ, Kim D, Park S, Kim J, Arai Y, Lee SH. Curcumin-PLGA NPs coated with targeting biomimetic personalized stem cell membranes for osteoarthritis therapy. J Control Release 2025;381:113625. [PMID: 40081740 DOI: 10.1016/j.jconrel.2025.113625] [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: 10/24/2024] [Revised: 03/07/2025] [Accepted: 03/09/2025] [Indexed: 03/16/2025]

Bai X, Liu T, Li C, Qiu C, Ge X, Gou H, Cai H, Yang L, Wei S, Yang W, Li T. PD-L1 and ICAM1 over expression empowers immunoregulation of mesenchymal stromal cells to improve the autoimmune hepatitis treatment efficacy. Stem Cell Res Ther 2025;16:209. [PMID: 40275361 PMCID: PMC12023376 DOI: 10.1186/s13287-025-04347-w] [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: 12/05/2024] [Accepted: 04/15/2025] [Indexed: 04/26/2025] Open

Huang Z, Li J, Wo J, Li C, Wu Z, Deng X, Liang Y, Li F, Chen B, Jia B, Wang L, Wang Y, Sun G, Li Z, Zhu H, Guest JD, So K, Fu Q, Zhou L. Intranasal Delivery of Brain-Derived Neurotrophic Factor (BDNF)-Loaded Small Extracellular Vesicles for Treating Acute Spinal Cord Injury in Rats and Monkeys. J Extracell Vesicles 2025;14:e70066. [PMID: 40194993 PMCID: PMC11975507 DOI: 10.1002/jev2.70066] [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: 09/27/2024] [Accepted: 03/10/2025] [Indexed: 04/09/2025] Open

Abstract

Besides surgical decompression, neuroprotection and neuroinflammation reduction are critical for acute spinal cord injury (SCI). In this study, we prepared small extracellular vesicles (sEVs) from immortalised mesenchymal stem cells overexpressing brain-derived neurotrophic factor (BDNF) and evaluated whether intranasal administration of BDNF-sEVs is a therapeutic option for acute SCI. In cultured neurons, BDNF loading enhanced neurite outgrowth promoted by sEVs. After intranasal administration, mCherry-labelled sEVs were transported to the injured spinal cords of rats and monkeys and mainly taken up by neurons. In acute SCI rats, intranasal administration of sEVs and BDNF-sEVs reduced glial responses and proinflammatory cytokine production, enhanced neuronal survival and angiogenesis in the lesion, promoted injured axon rewiring, delayed lumbar spinal motoneuron atrophy below the lesion, and improved functional performance. The rats receiving BDNF-sEV treatment showed improved neural repair and functional recovery compared to those with sEV treatment. Intranasal administration of BDNF-sEVs, but not of sEVs, increased BDNF levels and phosphorylation of downstream signals in the rat-injured spinal cord samples, indicating activation of the BDNF/TrkB signalling pathway. In acute SCI monkeys, intranasal administration of BDNF-sEVs was further confirmed to inhibit glial reactivities and proinflammatory cytokine release, increasing BDNF levels in the cerebrospinal fluid, enhancing neural network rewiring of injured spinal cords and neuronal activities of the brain, and improving functional performances in behavioural tests and electrophysiological recordings. In conclusion, BDNF-sEVs play a combinatory therapeutic role of sEVs and BDNF, and intranasal administration of BDNF-sEVs is a potential option for the clinical treatment of acute SCI.

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Affiliation(s)

Zhonghai Huang Guangdong Provincial Key Laboratory of Spine and Spinal Cord ReconstructionThe Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital)Jinan UniversityHeyuanChina Guangdong‐Hongkong‐Macau Institute of CNS RegenerationKey Laboratory of CNS Regeneration (Jinan University)‐Ministry of EducationGuangdong Key Laboratory of Non‐Human Primate ResearchJinan UniversityGuangzhouChina Department of OrthopedicsThe First Affiliated HospitalJinan UniversityGuangzhouChina
Jing Li Guangdong‐Hongkong‐Macau Institute of CNS RegenerationKey Laboratory of CNS Regeneration (Jinan University)‐Ministry of EducationGuangdong Key Laboratory of Non‐Human Primate ResearchJinan UniversityGuangzhouChina Department of Human Anatomy, The College of Basic Medical SciencesJinan UniversityGuangzhouChina
Jin Wo Guangdong Provincial Key Laboratory of Spine and Spinal Cord ReconstructionThe Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital)Jinan UniversityHeyuanChina Guangdong‐Hongkong‐Macau Institute of CNS RegenerationKey Laboratory of CNS Regeneration (Jinan University)‐Ministry of EducationGuangdong Key Laboratory of Non‐Human Primate ResearchJinan UniversityGuangzhouChina Department of OrthopedicsThe First Affiliated HospitalJinan UniversityGuangzhouChina
Cheng‐Lin Li Otorhinolaryngology Hospital of The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
Zi‐Cong Wu Otorhinolaryngology Hospital of The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
Xiao‐Hui Deng Otorhinolaryngology Hospital of The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina Extracellular Vesicle Research and Clinical Translational CenterThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
Yaying Liang Guangdong‐Hongkong‐Macau Institute of CNS RegenerationKey Laboratory of CNS Regeneration (Jinan University)‐Ministry of EducationGuangdong Key Laboratory of Non‐Human Primate ResearchJinan UniversityGuangzhouChina
Fuxiang Li Guangdong‐Hongkong‐Macau Institute of CNS RegenerationKey Laboratory of CNS Regeneration (Jinan University)‐Ministry of EducationGuangdong Key Laboratory of Non‐Human Primate ResearchJinan UniversityGuangzhouChina
Boli Chen Guangdong‐Hongkong‐Macau Institute of CNS RegenerationKey Laboratory of CNS Regeneration (Jinan University)‐Ministry of EducationGuangdong Key Laboratory of Non‐Human Primate ResearchJinan UniversityGuangzhouChina
Bin Jia Guangdong‐Hongkong‐Macau Institute of CNS RegenerationKey Laboratory of CNS Regeneration (Jinan University)‐Ministry of EducationGuangdong Key Laboratory of Non‐Human Primate ResearchJinan UniversityGuangzhouChina
Lu Wang Center of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine and PET/CT‐MRI CenterThe First Affiliated HospitalJinan UniversityGuangzhouChina
Ying Wang Medical Imaging CenterThe First Affiliated HospitalJinan UniversityGuangzhouChina
Guodong Sun Guangdong Provincial Key Laboratory of Spine and Spinal Cord ReconstructionThe Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital)Jinan UniversityHeyuanChina Department of OrthopedicsThe First Affiliated HospitalJinan UniversityGuangzhouChina
Zhizhong Li Guangdong Provincial Key Laboratory of Spine and Spinal Cord ReconstructionThe Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital)Jinan UniversityHeyuanChina Department of OrthopedicsThe First Affiliated HospitalJinan UniversityGuangzhouChina
Hui Zhu Kunming International Spine and Spinal Cord Injury Treatment CenterKunming Tongren HospitalKunmingChina
James D Guest Neurological Surgery and the Miami Project to Cure ParalysisMiller School of MedicineMiamiFloridaUSA
Kwok‐Fai So Guangdong‐Hongkong‐Macau Institute of CNS RegenerationKey Laboratory of CNS Regeneration (Jinan University)‐Ministry of EducationGuangdong Key Laboratory of Non‐Human Primate ResearchJinan UniversityGuangzhouChina Department of Human Anatomy, The College of Basic Medical SciencesJinan UniversityGuangzhouChina Neuroscience and Neurorehabilitation InstituteUniversity of Health and Rehabilitation SciencesQingdaoShandongChina Co‐Innovation Center of NeuroregenerationNantong UniversityJiangsuChina Center for Exercise and Brain ScienceSchool of PsychologyShanghai University of SportShanghaiChina
Qing‐Ling Fu Otorhinolaryngology Hospital of The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina Extracellular Vesicle Research and Clinical Translational CenterThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
Libing Zhou Guangdong Provincial Key Laboratory of Spine and Spinal Cord ReconstructionThe Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital)Jinan UniversityHeyuanChina Guangdong‐Hongkong‐Macau Institute of CNS RegenerationKey Laboratory of CNS Regeneration (Jinan University)‐Ministry of EducationGuangdong Key Laboratory of Non‐Human Primate ResearchJinan UniversityGuangzhouChina Department of OrthopedicsThe First Affiliated HospitalJinan UniversityGuangzhouChina Neuroscience and Neurorehabilitation InstituteUniversity of Health and Rehabilitation SciencesQingdaoShandongChina Co‐Innovation Center of NeuroregenerationNantong UniversityJiangsuChina Center for Exercise and Brain ScienceSchool of PsychologyShanghai University of SportShanghaiChina

