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For: Moreira A, Kahlenberg S, Hornsby P. Therapeutic potential of mesenchymal stem cells for diabetes. J Mol Endocrinol 2017;59:R109-R120. [PMID: 28739632 PMCID: PMC5570611 DOI: 10.1530/jme-17-0117] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 07/24/2017] [Indexed: 12/21/2022]

For:	Moreira A, Kahlenberg S, Hornsby P. Therapeutic potential of mesenchymal stem cells for diabetes. J Mol Endocrinol 2017;59:R109-R120. [PMID: 28739632 PMCID: PMC5570611 DOI: 10.1530/jme-17-0117] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 07/24/2017] [Indexed: 12/21/2022]

Number

Cited by Other Article(s)

Lee WS, Choi SJ, Shin YH, Kim JK. Mesenchymal Stem Cells Expressing Baculovirus-Engineered Brain-Derived Neurotrophic Factor Improve Peripheral Nerve Regeneration in a Rat Model. Tissue Eng Regen Med 2025;22:351-362. [PMID: 39962026 PMCID: PMC11926320 DOI: 10.1007/s13770-025-00703-2] [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: 09/20/2024] [Revised: 12/20/2024] [Accepted: 01/13/2025] [Indexed: 03/21/2025] Open

Abstract

BACKGROUND

Peripheral nerve injuries are a major clinical challenge because of their complex nature and limited regenerative capacity. This study aimed to improve peripheral nerve regeneration using Wharton's jelly mesenchymal stem cells (WJ-MSCs) engineered to express brain-derived neurotrophic factor (BDNF) via a baculovirus (BV) vector. The cells were evaluated for efficacy when seeded into acellular nerve grafts (ANGs) in a rat sciatic nerve defect model.

METHODS

WJ-MSCs were transfected with recombinant BV to upregulate BDNF expression. Conditioned medium (CM) from these cells was utilized to treat Schwann cells (SCs), and the impact on myelination-related markers, including KROX20, myelin basic protein (MBP), glial fibrillary acidic protein (GFAP), and S100 calcium-binding protein β (S100β), and the activation of the mammalian target of rapamycin (mTOR)/ protein kinase B (AKT)/p38 signaling pathways were evaluated. In vivo, BDNF-expressing WJ-MSCs were seeded into ANGs and implanted into a rat sciatic nerve defect model. Functional recovery was evaluated via video gait analysis, isometric tetanic force measurement, muscle weight evaluation, ankle contracture angle measurement, and histological analysis using toluidine blue staining.

RESULTS

BDNF expression was significantly upregulated in WJ-MSCs post-transfection. BDNF-MSC CM substantially promoted the expression of myelination markers in SCs and activated the mTOR/AKT/p38 signaling pathway. In the rat model, seeding of ANGs with BDNF-expressing WJ-MSCs resulted in improved functional outcomes, including enhanced toe-off angles, increased isometric tetanic force, greater muscle weight recovery, and a higher total number of myelinated axons compared with controls.

CONCLUSION

WJ-MSCs engineered to express BDNF significantly enhanced peripheral nerve regeneration when utilized in conjunction with ANGs. These findings indicate BDNF-expressing WJ-MSCs are a promising therapeutic approach for treating peripheral nerve injuries.

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Hsiao PJ, Kao WY, Sung LC, Lin CY, Tsou LLA, Kao YH, Chou CL, Lee KT. The Role of Mesenchymal Stem Cells in Treating Diabetic Kidney Disease: Immunomodulatory Effects and Kidney Regeneration. Int J Med Sci 2025;22:1720-1735. [PMID: 40093796 PMCID: PMC11905258 DOI: 10.7150/ijms.103806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 02/21/2025] [Indexed: 03/19/2025] Open

Abstract

Background: Diabetic kidney disease (DKD), also known as diabetic nephropathy (DN), is characterized by progressive glomerulosclerosis and chronic inflammation. The potential of mesenchymal stem cells (MSCs) in treating DKD could be explored. Methods: In this study, a streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) DKD mouse model was utilized to investigate the renoprotective potential of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) through immunohistochemical, histopathological, and biochemical analyses. Two separate experiments were conducted to assess the therapeutic efficacy of hUC-MSCs in a DN mouse model. The first experiment determined the optimal dose by assigning the body weight and food intake alterations, serum cytokines and kidney function changes post hUC-MSCs treatment. STZ-induced DKD mice were divided to four groups: DKD control and other three hUC-MSCs treatment groups (low-dose: 3x106, intermediate (middle)-dose: 1x107, and high-dose: 3x107 cells/kg), with intravenous administration at weeks 8, 10, and 12 over 14 weeks. The second experiment evaluated treatment frequency, with mice assigned to hUC-MSCs x1, x2, and x3 groups (3x107 cells/kg) administered at weeks 5, 6, and 7 across 12 weeks, assessing the kidney histology and morphometry changes. Results: In the first experiment, the body weight and food intake showed no significant alterations among the DN and other 3 hUC-MSCs treatment groups. Compared to the DKD control group, only high-dose hUC-MSCs (3x107 cells/kg) treatment group significantly reduced the levels of inflammatory cytokines (IL-1β, and TNF-α) (p <0.05). Additionally, the urine albumin-to-creatinine ratio (UACR) levels in the high-dose hUC-MSCs (3×10⁷ cells/kg) treatment group showed a decreasing trend compared to those in the DN control group (p = 0.06). In the second experiment, the hUC-MSCs x3 treatment group (3×10⁷ cells/kg) significantly alleviated kidney histopathology compared to the DKD group (p <0.05). Conclusion: hUC-MSCs treatment may present a potential avenue for reversing glomerulosclerosis and mitigating inflammation in DKD mice. The long-term therapeutic benefits of MSCs-based treatments in patients with DKD and other kidney diseases could be further investigated.

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Affiliation(s)

Po-Jen Hsiao Division of Nephrology, Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defence Medical Centre, Taipei, Taiwan Department of Life Sciences, National Central University, Taoyuan, Taiwan
Wen-Yi Kao Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
Li-Chin Sung Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan Taipei Medical University-Research Centre of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
Chia-Yi Lin Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
Liam Li-An Tsou Nephrology Division, Department of Medicine, Mount Sinai Hospital, New York, NY, USA Biochemistry, Department of Chemistry, Hofstra University, Hempstead, New York, USA
Yung-Hsi Kao Department of Life Sciences, National Central University, Taoyuan, Taiwan
Chu-Lin Chou Taipei Medical University-Research Centre of Urology and Kidney, Taipei Medical University, Taipei, Taiwan Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan Division of Nephrology, Department of Internal Medicine, Hsin Kuo Min Hospital, Taipei Medical University, Taoyuan City, Taiwan
Kung-Ta Lee Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan

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Mu-u-min RBA, Diane A, Allouch A, Al-Siddiqi HH. Immune Evasion in Stem Cell-Based Diabetes Therapy-Current Strategies and Their Application in Clinical Trials. Biomedicines 2025;13:383. [PMID: 40002796 PMCID: PMC11853723 DOI: 10.3390/biomedicines13020383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 01/28/2025] [Accepted: 02/03/2025] [Indexed: 02/27/2025] Open

Rodríguez-Valiente M, Fuente-Mora C, Sánchez-Gálvez J, Ortín-Pérez M, Pardo-Ríos M, Sánchez-Sáez JM, Pimenta IDSF, Piuvezam G, Ramos-Petersen L. Cellular therapy for the peripheral arterial disease treatment: Protocol for a systematic review and meta-analysis. PLoS One 2025;20:e0314070. [PMID: 39787254 PMCID: PMC11717238 DOI: 10.1371/journal.pone.0314070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 11/04/2024] [Indexed: 01/12/2025] Open

Ghassemifard L, Hasanlu M, Parsamanesh N, Atkin SL, Almahmeed W, Sahebkar A. Cell Therapies and Gene Therapy for Diabetes: Current Progress. Curr Diabetes Rev 2025;21:e130524229899. [PMID: 38747221 DOI: 10.2174/0115733998292392240425122326] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 03/07/2024] [Accepted: 03/21/2024] [Indexed: 04/23/2025]

Varalda M, Venetucci J, Nikaj H, Kankara CR, Garro G, Keivan N, Bettio V, Marzullo P, Antona A, Valente G, Gentilli S, Capello D. Second-Generation Antipsychotics Induce Metabolic Disruption in Adipose Tissue-Derived Mesenchymal Stem Cells Through an aPKC-Dependent Pathway. Cells 2024;13:2084. [PMID: 39768174 PMCID: PMC11674800 DOI: 10.3390/cells13242084] [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: 10/04/2024] [Revised: 12/06/2024] [Accepted: 12/14/2024] [Indexed: 01/11/2025] Open

Affiliation(s)