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Li Y, Jin M, Guo D, Shen S, Lu K, Pan R, Sun L, Zhang H, Shao J, Pan G. Unveiling the immunogenicity of allogeneic mesenchymal stromal cells: Challenges and strategies for enhanced therapeutic efficacy. Biomed Pharmacother 2024;180:117537. [PMID: 39405918 DOI: 10.1016/j.biopha.2024.117537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 10/01/2024] [Accepted: 10/04/2024] [Indexed: 11/14/2024] Open

Abstract

Mesenchymal stromal cells (MSCs) exhibit significant potential in the context of cell therapy because of their capacity to perform a range of interconnected functions in damaged tissues, including immune modulation, hematopoietic support, and tissue regeneration. MSCs are hypoimmunogenic because of their diminished expression of major histocompatibility molecules, absence of costimulatory molecules, and presence of coinhibitory molecules. While autologous MSCs reduce the risk of rejection and infection, variability in cell numbers and proliferation limits their potential applications. Conversely, allogeneic MSCs (allo-MSCs) possess broad clinical applications unconstrained by donor physiology. Nonetheless, preclinical and clinical investigations highlight that transplanted allo-MSCs are subject to immune attack from recipients. These cells exhibit anti-inflammatory and proinflammatory phenotypes contingent on the microenvironment. Notably, the proinflammatory phenotype features enhanced immunogenicity and diminished immunosuppression, potentially triggering allogeneic immune reactions that impede long-term clinical efficacy. Consequently, preserving the low immunogenicity of allo-MSCs in vivo and mitigating immune rejection in diverse microenvironments represent crucial challenges for the widespread clinical application of MSCs. In this review, we elucidate the immune regulation of allo-MSCs, specifically focusing on two distinct subgroups, MSC1 and MSC2, that exhibit varying polarization states and immunogenicity. We discuss the factors and underlying mechanisms that induce MSC immunogenicity and polarization, highlighting the crucial role of major histocompatibility complex class I/II molecules in rejection post-transplantation. Additionally, we summarize the immunogenic regulatory targets and applications of allo-MSCs and outline strategies to address challenges in this promising field, aiming to enhance allo-MSC therapeutic efficacy for patients.

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Wang P, Zhang Y, Li Z, Zhou S, Tang Q, Wang Z, Xiao R, Feng M, Wu L, Liang D. Mesenchymal Stem Cells Derived from Human Urine-Derived iPSCs Exhibit Low Immunogenicity and Reduced Immunomodulatory Profile. Int J Mol Sci 2024;25:10394. [PMID: 39408724 PMCID: PMC11476417 DOI: 10.3390/ijms251910394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 09/25/2024] [Accepted: 09/25/2024] [Indexed: 10/20/2024] Open

Affiliation(s)

Peiyun Wang Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China; (P.W.); (Y.Z.); (Z.L.); (S.Z.); (Q.T.); (Z.W.); (R.X.); (L.W.)
Ying Zhang Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China; (P.W.); (Y.Z.); (Z.L.); (S.Z.); (Q.T.); (Z.W.); (R.X.); (L.W.)
Zhixing Li Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China; (P.W.); (Y.Z.); (Z.L.); (S.Z.); (Q.T.); (Z.W.); (R.X.); (L.W.)
Shenglan Zhou Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China; (P.W.); (Y.Z.); (Z.L.); (S.Z.); (Q.T.); (Z.W.); (R.X.); (L.W.)
Qiyu Tang Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China; (P.W.); (Y.Z.); (Z.L.); (S.Z.); (Q.T.); (Z.W.); (R.X.); (L.W.)
Zujia Wang Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China; (P.W.); (Y.Z.); (Z.L.); (S.Z.); (Q.T.); (Z.W.); (R.X.); (L.W.)
Rou Xiao Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China; (P.W.); (Y.Z.); (Z.L.); (S.Z.); (Q.T.); (Z.W.); (R.X.); (L.W.)
Mai Feng Hunan Key Laboratory of Animal Models for Human Diseases, School of Life Sciences, Central South University, Changsha 410078, China;
Lingqian Wu Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China; (P.W.); (Y.Z.); (Z.L.); (S.Z.); (Q.T.); (Z.W.); (R.X.); (L.W.)
Desheng Liang Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China; (P.W.); (Y.Z.); (Z.L.); (S.Z.); (Q.T.); (Z.W.); (R.X.); (L.W.)

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Zhou J, Li F, Jia B, Wu Z, Huang Z, He M, Weng H, So KF, Qu W, Fu QL, Zhou L. Intranasal delivery of small extracellular vesicles reduces the progress of amyotrophic lateral sclerosis and the overactivation of complement-coagulation cascade and NF-ĸB signaling in SOD1^G93A mice. J Nanobiotechnology 2024;22:503. [PMID: 39174972 PMCID: PMC11340036 DOI: 10.1186/s12951-024-02764-2] [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: 03/19/2024] [Accepted: 08/12/2024] [Indexed: 08/24/2024] Open

Affiliation(s)

Jinrui Zhou Department of Hand Surgery, The Second Hospital of Jilin University, Changchun, 130041, P. R. China
Fuxiang Li Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Guangzhou, 510632, P. R. China
Bin Jia Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Guangzhou, 510632, P. R. China
Zicong Wu Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China
Zhonghai Huang Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Guangzhou, 510632, P. R. China
Meiting He Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Guangzhou, 510632, P. R. China
Huandi Weng Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Guangzhou, 510632, P. R. China
Kwok-Fai So Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Guangzhou, 510632, P. R. China Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, P. R. China Neuroscience and Neurorehabilitation Institute, University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266071, P. R. China Department of Neurology and Stroke Center, The First Affiliated Hospital & Clinical, Neuroscience Institute of Jinan University, Guangzhou, 510632, P. R. China Center for Exercise and Brain Science, School of Psychology, Shanghai University of Sport, Shanghai, 200438, P. R. China
Wenrui Qu Department of Hand Surgery, The Second Hospital of Jilin University, Changchun, 130041, P. R. China.
Qing-Ling Fu Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China. Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China. Otorhinolaryngology Hospital, Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Zhongshan Road II 58, Guangzhou, 510080, P. R. China.
Libing Zhou Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Guangzhou, 510632, P. R. China. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, P. R. China. Neuroscience and Neurorehabilitation Institute, University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266071, P. R. China. Department of Neurology and Stroke Center, The First Affiliated Hospital & Clinical, Neuroscience Institute of Jinan University, Guangzhou, 510632, P. R. China. Center for Exercise and Brain Science, School of Psychology, Shanghai University of Sport, Shanghai, 200438, P. R. China. Guangdong-Hongkong-Macau CNS Regeneration Institute, Jinan University, Huangpu Avenue West 601, Guangzhou, 510632, P. R. China.

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van Rhijn-Brouwer FCCC, Wever KE, Kiffen R, van Rhijn JR, Gremmels H, Fledderus JO, Vernooij RWM, Verhaar MC. Systematic review and meta-analysis of the effect of bone marrow-derived cell therapies on hind limb perfusion. Dis Model Mech 2024;17:dmm050632. [PMID: 38616715 PMCID: PMC11139036 DOI: 10.1242/dmm.050632] [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: 11/27/2023] [Accepted: 04/03/2024] [Indexed: 04/16/2024] Open

Zheng H, Liang X, Liu B, Huang X, Shen Y, Lin F, Chen J, Gao X, He H, Li W, Hu B, Li X, Zhang Y. Exosomal miR-9-5p derived from iPSC-MSCs ameliorates doxorubicin-induced cardiomyopathy by inhibiting cardiomyocyte senescence. J Nanobiotechnology 2024;22:195. [PMID: 38643173 PMCID: PMC11032595 DOI: 10.1186/s12951-024-02421-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 03/18/2024] [Indexed: 04/22/2024] Open

Abstract

Doxorubicin (DOX) is a chemotherapeutic agent widely used for tumor treatment. Nonetheless its clinical application is heavily limited by its cardiotoxicity. There is accumulated evidence that transplantation of mesenchymal stem cell-derived exosomes (MSC-EXOs) can protect against Dox-induced cardiomyopathy (DIC). This study aimed to examine the cardioprotective effects of EXOs isolated from human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) against DIC and explore the potential mechanisms. EXOs were isolated from the cultural supernatant of human BM-MSCs (BM-MSC-EXOs) and iPSC-MSCs (iPSC-MSC-EXOs) by ultracentrifugation. A mouse model of DIC was induced by intraperitoneal injection of Dox followed by tail vein injection of PBS, BM-MSC-EXOs, or iPSC-MSC-EXOs. Cardiac function, cardiomyocyte senescence and mitochondrial dynamics in each group were assessed. In vitro, neonatal mouse cardiomyocytes (NMCMs) were subjected to Dox and treated with BM-MSC-EXOs or iPSC-MSC-EXOs. The mitochondrial morphology and cellular senescence of NMCMs were examined by Mitotracker staining and senescence-associated-β-galactosidase assay, respectively. Compared with BM-MSC-EXOs, mice treated with iPSC-MSC-EXOs displayed improved cardiac function and decreased cardiomyocyte mitochondrial fragmentation and senescence. In vitro, iPSC-MSC-EXOs were superior to BM-MSC-EXOs in attenuation of cardiomyocyte mitochondrial fragmentation and senescence caused by DOX. MicroRNA sequencing revealed a higher level of miR-9-5p in iPSC-MSC-EXOs than BM-MSC-EXOs. Mechanistically, iPSC-MSC-EXOs transported miR-9-5p into DOX-treated cardiomyocytes, thereby suppressing cardiomyocyte mitochondrial fragmentation and senescence via regulation of the VPO1/ERK signal pathway. These protective effects and cardioprotection against DIC were largely reversed by knockdown of miR-9-5p in iPSC-MSC-EXOs. Our results showed that miR-9-5p transferred by iPSC-MSC-EXOs protected against DIC by alleviating cardiomyocyte senescence via inhibition of the VPO1/ERK pathway. This study offers new insight into the application of iPSC-MSC-EXOs as a novel therapeutic strategy for DIC treatment.

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Affiliation(s)

Huifeng Zheng Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China Department of Intensive Care Unit, Chongqing General Hospital, Chongqing, China
Xiaoting Liang Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Baojuan Liu Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Xinran Huang Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Ying Shen Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Fang Lin Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Jiaqi Chen Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Xiaoyan Gao Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Haiwei He Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Weifeng Li Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Bei Hu Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China.
Xin Li Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China.
Yuelin Zhang Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China.

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Wu Y, Meng X, Cheng WY, Yan Z, Li K, Wang J, Jiang T, Zhou F, Wong KH, Zhong C, Dong Y, Gao S. Can pluripotent/multipotent stem cells reverse Parkinson's disease progression? Front Neurosci 2024;18:1210447. [PMID: 38356648 PMCID: PMC10864507 DOI: 10.3389/fnins.2024.1210447] [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: 04/22/2023] [Accepted: 01/02/2024] [Indexed: 02/16/2024] Open

Kuang PP, Liu XQ, Li CG, He BX, Xie YC, Wu ZC, Li CL, Deng XH, Fu QL. Mesenchymal stem cells overexpressing interleukin-10 prevent allergic airway inflammation. Stem Cell Res Ther 2023;14:369. [PMID: 38093354 PMCID: PMC10720159 DOI: 10.1186/s13287-023-03602-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 12/05/2023] [Indexed: 12/17/2023] Open

Abstract

BACKGROUNDS

Allergic airway inflammation is prevalent worldwide and imposes a considerable burden on both society and affected individuals. This study aimed to investigate the therapeutic advantages of mesenchymal stem cells (MSCs) overexpressed interleukin-10 (IL-10) for the treatment of allergic airway inflammation, as both IL-10 and MSCs possess immunosuppressive properties.

METHODS

Induced pluripotent stem cell (iPSC)-derived MSCs were engineered to overexpress IL-10 via lentiviral transfection (designated as IL-10-MSCs). MSCs and IL-10-MSCs were administered intravenously to mice with allergic inflammation induced by ovalbumin (OVA), and the features of allergic inflammation including inflammatory cell infiltration, Th cells in the lungs, and T helper 2 cell (Th2) cytokine levels in bronchoalveolar lavage fluid (BALF) were examined. MSCs and IL-10-MSCs were co-cultured with CD4+ T cells from patients with allergic rhinitis (AR), and the levels of Th2 cells and corresponding type 2 cytokines were studied. RNA-sequence was performed to further investigate the potential effects of MSCs and IL-10-MSCs on CD4+ T cells.

RESULTS

Stable IL-10-MSCs were established and characterised by high IL-10 expression. IL-10-MSCs significantly reduced inflammatory cell infiltration and epithelial goblet cell numbers in the lung tissues of mice with allergic airway inflammation. Inflammatory cell and cytokine levels in BALF also decreased after the administration of IL-10-MSCs. Moreover, IL-10-MSCs showed a stronger capacity to inhibit the levels of Th2 after co-cultured with CD4+ T cells from patients with AR. Furthermore, we elucidated lower levels of IL-5 and IL-13 in IL-10-MSCs treated CD4+ T cells, and blockade of IL-10 significantly reversed the inhibitory effects of IL-10-MSCs. We also reported the mRNA profiles of CD4+ T cells treated with IL-10-MSCs and MSCs, in which IL-10 played an important role.

CONCLUSION

IL-10-MSCs showed positive effects in the treatment of allergic airway inflammation, providing solid support for the use of genetically engineered MSCs as a potential novel therapy for allergic airway inflammation.

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Affiliation(s)

Peng-Peng Kuang Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
Xiao-Qing Liu Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
Chan-Gu Li Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
Bi-Xin He Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
Ying-Chun Xie Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
Zi-Cong Wu Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
Cheng-Lin Li Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China
Xiao-Hui Deng Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
Qing-Ling Fu Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China. Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China. Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.