Marco Varalda Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.) UPO Biobank, University of Piemonte Orientale, 28100 Novara, Italy
Jacopo Venetucci Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.) UPO Biobank, University of Piemonte Orientale, 28100 Novara, Italy
Herald Nikaj General Surgery Division, University of Piemonte Orientale, AOU Maggiore della Carità, 28100 Novara, Italy;
Chaitanya Reddy Kankara Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.)
Giulia Garro Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.) UPO Biobank, University of Piemonte Orientale, 28100 Novara, Italy
Nazanin Keivan Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.)
Valentina Bettio Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.) UPO Biobank, University of Piemonte Orientale, 28100 Novara, Italy
Paolo Marzullo Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.)
Annamaria Antona Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.)
Guido Valente Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.) Pathology Unity, Ospedale “Sant’Andrea”, 13100 Vercelli, Italy
Sergio Gentilli Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.) General Surgery Division, University of Piemonte Orientale, AOU Maggiore della Carità, 28100 Novara, Italy; Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy
Daniela Capello Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (J.V.); (C.R.K.); (G.G.); (N.K.); (V.B.); (P.M.); (A.A.); (G.V.); (S.G.); (D.C.) UPO Biobank, University of Piemonte Orientale, 28100 Novara, Italy

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Montagnoli TL, Santos AD, Sudo SZ, Gubert F, Vasques JF, Mendez-Otero R, de Sá MPL, Zapata-Sudo G. Perspectives on Stem Cell Therapy in Diabetic Neuropathic Pain. Neurol Int 2024;16:933-944. [PMID: 39311343 PMCID: PMC11417725 DOI: 10.3390/neurolint16050070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 08/15/2024] [Accepted: 08/21/2024] [Indexed: 09/26/2024] Open

Affiliation(s)

Tadeu Lima Montagnoli Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (T.L.M.); (A.D.S.)
Aimeé Diogenes Santos Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (T.L.M.); (A.D.S.)
Susumu Zapata Sudo Programa de Pós-Graduação em Medicina (Cirurgia), Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (S.Z.S.); (M.P.L.d.S.)
Fernanda Gubert Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil;
Juliana Ferreira Vasques Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (J.F.V.); (R.M.-O.)
Rosalia Mendez-Otero Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (J.F.V.); (R.M.-O.)
Mauro Paes Leme de Sá Programa de Pós-Graduação em Medicina (Cirurgia), Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (S.Z.S.); (M.P.L.d.S.) Instituto do Coração Edson Saad, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
Gisele Zapata-Sudo Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (T.L.M.); (A.D.S.) Programa de Pós-Graduação em Medicina (Cirurgia), Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (S.Z.S.); (M.P.L.d.S.) Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; Instituto do Coração Edson Saad, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil

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Xu W, Zhou Y, Wang T, Ni C, Wang C, Li R, Liu X, Liang J, Hong T, Liu B, King AJF, Persaud SJ, Sun Z, Jones PM. Mouse islet-derived stellate cells are similar to, but distinct from, mesenchymal stromal cells and influence the beta cell function. Diabet Med 2024;41:e15279. [PMID: 38185936 PMCID: PMC11451341 DOI: 10.1111/dme.15279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/09/2024]

Affiliation(s)