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Yin X, Lin L, Fang F, Zhang B, Shen C. Mechanisms and Optimization Strategies of Paracrine Exosomes from Mesenchymal Stem Cells in Ischemic Heart Disease. Stem Cells Int 2023;2023:6500831. [PMID: 38034060 PMCID: PMC10686715 DOI: 10.1155/2023/6500831] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 10/11/2023] [Accepted: 10/25/2023] [Indexed: 12/02/2023] Open

Zhang H, Wan X, Tian J, An Z, Liu L, Zhao X, Zhou Y, Zhang L, Ge C, Song X. The therapeutic efficacy and clinical translation of mesenchymal stem cell-derived exosomes in cardiovascular diseases. Biomed Pharmacother 2023;167:115551. [PMID: 37783149 DOI: 10.1016/j.biopha.2023.115551] [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: 06/19/2023] [Revised: 09/08/2023] [Accepted: 09/18/2023] [Indexed: 10/04/2023] Open

Dharra R, Kumar Sharma A, Datta S. Emerging aspects of cytokine storm in COVID-19: The role of proinflammatory cytokines and therapeutic prospects. Cytokine 2023;169:156287. [PMID: 37402337 PMCID: PMC10291296 DOI: 10.1016/j.cyto.2023.156287] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 06/24/2023] [Indexed: 07/06/2023]

Peng W, Yang Y, Chen J, Xu Z, Lou Y, Li Q, Zhao N, Qian K, Liu F. Small Extracellular Vesicles Secreted by iPSC-Derived MSCs Ameliorate Pulmonary Inflammation and Lung Injury Induced by Sepsis through Delivery of miR-125b-5p. J Immunol Res 2023;2023:8987049. [PMID: 37425491 PMCID: PMC10329558 DOI: 10.1155/2023/8987049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 12/07/2022] [Accepted: 05/18/2023] [Indexed: 07/11/2023] Open

Abstract

Background

Sepsis-induced acute lung injury is a common critical illness in intensive care units with no effective treatment is currently available. Small extracellular vesicles, secreted by mesenchymal stem cells (MSCs), derived from human-induced pluripotent stem cells (iMSC-sEV), possess striking advantages when incorporated MSCs and iPSCs, which are considered extremely promising cell-free therapeutic agents. However, no studies have yet been conducted to systemically examine the effects and underlying mechanisms of iMSC-sEV application on attenuated lung injury under sepsis conditions.

Method

iMSC-sEV were intraperitoneally administered in a rat septic lung injury model induced by cecal ligation and puncture (CLP). The efficacy of iMSC-sEV was assessed by histology, immunohistochemistry, and pro-inflammatory cytokines of bronchoalveolar lavage fluid. We also evaluated the in vitro effects of iMSC-sEV on the activation of the inflammatory response in alveolar macrophages (AMs). Small RNA sequencing was utilized to detect changes in the miRNA expression profile in lipopolysaccharide (LPS)-treated AMs after iMSC-sEV administration. The effects of miR-125b-5p on the function of AMs were studied.

Results

iMSC-sEV were able to attenuate pulmonary inflammation and lung injury following CLP-induced lung injury. iMSC-sEV were internalized by AMs and alleviated the release of inflammatory factors by inactivating the NF-κB signaling pathway. Moreover, miR-125b-5p showed a fold-change in LPS-treated AMs after iMSC-sEV administration and was enriched in iMSC-sEV. Mechanistically, iMSC-sEV transmitted miR-125b-5p into LPS-treated AMs to target TRAF6.

Conclusion

Our findings demonstrated that iMSC-sEV treatment protects against septic lung injury and exerts anti-inflammatory effects on AMs at least partially through miR-125b-5p, suggesting that iMSC-sEV may provide a novel cell-free strategy for the treatment of septic lung injury.

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Affiliation(s)

Wei Peng Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
Yun Yang Department of Critical Care Medicine, The People's Hospital of Fengcheng City, Yichun, Jiangxi, China
Jiaquan Chen Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
Zeyao Xu Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
Yuanlei Lou Institute of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
Qi Li Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
Ning Zhao Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
Kejian Qian Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
Fen Liu Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China

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Clavellina D, Balkan W, Hare JM. Stem cell therapy for acute myocardial infarction: Mesenchymal Stem Cells and induced Pluripotent Stem Cells. Expert Opin Biol Ther 2023;23:951-967. [PMID: 37542462 PMCID: PMC10837765 DOI: 10.1080/14712598.2023.2245329] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/01/2023] [Accepted: 08/03/2023] [Indexed: 08/07/2023]

Xing J, Zhang M, Zhao S, Lu M, Lin L, Chen L, Gao W, Li W, Shang J, Zhou J, Zhu X. EIF4A3-Induced Exosomal circLRRC8A Alleviates Granulosa Cells Senescence Via the miR-125a-3p/NFE2L1 axis. Stem Cell Rev Rep 2023:10.1007/s12015-023-10564-8. [PMID: 37243831 PMCID: PMC10390409 DOI: 10.1007/s12015-023-10564-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/16/2023] [Indexed: 05/29/2023]

Affiliation(s)

Jie Xing Reproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China Department of Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
Mengxue Zhang Reproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China Department of Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
Shijie Zhao Reproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China Department of Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
Mingjun Lu Reproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China Department of Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
Li Lin Reproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China Department of Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
Lu Chen Reproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China Department of Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
Wujiang Gao Reproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China Department of Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
Wenxin Li Reproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China Department of Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
Junyu Shang Reproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China Department of Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
Jiamin Zhou Reproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China Department of Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China
Xiaolan Zhu Reproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China. Department of Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, China. Reproductive Sciences Institute, Jiangsu University, Zhenjiang, China.

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Yudhawati R, Shimizu K. PGE2 Produced by Exogenous MSCs Promotes Immunoregulation in ARDS Induced by Highly Pathogenic Influenza A through Activation of the Wnt-β-Catenin Signaling Pathway. Int J Mol Sci 2023;24:ijms24087299. [PMID: 37108459 PMCID: PMC10138595 DOI: 10.3390/ijms24087299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open

Baliña-Sánchez C, Aguilera Y, Adán N, Sierra-Párraga JM, Olmedo-Moreno L, Panadero-Morón C, Cabello-Laureano R, Márquez-Vega C, Martín-Montalvo A, Capilla-González V. Generation of mesenchymal stromal cells from urine-derived iPSCs of pediatric brain tumor patients. Front Immunol 2023;14:1022676. [PMID: 36776860 PMCID: PMC9910217 DOI: 10.3389/fimmu.2023.1022676] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 01/03/2023] [Indexed: 01/28/2023] Open

iPSC-Derived MSCs Are a Distinct Entity of MSCs with Higher Therapeutic Potential than Their Donor-Matched Parental MSCs. Int J Mol Sci 2023;24:ijms24010881. [PMID: 36614321 PMCID: PMC9821152 DOI: 10.3390/ijms24010881] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 12/23/2022] [Accepted: 12/28/2022] [Indexed: 01/05/2023] Open

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

Shirbaghaee Z, Hassani M, Heidari Keshel S, Soleimani M. Emerging roles of mesenchymal stem cell therapy in patients with critical limb ischemia. Stem Cell Res Ther 2022;13:462. [PMID: 36068595 PMCID: PMC9449296 DOI: 10.1186/s13287-022-03148-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/19/2022] [Indexed: 11/25/2022] Open

Repeated intravenous administration of hiPSC-MSCs enhance the efficacy of cell-based therapy in tissue regeneration. Commun Biol 2022;5:867. [PMID: 36008710 PMCID: PMC9411616 DOI: 10.1038/s42003-022-03833-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 08/11/2022] [Indexed: 01/02/2023] Open

Ahmed L, Al-Massri K. New Approaches for Enhancement of the Efficacy of Mesenchymal Stem Cell-Derived Exosomes in Cardiovascular Diseases. Tissue Eng Regen Med 2022;19:1129-1146. [PMID: 35867309 DOI: 10.1007/s13770-022-00469-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 06/03/2022] [Accepted: 06/08/2022] [Indexed: 11/28/2022] Open

Interferon-γ enhances the immunosuppressive ability of canine bone marrow-derived mesenchymal stem cells by activating the TLR3-dependent IDO/kynurenine pathway. Mol Biol Rep 2022;49:8337-8347. [PMID: 35690960 DOI: 10.1007/s11033-022-07648-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 05/25/2022] [Indexed: 10/18/2022]

Gao S, Jin Y, Ma J, Wang J, Wang J, Shao Z, Fan T, Zhang M, Chang D. Preclinical study of human umbilical cord mesenchymal stem cell sheets for the recovery of ischemic heart tissue. Stem Cell Res Ther 2022;13:252. [PMID: 35690871 PMCID: PMC9188245 DOI: 10.1186/s13287-022-02919-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/03/2022] [Indexed: 01/14/2023] Open

Abstract

BACKGROUND

Human umbilical cord mesenchymal stem cells (hUC-MSCs) have been widely used due to their multipotency, a broad range of sources, painless collection, and compliance with standard amplification. Cell sheet technology is a tissue engineering methodology requiring scaffolds free, and it provides an effective method for cell transplantation. To improve the therapeutic efficacy, we combined hUC-MSCs with cell sheet technology to evaluate the safety and efficacy of hUC-MSC sheets in preclinical studies using appropriate animal models.