Wei Xu Department of Endocrinology, Xuzhou Central HospitalXuzhou Institute of Medical Sciences, Xuzhou Medical University, Xuzhou Clinical School of Nanjing Medical University, Affiliated Hospital of Medical School of Southeast UniversityXuzhouChina Diabetes & Obesity, School of Cardiovascular and Metabolic Medicine & SciencesKing's College LondonLondonUK
Yunting Zhou Department of EndocrinologyNanjing First Hospital, Nanjing Medical UniversityNanjingChina
Tianyuan Wang Endocrinology DepartmentAir Force Hospital of Eastern Theater CommandNanjingChina
Chengming Ni Department of Endocrinology, Zhongda HospitalInstitute of Diabetes, Medical School, Southeast UniversityNanjingChina
Chunlei Wang Department of EndocrinologyYancheng Clinical College of Xuzhou Medical UniversityYanchenChina
Rui Li Department of Endocrinology, Xuzhou Central HospitalXuzhou Institute of Medical Sciences, Xuzhou Medical University, Xuzhou Clinical School of Nanjing Medical University, Affiliated Hospital of Medical School of Southeast UniversityXuzhouChina
Xuekui Liu Department of Endocrinology, Xuzhou Central HospitalXuzhou Institute of Medical Sciences, Xuzhou Medical University, Xuzhou Clinical School of Nanjing Medical University, Affiliated Hospital of Medical School of Southeast UniversityXuzhouChina
Jun Liang Department of Endocrinology, Xuzhou Central HospitalXuzhou Institute of Medical Sciences, Xuzhou Medical University, Xuzhou Clinical School of Nanjing Medical University, Affiliated Hospital of Medical School of Southeast UniversityXuzhouChina
Tzu‐wen Hong Diabetes & Obesity, School of Cardiovascular and Metabolic Medicine & SciencesKing's College LondonLondonUK
Bo Liu Diabetes & Obesity, School of Cardiovascular and Metabolic Medicine & SciencesKing's College LondonLondonUK
Aileen J. F. King Diabetes & Obesity, School of Cardiovascular and Metabolic Medicine & SciencesKing's College LondonLondonUK
Shanta J. Persaud Diabetes & Obesity, School of Cardiovascular and Metabolic Medicine & SciencesKing's College LondonLondonUK
Zilin Sun Department of Endocrinology, Zhongda HospitalInstitute of Diabetes, Medical School, Southeast UniversityNanjingChina
Peter M. Jones Diabetes & Obesity, School of Cardiovascular and Metabolic Medicine & SciencesKing's College LondonLondonUK

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Pokorska J, Sawicki S, Gabryś J, Kułaj D, Bauer EA, Lenart-Boroń A, Bulanda K, Kuchta-Gładysz M, Grzesiakowska A, Kemilew J, Barton PM, Lasek O, Bugno-Poniewierska M. The use of stem cells in the treatment of mastitis in dairy cows. Sci Rep 2024;14:10349. [PMID: 38710789 DOI: 10.1038/s41598-024-61051-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 04/30/2024] [Indexed: 05/08/2024] Open

Affiliation(s)

Joanna Pokorska Department of Animal Reproduction, Anatomy and Genomics, University of Agriculture in Krakow, al. Mickiewicza 24/28, 30-059, Krakow, Poland.
Sebastian Sawicki Department of Animal Reproduction, Anatomy and Genomics, University of Agriculture in Krakow, al. Mickiewicza 24/28, 30-059, Krakow, Poland
Julia Gabryś Department of Animal Reproduction, Anatomy and Genomics, University of Agriculture in Krakow, al. Mickiewicza 24/28, 30-059, Krakow, Poland
Dominika Kułaj Department of Animal Reproduction, Anatomy and Genomics, University of Agriculture in Krakow, al. Mickiewicza 24/28, 30-059, Krakow, Poland
Edyta Agnieszka Bauer Department of Animal Reproduction, Anatomy and Genomics, University of Agriculture in Krakow, al. Mickiewicza 24/28, 30-059, Krakow, Poland
Anna Lenart-Boroń Department of Microbiology and Biomonitoring, University of Agriculture in Krakow, al. Mickiewicza 24/28, 30-059, Krakow, Poland
Klaudia Bulanda Department of Microbiology and Biomonitoring, University of Agriculture in Krakow, al. Mickiewicza 24/28, 30-059, Krakow, Poland
Marta Kuchta-Gładysz Department of Animal Reproduction, Anatomy and Genomics, University of Agriculture in Krakow, al. Mickiewicza 24/28, 30-059, Krakow, Poland
Anna Grzesiakowska Department of Animal Reproduction, Anatomy and Genomics, University of Agriculture in Krakow, al. Mickiewicza 24/28, 30-059, Krakow, Poland
Jerzy Kemilew "Kemilew Stem Cells for Animals" Company, Warsaw, Poland
Patryk Mikołaj Barton Department of Animal Reproduction, Anatomy and Genomics, University of Agriculture in Krakow, al. Mickiewicza 24/28, 30-059, Krakow, Poland Kietrz Agricultural Combine LLC, ul. Zatorze 2, 48-130, Kietrz, Poland
Olga Lasek Department of Animal Nutrition, Biotechnology, and Fisheries, University of Agriculture in Krakow, al. Mickiewicza 24/28, 30-059, Krakow, Poland
Monika Bugno-Poniewierska Department of Animal Reproduction, Anatomy and Genomics, University of Agriculture in Krakow, al. Mickiewicza 24/28, 30-059, Krakow, Poland

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Badr OI, Kamal MM, El-Maraghy SA, Ghaiad HR. The effect of diabetes mellitus on differentiation of mesenchymal stem cells into insulin-producing cells. Biol Res 2024;57:20. [PMID: 38698488 PMCID: PMC11067316 DOI: 10.1186/s40659-024-00502-4] [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: 06/24/2023] [Accepted: 04/16/2024] [Indexed: 05/05/2024] Open

Abstract

BACKGROUND

Diabetes mellitus (DM) is a global epidemic with increasing incidences. DM is a metabolic disease associated with chronic hyperglycemia. Aside from conventional treatments, there is no clinically approved cure for DM up till now. Differentiating mesenchymal stem cells (MSCs) into insulin-producing cells (IPCs) is a promising approach for curing DM. Our study was conducted to investigate the effect of DM on MSCs differentiation into IPCs in vivo and in vitro.

METHODS

We isolated adipose-derived mesenchymal stem cells (Ad-MSCs) from the epididymal fat of normal and STZ-induced diabetic Sprague-Dawley male rats. Afterwards, the in vitro differentiation of normal-Ad-MSCs (N-Ad-MSCs) and diabetic-Ad-MSCs (DM-Ad-MSCs) into IPCs was compared morphologically then through determining the gene expression of β-cell markers including neurogenin-3 (Ngn-3), homeobox protein (Nkx6.1), musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), and insulin-1 (Ins-1) and eventually, through performing glucose-stimulated insulin secretion test (GSIS). Finally, the therapeutic potential of N-Ad-MSCs and DM-Ad-MSCs transplantation was compared in vivo in STZ-induced diabetic animals.

RESULTS

Our results showed no significant difference in the characteristics of N-Ad-MSCs and DM-Ad-MSCs. However, we demonstrated a significant difference in their abilities to differentiate into IPCs in vitro morphologically in addition to β-cell markers expression, and functional assessment via GSIS test. Furthermore, the abilities of both Ad-MSCs to control hyperglycemia in diabetic rats in vivo was assessed through measuring fasting blood glucose (FBGs), body weight (BW), histopathological examination of both pancreas and liver and immunoexpression of insulin in pancreata of study groups.

CONCLUSION

Our findings reveal the effectiveness of N-Ad-MSCs in differentiating into IPCs in vitro and controlling the hyperglycemia of STZ-induced diabetic rats in vivo compared to DM-Ad-MSCs.

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Poomani MS, Regurajan R, Perumal R, Ramachandran A, Mariappan I, Muthan K, Subramanian V. Differentiation of placenta-derived MSCs cultured in human platelet lysate: a xenofree supplement. 3 Biotech 2024;14:116. [PMID: 38524240 PMCID: PMC10959853 DOI: 10.1007/s13205-024-03966-z] [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: 03/16/2022] [Accepted: 02/22/2024] [Indexed: 03/26/2024] Open

Wang X, Tian H, Yang X, Zhao H, Liang X, Li Y. Mesenchymal Stem Cells‐Derived Extracellular Vesicles in Orthopedic Diseases: Recent Advances and Therapeutic Potential. ADVANCED THERAPEUTICS 2023;6. [DOI: 10.1002/adtp.202300193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Indexed: 01/06/2025]

Rather HA, Almousa S, Craft S, Deep G. Therapeutic efficacy and promise of stem cell-derived extracellular vesicles in Alzheimer's disease and other aging-related disorders. Ageing Res Rev 2023;92:102088. [PMID: 37827304 PMCID: PMC10842260 DOI: 10.1016/j.arr.2023.102088] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 10/01/2023] [Accepted: 10/09/2023] [Indexed: 10/14/2023]