METHODS

hUC-MSC sheets were fabricated by hUC-MSCs from a cell bank established by a standard operation process and quality control. Cytokine secretion, immunoregulation, and angiopoiesis were evaluated in vitro. Oncogenicity and cell diffusion assays of hUC-MSC sheets were conducted to verify the safety of hUC-MSCs sheet transplantation in mice. To provide more meaningful animal experimental data for clinical trials, porcine myocardial infarction (MI) models were established by constriction of the left circumflex, and hUC-MSC sheets were transplanted onto the ischemic area of the heart tissue. Cardiac function was evaluated and compared between the experimental and MI groups.

RESULTS

The in vitro results showed that hUC-MSC sheets could secrete multiple cellular factors, including VEGF, HGF, IL-6, and IL-8. Peripheral blood mononuclear cells had a lower proliferation rate and lower TNF-α secretion when co-cultured with hUC-MSC sheets. TH1 cells had a smaller proportion after activation. In vivo safety results showed that the hUC-MSCs sheet had no oncogenicity and was mainly distributed on the surface of the ischemic myocardial tissue. Echocardiography showed that hUC-MSC sheets effectively improved the left ventricular ejection fraction (LVEF), and the LVEF significantly changed (42.25 ± 1.23% vs. 66.9 ± 1.10%) in the hUC-MSC transplantation group compared with the MI group (42.52 ± 0.65% vs. 39.55 ± 1.97%) at 9 weeks. The infarct ratio of the hUC-MSCs sheet transplantation groups was also significantly reduced (14.2 ± 4.53% vs. 4.00 ± 2.00%) compared with that of the MI group.

CONCLUSION

Allogeneic source and cell bank established by the standard operation process and quality control make hUC-MSCs sheet possible to treat MI by off-the-shelf drug with universal quality instead of individualized medical technology.

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Peng YQ, Wu ZC, Xu ZB, Fang SB, Chen DH, Zhang HY, Liu XQ, He BX, Chen D, Akdis CA, Fu QL. Mesenchymal stromal cells-derived small extracellular vesicles modulate DC function to suppress Th2 responses via IL-10 in patients with allergic rhinitis. Eur J Immunol 2022;52:1129-1140. [PMID: 35415925 PMCID: PMC9545324 DOI: 10.1002/eji.202149497] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 02/01/2022] [Accepted: 04/11/2022] [Indexed: 12/02/2022]

Joladarashi D, Kishore R. Mesenchymal Stromal Cell Exosomes in Cardiac Repair. Curr Cardiol Rep 2022;24:405-417. [PMID: 35092595 PMCID: PMC9885380 DOI: 10.1007/s11886-022-01660-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/14/2021] [Indexed: 02/01/2023]

Yen BL, Liu K, Sytwu H, Yen M. Clinical implications of differential functional capacity between tissue‐specific human mesenchymal stromal/stem cells. FEBS J 2022. [DOI: 10.1111/febs.16438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 01/30/2022] [Accepted: 03/16/2022] [Indexed: 11/28/2022]

Henriques-Pons A, Beghini DG, Silva VDS, Iwao Horita S, da Silva FAB. Pulmonary Mesenchymal Stem Cells in Mild Cases of COVID-19 Are Dedicated to Proliferation; In Severe Cases, They Control Inflammation, Make Cell Dispersion, and Tissue Regeneration. Front Immunol 2022;12:780900. [PMID: 35095855 PMCID: PMC8793136 DOI: 10.3389/fimmu.2021.780900] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/17/2021] [Indexed: 12/29/2022] Open

Abstract

Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have potent self-renewal capacity and differentiate into multiple cell types. For many reasons, these cells are a promising therapeutic alternative to treat patients with severe COVID-19 and pulmonary post-COVID sequelae. These cells are not only essential for tissue regeneration; they can also alter the pulmonary environment through the paracrine secretion of several mediators. They can control or promote inflammation, induce other stem cells differentiation, restrain the virus load, and much more. In this work, we performed single-cell RNA-seq data analysis of MSCs in bronchoalveolar lavage samples from control individuals and COVID-19 patients with mild and severe clinical conditions. When we compared samples from mild cases with control individuals, most genes transcriptionally upregulated in COVID-19 were involved in cell proliferation. However, a new set of genes with distinct biological functions was upregulated when we compared severely affected with mild COVID-19 patients. In this analysis, the cells upregulated genes related to cell dispersion/migration and induced the γ-activated sequence (GAS) genes, probably triggered by IFNGR1 and IFNGR2. Then, IRF-1 was upregulated, one of the GAS target genes, leading to the interferon-stimulated response (ISR) and the overexpression of many signature target genes. The MSCs also upregulated genes involved in the mesenchymal-epithelial transition, virus control, cell chemotaxis, and used the cytoplasmic RNA danger sensors RIG-1, MDA5, and PKR. In a non-comparative analysis, we observed that MSCs from severe cases do not express many NF-κB upstream receptors, such as Toll-like (TLRs) TLR-3, -7, and -8; tumor necrosis factor (TNFR1 or TNFR2), RANK, CD40, and IL-1R1. Indeed, many NF-κB inhibitors were upregulated, including PPP2CB, OPTN, NFKBIA, and FHL2, suggesting that MSCs do not play a role in the "cytokine storm" observed. Therefore, lung MSCs in COVID-19 sense immune danger and act protectively in concert with the pulmonary environment, confirming their therapeutic potential in cell-based therapy for COVID-19. The transcription of MSCs senescence markers is discussed.

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Zohrabi M, Dehghan Marvast L, Izadi M, Mousavi SA, Aflatoonian B. Potential of Mesenchymal Stem Cell-Derived Exosomes as a Novel Treatment for Female Infertility Caused by Bacterial Infections. Front Microbiol 2022;12:785649. [PMID: 35154028 PMCID: PMC8834364 DOI: 10.3389/fmicb.2021.785649] [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: 09/29/2021] [Accepted: 12/08/2021] [Indexed: 12/29/2022] Open

Abstract

Neisseria gonorrhoeae and Chlamydia trachomatis are the most common causes of bacterial sexually transmitted diseases (STDs) with complications in women, including pelvic inflammatory disease (PID), ectopic pregnancy, and infertility. The main concern with these infections is that 70% of infected women are asymptomatic and these infections ascend to the upper female reproductive tract (FRT). Primary infection in epithelial cells creates a cascade of events that leads to secretion of pro-inflammatory cytokines that stimulate innate immunity. Production of various cytokines is damaging to mucosal barriers, and tissue destruction leads to ciliated epithelial destruction that is associated with tubal scarring and ultimately provides the conditions for infertility. Mesenchymal stem cells (MSCs) are known as tissue specific stem cells with limited self-renewal capacity and the ability to repair damaged tissues in a variety of pathological conditions due to their multipotential differentiation capacity. Moreover, MSCs secrete exosomes that contain bioactive factors such as proteins, lipids, chemokines, enzymes, cytokines, and immunomodulatory factors which have therapeutic properties to enhance recovery activity and modulate immune responses. Experimental studies have shown that local and systemic treatment of MSC-derived exosomes (MSC-Exos) suppresses the destructive immune response due to the delivery of immunomodulatory proteins. Interestingly, some recent data have indicated that MSC-Exos display strong antimicrobial effects, by the secretion of antimicrobial peptides and proteins (AMPs), and increase bacterial clearance by enhancing the phagocytic activity of host immune cells. Considering MSC-Exos can secrete different bioactive factors that can modulate the immune system and prevent infection, exosome therapy is considered as a new therapeutic method in the treatment of inflammatory and microbial diseases. Here we intend to review the possible application of MSC-Exos in female reproductive system bacterial diseases.