Abstract

The term extracellular vesicles (EVs) refers to a variety of heterogeneous nanovesicles secreted by almost all cell types, primarily for intercellular communication and maintaining cellular homeostasis. The role of EVs has been widely reported in the genesis and progression of multiple pathological conditions, and these vesicles are suggested to serve as 'liquid biopsies'. In addition to their use as biomarkers, EVs secreted by specific cell types, especially with stem cell properties, have shown promise as cell-free nanotherapeutics. Stem cell-derived EVs (SC-EVs) have been increasingly used as an attractive alternative to stem cell therapies and have been reported to promote regeneration of aging-associated tissue loss and function. SC-EVs treatment ameliorates brain and peripheral aging, reproductive dysfunctions and inhibits cellular senescence, thereby reversing several aging-related disorders and dysfunctions. The anti-aging therapeutic potential of SC-EVs depends on multiple factors, including the type of stem cells, the age of the source stem cells, and their physiological state. In this review, we briefly describe studies related to the promising effects of SC-EVs against various aging-related pathologies, and then we focus in-depth on the therapeutic benefits of SC-EVs against Alzheimer's disease, one of the most devastating neurodegenerative diseases in elderly individuals. Numerous studies in transgenic mouse models have reported the usefulness of SC-EVs in targeting the pathological hallmarks of Alzheimer's disease, including amyloid plaques, neurofibrillary tangles, and neuroinflammation, leading to improved neuronal protection, synaptic plasticity, and cognitive measures. Cell culture studies have further identified the underlying molecular mechanisms through which SC-EVs reduce amyloid beta (Aβ) levels or shift microglia phenotype from pro-inflammatory to anti-inflammatory state. Interestingly, multiple routes of administration, including nasal delivery, have confirmed that SC-EVs could cross the blood-brain barrier. Due to this, SC-EVs have also been tested to deliver specific therapeutic cargo molecule/s (e.g., neprilysin) to the brain. Despite these promises, several challenges related to quality control, scalability, and biodistribution remain, hindering the realization of the vast clinical promise of SC-EVs.

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Shin YH, Choi SJ, Kim JK. Mechanisms of Wharton's Jelly-derived MSCs in enhancing peripheral nerve regeneration. Sci Rep 2023;13:21214. [PMID: 38040829 PMCID: PMC10692106 DOI: 10.1038/s41598-023-48495-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 11/27/2023] [Indexed: 12/03/2023] Open

Goshadezehn P, Babaei-Balderlou F, Razi M, Najafi GR, Abtahi-Foroushani M. A caffeine pre-treatment and sole effect of bone-marrow mesenchymal stem cells-derived conditioned media on hyperglycemia-suppressed fertilization. Biomed Pharmacother 2023;165:115130. [PMID: 37413898 DOI: 10.1016/j.biopha.2023.115130] [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: 03/31/2023] [Revised: 06/26/2023] [Accepted: 07/02/2023] [Indexed: 07/08/2023] Open

Abstract

As a common metabolic disorder, hyperglycemia (HG) affects and disrupts the physiology of various systems in the body. Transplantation of mesenchymal stem cells (MSCs) has been used to control the complications of disease. Most of the therapeutic properties of MSCs are attributed to their secretome. This study aimed to investigate the effects of conditioned media extracted from sole or caffeine pre-treated bone-marrow-derived MSCs on hyperglycemia-induced detrimental impact on some aspects of reproduction. The HG was induced by intraperitoneally injection of streptozotocin (65 mg/kg) and nicotinamide (110 mg/kg). Twenty-four male Wistar rats (190 ± 20 g) were divided into control, HG, and the hyperglycemic groups receiving conditioned media of proliferated MSCs solely (CM) or MSCs pre-treated with caffeine (CCM). During the 49-day treatment, body weight and blood glucose were measured weekly. Finally, HbA1c, spermatogenesis development, sperm count, morphology, viability, motility, chromatin condensation, and DNA integrity were examined. Also, testicular total antioxidant capacity (TAC), malondialdehyde, sperm fertilization potential, and pre-implantation embryo development were evaluated. A one-way ANOVA and Tukey's post-hoc tests were used to analyze the quantitative data. The p < 0.05 was considered statistically significant. The CM and with a higher efficiency, the CCM remarkably (p < 0.05) improved body weight and HG-suppressed spermatogenesis, enhanced sperm parameters, chromatin condensation, DNA integrity, and TAC, reduced HbA1c, sperm abnormalities, and malondialdehyde, and significantly improved pre-implantation embryo development versus HG group. The conditioned media of MSCs solely (CM) and more effectively after pre-treatment of MSCs with caffeine (CCM) could improve spermatogenesis development, sperm quality, pre-implantation embryo development, and testicular global antioxidant potential during hyperglycemia.