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Chang H, Zou Z, Li J, Shen Q, Liu L, An X, Yang S, Xing D. Photoactivation of mitochondrial reactive oxygen species-mediated Src and protein kinase C pathway enhances MHC class II-restricted T cell immunity to tumours. Cancer Lett 2021;523:57-71. [PMID: 34563641 DOI: 10.1016/j.canlet.2021.09.032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 09/08/2021] [Accepted: 09/21/2021] [Indexed: 10/20/2022]

Affiliation(s)

Haocai Chang MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
Zhengzhi Zou MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
Jie Li MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
Qi Shen MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
Lei Liu Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, China.
Xiaorui An MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
Sihua Yang MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
Da Xing MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.

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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

Generali M, Kehl D, Wanner D, Okoniewski MJ, Hoerstrup SP, Cinelli P. Heterogeneous expression of ACE2 and TMPRRS2 in mesenchymal stromal cells. J Cell Mol Med 2021;26:228-234. [PMID: 34821008 PMCID: PMC8742235 DOI: 10.1111/jcmm.17048] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 10/19/2021] [Accepted: 10/25/2021] [Indexed: 12/18/2022] Open

Chicken bone marrow mesenchymal stem cells improve lung and distal organ injury. Sci Rep 2021;11:17937. [PMID: 34508136 PMCID: PMC8433226 DOI: 10.1038/s41598-021-97383-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 08/23/2021] [Indexed: 02/07/2023] Open

Abstract

Mesenchymal stem cells (MSCs) are associated with pulmonary protection and longevity. We separated chicken bone marrow-derived mesenchymal stem cells (BM-MSCs); investigated whether BM-MSCs can improve lipopolysaccharide (LPS)-induced lung and distal organ injury; and explored the underlying mechanisms. Ninety-six male ICR (6 weeks old) mice were randomly divided into three groups: Sham, LPS, and LPS + MSC groups. The mice were intratracheally injected with 5 mg/kg LPS to induce acute lung injury (ALI). The histopathological severity of injury to the lung, liver, kidney, heart, and aortic tissues was detected. Wet/dry ratio, protein concentrations in bronchoalveolar lavage fluid (BALF), BALF cell counts, inflammatory cytokine levels in serum, inflammatory cytokine gene expression, and oxidative stress-related indicators were detected. In addition, a survival analysis was performed in sixty male ICR mice (6 weeks old, 18–20 g). This study used chicken BM-MSCs, which are easier to obtain and more convenient than other animal or human MSCs, and have MSC-associated properties, such as a colony forming ability, multilineage differentiation potential, and certain phenotypes. BM-MSCs administration significantly improved the survival rate, systemic inflammation, and the histopathological severity of lung, liver, kidney, and aortic injury during ALI. BM-MSCs administration reduced the levels of inflammatory factors in BALF, the infiltration of neutrophils, and oxidative stress injury in lung tissue. In addition, BM-MSCs administration reduced TRL4 and Mdy88 mRNA expression during ALI. Chicken BM-MSCs serve as a potential alternative resource for stem cell therapy and exert a prominent effect on LPS-induced ALI and extrapulmonary injury, in part through TRL4/Mdy88 signaling and inhibition of neutrophil inflammation and oxidative stress injury.

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Functions of Mesenchymal Stem Cells in Cardiac Repair. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021;1312:39-50. [PMID: 33330961 DOI: 10.1007/5584_2020_598] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]

Zha S, Tay JCK, Zhu S, Li Z, Du Z, Wang S. Generation of Mesenchymal Stromal Cells with Low Immunogenicity from Human PBMC-Derived β2 Microglobulin Knockout Induced Pluripotent Stem Cells. Cell Transplant 2021;29:963689720965529. [PMID: 33172291 PMCID: PMC7784598 DOI: 10.1177/0963689720965529] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open

Sun SJ, Wei R, Li F, Liao SY, Tse HF. Mesenchymal stromal cell-derived exosomes in cardiac regeneration and repair. Stem Cell Reports 2021;16:1662-1673. [PMID: 34115984 PMCID: PMC8282428 DOI: 10.1016/j.stemcr.2021.05.003] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 05/08/2021] [Accepted: 05/10/2021] [Indexed: 02/08/2023] Open

Tong Y, Zuo J, Yue D. Application Prospects of Mesenchymal Stem Cell Therapy for Bronchopulmonary Dysplasia and the Challenges Encountered. BIOMED RESEARCH INTERNATIONAL 2021;2021:9983664. [PMID: 33997051 PMCID: PMC8110410 DOI: 10.1155/2021/9983664] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/27/2021] [Accepted: 04/29/2021] [Indexed: 01/01/2023]

Functional Properties of Human-Derived Mesenchymal Stem Cell Spheroids: A Meta-Analysis and Systematic Review. Stem Cells Int 2021;2021:8825332. [PMID: 33884001 PMCID: PMC8041538 DOI: 10.1155/2021/8825332] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 01/31/2021] [Accepted: 02/12/2021] [Indexed: 02/06/2023] Open

Sun SJ, Lai WH, Jiang Y, Zhen Z, Wei R, Lian Q, Liao SY, Tse HF. Immunomodulation by systemic administration of human-induced pluripotent stem cell-derived mesenchymal stromal cells to enhance the therapeutic efficacy of cell-based therapy for treatment of myocardial infarction. Am J Cancer Res 2021;11:1641-1654. [PMID: 33408772 PMCID: PMC7778603 DOI: 10.7150/thno.46119] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 09/11/2020] [Indexed: 12/20/2022] Open

Abstract

Rationale: Poor survival and engraftment are major hurdles of stem cell therapy in the treatment of myocardial infarction (MI). We sought to determine whether pre-transplantation systemic intravenous administration of human induced pluripotent stem cell (hiPSC)-derived mesenchymal stromal cells (hiPSC-MSCs) could improve the survival of hiPSC-MSCs or hiPSC-derived cardiomyocytes (hiPSC-CMs) following direct intramyocardial transplantation in a mouse model of MI.

Methods: Mice were randomized to undergo intravenous administration of saline or 5×10⁵ hiPSC-MSCs one week prior to MI, induced by ligation of the left anterior descending coronary artery. Mice were further assigned to undergo direct intramyocardial transplantation of hiPSC-MSCs (1×10⁶) or hiPSC-CMs (1×10⁶) 10 minutes following MI. Echocardiographic and invasive hemodynamic assessment were performed to determine cardiac function. In-vivo fluorescent imaging analysis, immunofluorescence staining and polymerase chain reaction were performed to detect cell engraftment. Flow cytometry of splenic regulatory T cells (Tregs) and natural killer (NK) cells was performed to assess the immunomodulatory effects.