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Park HS, Cetin E, Siblini H, Seok J, Alkelani H, Alkhrait S, Liakath Ali F, Mousaei Ghasroldasht M, Beckman A, Al-Hendy A. Therapeutic Potential of Mesenchymal Stem Cell-Derived Extracellular Vesicles to Treat PCOS. Int J Mol Sci 2023;24:11151. [PMID: 37446328 DOI: 10.3390/ijms241311151] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 06/30/2023] [Accepted: 07/04/2023] [Indexed: 07/15/2023] Open

Drobiova H, Sindhu S, Ahmad R, Haddad D, Al-Mulla F, Al Madhoun A. Wharton's jelly mesenchymal stem cells: a concise review of their secretome and prospective clinical applications. Front Cell Dev Biol 2023;11:1211217. [PMID: 37440921 PMCID: PMC10333601 DOI: 10.3389/fcell.2023.1211217] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 06/13/2023] [Indexed: 07/15/2023] Open

Ahmed OM, Saleh AS, Ahmed EA, Ghoneim MM, Ebrahim HA, Abdelgawad MA, Abdel-Gabbar M. Efficiency of Bone Marrow-Derived Mesenchymal Stem Cells and Hesperetin in the Treatment of Streptozotocin-Induced Type 1 Diabetes in Wistar Rats. Pharmaceuticals (Basel) 2023;16:859. [PMID: 37375806 DOI: 10.3390/ph16060859] [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: 03/09/2023] [Revised: 05/22/2023] [Accepted: 05/26/2023] [Indexed: 06/29/2023] Open

Abstract

Type 1 diabetes mellitus (T1DM) was established to be ameliorated by islet transplantation, but the shortage of the transplanted human islet tissue and the use of immunosuppressive drugs to inhibit the rejection of allogeneic grafts make this type of therapy is limited. Nowadays, therapy with stem cells is one of the most promising future treatments. This kind of therapy could have a profound impact on both replacement, as well as regenerative therapies, to improve or even cure various disorders, including diabetes mellitus. Flavonoids have also been shown to possess anti-diabetic effects. Thus, this study aims to evaluate the effectiveness of the bone marrow-derived mesenchymal stem cells (BM-MSCs) and hesperetin in the treatment of a T1DM rat model. T1DM was induced in male Wistar rats that had been starved for 16 h via intraperitoneal injection of STZ at a dose of 40 mg/kg body weight (b.wt.). After 10 days of STZ injection, the diabetic rats were allocated into four groups. The first diabetic animal group was considered a diabetic control, while the other three diabetic animal groups were treated for six weeks, respectively, with hesperetin (given orally at a dose of 20 mg/kg b.wt.), BM-MSCs (injected intravenously at a dose of 1 × 10⁶ cells/rat/week), and their combination (hesperetin and BM-MSCs). The use of hesperetin and BM-MSCs in the treatment of STZ-induced diabetic animals significantly improved the glycemic state, serum fructosamine, insulin and C-peptide levels, liver glycogen content, glycogen phosphorylase, glucose-6-phosphatase activities, hepatic oxidative stress, and mRNA expressions of NF-κB, IL-1β, IL-10, P53, and Bcl-2 in pancreatic tissue. The study suggested the therapy with both hesperetin and BM-MSCs produced marked antihyperglycemic effects, which may be mediated via their potencies to ameliorate pancreatic islet architecture and insulin secretory response, as well as to decrease hepatic glucose output in diabetic animals. The improvement effects of hesperetin and BM-MSCs on the pancreatic islets of diabetic rats may be mediated via their antioxidant, anti-inflammatory, and antiapoptotic actions.

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Mathur A, Taurin S, Alshammary S. The Safety and Efficacy of Mesenchymal Stem Cells in the Treatment of Type 2 Diabetes- A Literature Review. Diabetes Metab Syndr Obes 2023;16:769-777. [PMID: 36941907 PMCID: PMC10024492 DOI: 10.2147/dmso.s392161] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 01/24/2023] [Indexed: 03/15/2023] Open

Hu Q, Zhu B, Yang G, Jia J, Wang H, Tan R, Zhang Q, Wang L, Kantawong F. Calycosin pretreatment enhanced the therapeutic efficacy of mesenchymal stem cells to alleviate unilateral ureteral obstruction-induced renal fibrosis by inhibiting necroptosis. J Pharmacol Sci 2023;151:72-83. [PMID: 36707181 DOI: 10.1016/j.jphs.2022.12.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 11/25/2022] [Accepted: 12/05/2022] [Indexed: 12/15/2022] Open

Affiliation(s)

Qiongdan Hu Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand; Research Center of Integrated Traditional Chinese and Western Medicine, Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Sichuan, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Sichuan, China
Bingwen Zhu Research Center of Integrated Traditional Chinese and Western Medicine, Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Sichuan, China
Guoqiang Yang Research Center of Integrated Traditional Chinese and Western Medicine, Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Sichuan, China; Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Sichuan, China
Jian Jia Research Center of Integrated Traditional Chinese and Western Medicine, Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Sichuan, China
Honglian Wang Research Center of Integrated Traditional Chinese and Western Medicine, Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Sichuan, China
Ruizhi Tan Research Center of Integrated Traditional Chinese and Western Medicine, Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Sichuan, China
Qiong Zhang Research Center of Integrated Traditional Chinese and Western Medicine, Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Sichuan, China
Li Wang Research Center of Integrated Traditional Chinese and Western Medicine, Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Sichuan, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Sichuan, China.
Fahsai Kantawong Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.