Results: Pre-transplantation systemic administration of hiPSC-MSCs increased systemic Tregs activation, decreased the number of splenic NK cells and inflammation, and enhanced survival of transplanted hiPSC-MSCs and hiPSC-CMs. These improvements were associated with increased neovascularization and decreased myocardial inflammation and apoptosis at the peri-infract zone with consequent improved left ventricular function four weeks later. Co-culture of splenic CD4 cells with hiPSC-MSCs also modulated their cytokine expression profile with a decreased level of interferon-γ, tumor necrosis factor-α, and interleukin (IL)-17A, but not IL-2, IL-6 and IL-10.

Conclusion: Pre-transplantation systemic intravenous administration of hiPSC-MSCs induced immunomodulation and facilitated the survival of intramyocardially transplanted cells to improve cardiac function in MI.

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Lin J, Deng H, Zhang Y, Zou L, Fu Z, Dai J. Effect of human umbilical cord-derived mesenchymal stem cells on murine model of bronchiolitis obliterans like injury. Pediatr Pulmonol 2021;56:129-137. [PMID: 33085211 DOI: 10.1002/ppul.25128] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 10/15/2020] [Accepted: 10/16/2020] [Indexed: 11/11/2022]

Abstract

BACKGROUND

Bronchiolitis obliterans is a fatal respiratory disease characterized by the obliteration of small airways. Mesenchymal stem cells (MSCs) is a promising candidate for cell-based therapy.

OBJECTIVE

To evaluate the therapeutic effect of human umbilical cord-derived mesenchymal stem cells (HUC-MSCs) on a murine model of bronchiolitis obliterans like injury (BOLI).

METHOD

The murine model of BOLI was established by administrating of diacetyl (DA) via intratracheal instillation. Treatment of HUC-MSCs or HUC-MSCs culture medium (HUC-MSCs-CM) was conducted in the BOLI model.

RESULTS

The pathogenic manifestations, lung function, and the number of neutrophils were similar between the oropharyngeal inhalation DA group (OPI-DA), intratracheal instillation group (ITI-DA); however, less reduction of weight and higher survival rate were observed in ITI-DA groups. Compared with the control groups, the trend of weight loss was significantly reduced (p < .05), and the pulmonary function was significantly improved (p < .05) in HUC-MSCs and HUC-MSCs-CM groups. Masson staining and hematoxylin and eosin staining showed that the deposition of collagen around bronchioles and blood vessels is less and airway epithelial cells and basal cells in lung tissue repaired better in HUC-MSCs and HUC-MSCs-CM groups compared with the control groups. Immunofluorescence shows the expression of E-cadherin and cytokeratin 5 (CK-5) were significantly higher in HUC-MSCs and HUC-MSCs-CM groups compared with control groups, while HUC-MSCs themselves did not express E-cadherin or CK-5. The DiI label showed HUC-MSCs gradually reduced after 2 days in the bronchus and 4 days in bronchiole.

CONCLUSION

HUC-MSCs could help to repair airway epithelial cells in a murine model of BOLI. It might be related to paracrine factors of HUC-MSCs.

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Sareen N, Abu-El-Rub E, Ammar HI, Yan W, Sequiera GL, ShamsEldeen AM, Moudgil M, Dhingra R, Shokry HS, Rashed LA, Kirshenbaum LA, Dhingra S. Hypoxia-induced downregulation of cyclooxygenase 2 leads to the loss of immunoprivilege of allogeneic mesenchymal stem cells. FASEB J 2020;34:15236-15251. [PMID: 32959405 DOI: 10.1096/fj.202001478r] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 08/31/2020] [Accepted: 09/03/2020] [Indexed: 12/16/2022]

Abstract

Allogeneic mesenchymal stem cells (MSCs) from young and healthy donors are reported to hold the potential to treat several immunological and degenerative disorders. However, recent data from animal studies and clinical trials demonstrate that immunogenicity and poor survival of transplanted MSCs impaired the efficacy of cells for regenerative applications. It is reported that initially immunoprivileged under in vitro conditions, MSCs are targeted by the host immune system after transplantation in the ischemic tissues in vivo. We performed in vitro (in MSCs) and in vivo (in the rat model of myocardial infarction [MI]) studies to elucidate the mechanisms responsible for the change in the immunophenotype of MSCs from immunoprivileged to immunogenic under ischemic conditions. We have recently reported that a soluble factor prostaglandin E2 (PGE2) preserves the immunoprivilege of allogeneic MSCs. In the current study, we found that PGE2 levels, which were elevated during normoxia, decreased in MSCs following exposure to hypoxia. Further, we found that proteasome-mediated degradation of cyclooxygenase-2 (COX2, rate-limiting enzyme in PGE2 biosynthesis) in hypoxic MSCs is responsible for PGE2 decrease and loss of immunoprivilege of MSCs. While investigating the mechanisms of COX2 degradation in hypoxic MSCs, we found that in normoxic MSCs, COP9 signalosome subunit 5 (CSN5) binds to COX2 and prevents its degradation by the proteasome. However, exposure to hypoxia leads to a decrease in CSN5 levels and its binding to COX2, rendering COX2 protein susceptible to proteasome-mediated degradation. This subsequently causes PGE2 downregulation and loss of immunoprivilege of MSCs. Maintaining COX2 levels in MSCs preserves immunoprivilege in vitro and improves the survival of transplanted MSCs in a rat model of MI. These data provide novel mechanistic evidence that PGE2 is downregulated in hypoxic MSCs which is responsible for the post-transplantation rejection of allogeneic MSCs. Therefore, our data suggest that the new strategies that target CSN5-COX2 signaling may improve survival and utility of transplanted allogeneic MSCs in the ischemic heart.

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Affiliation(s)

Niketa Sareen Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada
Ejlal Abu-El-Rub Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada
Hania I Ammar Department of Physiology and Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt
Weiang Yan Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada
Glen Lester Sequiera Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada
Asmaa M ShamsEldeen Department of Physiology and Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt
Meenal Moudgil Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada
Rimpy Dhingra Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada
Heba S Shokry Department of Physiology and Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt
Laila A Rashed Department of Physiology and Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt
Lorrie A Kirshenbaum Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada
Sanjiv Dhingra Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada

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Jang KW, Tu TW, Rosenblatt RB, Burks SR, Frank JA. MR-guided pulsed focused ultrasound improves mesenchymal stromal cell homing to the myocardium. J Cell Mol Med 2020;24:13278-13288. [PMID: 33067927 PMCID: PMC7701528 DOI: 10.1111/jcmm.15944] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 08/28/2020] [Accepted: 09/14/2020] [Indexed: 12/26/2022] Open

Al-Khawaga S, Abdelalim EM. Potential application of mesenchymal stem cells and their exosomes in lung injury: an emerging therapeutic option for COVID-19 patients. Stem Cell Res Ther 2020;11:437. [PMID: 33059757 PMCID: PMC7558244 DOI: 10.1186/s13287-020-01963-6] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 10/04/2020] [Indexed: 02/06/2023] Open

Luo L, Zhou Y, Zhang C, Huang J, Du J, Liao J, Bergholt NL, Bünger C, Xu F, Lin L, Tong G, Zhou G, Luo Y. Feeder-free generation and transcriptome characterization of functional mesenchymal stromal cells from human pluripotent stem cells. Stem Cell Res 2020;48:101990. [PMID: 32950887 DOI: 10.1016/j.scr.2020.101990] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 08/23/2020] [Accepted: 09/05/2020] [Indexed: 01/18/2023] Open

Affiliation(s)

Lidan Luo Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen 518033, China; Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
Yan Zhou Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark; 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, and Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopaedic Diseases, Health Sciences Center, Shenzhen University, Shenzhen 518060, China; Lungene Technologies Co., Ltd, Shenzhen, China.
Chenxi Zhang Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, BGI-Shenzhen, Shenzhen 518083, China.
Jinrong Huang Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, BGI-Shenzhen, Shenzhen 518083, China; Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark.
Jie Du 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, and Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopaedic Diseases, Health Sciences Center, Shenzhen University, Shenzhen 518060, China; Lungene Technologies Co., Ltd, Shenzhen, China.
Jinqi Liao 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, and Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopaedic Diseases, Health Sciences Center, Shenzhen University, Shenzhen 518060, China; Lungene Technologies Co., Ltd, Shenzhen, China.
Natasja Leth Bergholt Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
Cody Bünger Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
Fengping Xu Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, BGI-Shenzhen, Shenzhen 518083, China.
Lin Lin Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
Guangdong Tong Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen 518033, China.
Guangqian 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, and Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopaedic Diseases, Health Sciences Center, Shenzhen University, Shenzhen 518060, China.
Yonglun Luo Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, BGI-Shenzhen, Shenzhen 518083, China; Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.

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Fan XL, Zhang Y, Li X, Fu QL. Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy. Cell Mol Life Sci 2020;77:2771-2794. [PMID: 31965214 PMCID: PMC7223321 DOI: 10.1007/s00018-020-03454-6] [Citation(s) in RCA: 327] [Impact Index Per Article: 65.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 01/02/2020] [Accepted: 01/03/2020] [Indexed: 02/06/2023]

Fang SB, Zhang HY, Meng XC, Wang C, He BX, Peng YQ, Xu ZB, Fan XL, Wu ZJ, Wu ZC, Zheng SG, Fu QL. Small extracellular vesicles derived from human MSCs prevent allergic airway inflammation via immunomodulation on pulmonary macrophages. Cell Death Dis 2020;11:409. [PMID: 32483121 PMCID: PMC7264182 DOI: 10.1038/s41419-020-2606-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 05/11/2020] [Accepted: 05/13/2020] [Indexed: 12/13/2022]

Abstract

Allergic airway inflammation is a major public health disease that affects up to 300 million people in the world. However, its management remains largely unsatisfactory. The dysfunction of pulmonary macrophages contributes greatly to the development of allergic airway inflammation. It has been reported that small extracellular vesicles derived from mesenchymal stromal cells (MSC-sEV) were able to display extensive therapeutic effects in some immune diseases. This study aimed to investigate the effects of MSC-sEV on allergic airway inflammation, and the role of macrophages involved in it. We successfully isolated MSC-sEV by using anion exchange chromatography, which were morphologically intact and positive for the specific EV markers. MSC-sEV significantly reduced infiltration of inflammatory cells and number of epithelial goblet cells in lung tissues of mice with allergic airway inflammation. Levels of inflammatory cells and cytokines in bronchoalveolar lavage fluid were also significantly decreased. Importantly, levels of monocytes-derived alveolar macrophages and M2 macrophages were significantly reduced by MSC-sEV. MSC-sEV were excreted through spleen and liver at 24 h post-administration in mice, and were able to be taken in by macrophages both in vivo and in vitro. In addition, proteomics analysis of MSC-sEV revealed that the indicated three types of MSC-sEV contained different quantities of proteins and shared 312 common proteins, which may be involved in the therapeutic effects of MSC-sEV. In total, our study demonstrated that MSC-sEV isolated by anion exchange chromatography were able to ameliorate Th2-dominant allergic airway inflammation through immunoregulation on pulmonary macrophages, suggesting that MSC-sEV were promising alternative therapy for allergic airway inflammation in the future.

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Guo L, Lai P, Wang Y, Huang T, Chen X, Geng S, Huang X, Luo C, Wu S, Ling W, Huang L, Du X, Weng J. Extracellular vesicles derived from mesenchymal stem cells prevent skin fibrosis in the cGVHD mouse model by suppressing the activation of macrophages and B cells immune response. Int Immunopharmacol 2020;84:106541. [PMID: 32402950 DOI: 10.1016/j.intimp.2020.106541] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 04/10/2020] [Accepted: 04/23/2020] [Indexed: 02/06/2023]

Affiliation(s)

Liyan Guo Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China
Peilong Lai Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China
Yulian Wang Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China
Tian Huang Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China; South China University of Technology, Guangzhou, Guangdong 510006, PR China
Xiaomei Chen Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China
Suxia Geng Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China
Xin Huang Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China
Chenwei Luo Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China
Suijing Wu Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China
Wei Ling Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China
Lisi Huang Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China
Xin Du Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China; South China University of Technology, Guangzhou, Guangdong 510006, PR China.
Jianyu Weng Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China; South China University of Technology, Guangzhou, Guangdong 510006, PR China.

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Fang SB, Zhang HY, Wang C, He BX, Liu XQ, Meng XC, Peng YQ, Xu ZB, Fan XL, Wu ZJ, Chen D, Zheng L, Zheng SG, Fu QL. Small extracellular vesicles derived from human mesenchymal stromal cells prevent group 2 innate lymphoid cell-dominant allergic airway inflammation through delivery of miR-146a-5p. J Extracell Vesicles 2020;9:1723260. [PMID: 32128074 PMCID: PMC7034457 DOI: 10.1080/20013078.2020.1723260] [Citation(s) in RCA: 150] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Revised: 12/29/2019] [Accepted: 01/19/2020] [Indexed: 02/09/2023] Open

Abstract

Group 2 innate lymphoid cells (ILC2s) are recently reported to play a more critical role in allergic diseases. We previously identified that mesenchymal stromal cells (MSCs) elicited therapeutic effects on allergic airway inflammation. Small extracellular vesicles (sEV) derived from MSCs possess striking advantages including low immunogenicity and high biosafety, and is extremely promising cell-free therapeutic agents. However, the effects of MSC-sEV on ILC2s are still unclear. Additionally, scalable isolation protocols are required for the mass production of homogenous MSC-sEV especially in clinical application. We previously reported that induced pluripotent stem cells-derived MSCs were the ideal cellular source for the large preparation of MSC-sEV. Here we developed a standardized scalable protocol of anion-exchange chromatography for isolation of MSC-sEV, and investigated the effects of MSC-sEV on ILC2 function from patients with allergic rhinitis and in a mouse ILC2-dominant asthma model. The characterization of MSC-sEV was successfully demonstrated in terms of size, morphology and specific markers. Using flow cytometry and human Cytokine Antibody Array, MSC-sEV but not fibroblasts-sEV (Fb-sEV) were found to significantly inhibit the function of human ILC2s. Similarly, systemic administration of MSC-sEV but not Fb-sEV exhibited an inhibition of ILC2 levels, inflammatory cell infiltration and mucus production in the lung, a reduction in levels of T helper 2 cytokines, and alleviation of airway hyperresponsiveness in a mouse model of asthma. Using RNA sequencing, miR-146a-5p was selected as the candidate to mediate the above effects of MSC-sEV. We next revealed the uptake of ILC2s to MSC-sEV, and that transfer of miR-146a-5p in MSC-sEV to ILC2s in part contributed to the effects of MSC-sEV on ILC2s in vitro and in a mouse model. In conclusion, we demonstrated that MSC-sEV were able to prevent ILC2-dominant allergic airway inflammation at least partially through miR-146a-5p, suggesting that MSC-sEV could be a novel cell-free strategy for the treatment of allergic diseases.

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Umrath F, Weber M, Reinert S, Wendel HP, Avci-Adali M, Alexander D. iPSC-Derived MSCs Versus Originating Jaw Periosteal Cells: Comparison of Resulting Phenotype and Stem Cell Potential. Int J Mol Sci 2020;21:ijms21020587. [PMID: 31963278 PMCID: PMC7013802 DOI: 10.3390/ijms21020587] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 01/04/2020] [Accepted: 01/14/2020] [Indexed: 02/07/2023] Open