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Future regenerative medicine developments and their therapeutic applications. Biomed Pharmacother 2023;158:114131. [PMID: 36538861 DOI: 10.1016/j.biopha.2022.114131] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/05/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open

Abstract

Although the currently available pharmacological assays can cure most pathological disorders, they have limited therapeutic value in relieving certain disorders like myocardial infarct, peripheral vascular disease, amputated limbs, or organ failure (e.g. renal failure). Pilot studies to overcome such problems using regenerative medicine (RM) delivered promising data. Comprehensive investigations of RM in zebrafish or reptilians are necessary for better understanding. However, the precise mechanisms remain poorly understood despite the tremendous amount of data obtained using the zebrafish model investigating the exact mechanisms behind their regenerative capability. Indeed, understanding such mechanisms and their application to humans can save millions of lives from dying due to potentially life-threatening events. Recent studies have launched a revolution in replacing damaged human organs via different approaches in the last few decades. The newly established branch of medicine (known as Regenerative Medicine aims to enhance natural repair mechanisms. This can be done through the application of several advanced broad-spectrum technologies such as organ transplantation, tissue engineering, and application of Scaffolds technology (support vascularization using an extracellular matrix), stem cell therapy, miRNA treatment, development of 3D mini-organs (organoids), and the construction of artificial tissues using nanomedicine and 3D bio-printers. Moreover, in the next few decades, revolutionary approaches in regenerative medicine will be applied based on artificial intelligence and wireless data exchange, soft intelligence biomaterials, nanorobotics, and even living robotics capable of self-repair. The present work presents a comprehensive overview that summarizes the new and future advances in the field of RM.

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Liang F, Luo YF, Guo Z, Qian Q, Meng XB, Mo ZH. MicroRNA-139-5p mediates BMSCs impairment in diabetes by targeting HOXA9/c-Fos. FASEB J 2023;37:e22697. [PMID: 36527387 DOI: 10.1096/fj.202201059r] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 10/13/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022]

Kian M, Mirzavand S, Sharifzadeh S, Kalantari T, Ashrafmansouri M, Nasri F. Efficacy of Mesenchymal Stem Cells Therapy in Parasitic Infections: Are Anti-parasitic Drugs Combined with MSCs More Effective? Acta Parasitol 2022;67:1487-1499. [DOI: 10.1007/s11686-022-00620-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 09/20/2022] [Indexed: 11/01/2022]

Hernandez JC, Yeh DW, Marh J, Choi HY, Kim J, Chopra S, Ding L, Thornton M, Grubbs B, Makowka L, Sher L, Machida K. Activated and nonactivated MSCs increase survival in humanized mice after acute liver injury through alcohol binging. Hepatol Commun 2022;6:1549-1560. [PMID: 35246968 PMCID: PMC9234635 DOI: 10.1002/hep4.1924] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 01/15/2022] [Accepted: 01/31/2022] [Indexed: 11/08/2022] Open

Extracellular Vesicles Delivered by Injectable Collagen Promote Bone-Tendon Interface Healing and Prevent Fatty Degeneration of Rotator Cuff Muscle. Arthroscopy 2022;38:2142-2153. [PMID: 35042006 DOI: 10.1016/j.arthro.2022.01.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 01/06/2022] [Accepted: 01/07/2022] [Indexed: 02/02/2023]

Abstract

PURPOSE

This study aimed (1) to confirm the maintenance of the extracellular vesicles (EVs) delivered via injectable collagen at the application site, and (2) to evaluate the effect of EVs derived from the human umbilical cord-derived mesenchymal stem cells and loaded in an injectable collagen gel after rotator cuff repair (RCR).

METHODS

Rabbits (n = 20) were assigned to normal (N), repair-only (R), and those administered with injectable collagen after repair (RC), and EV-laden injectable collagen after repair (RCE) groups. The EVs isolated by ultra-centrifugation from the human umbilical cord-derived mesenchymal stem cells spent medium were mixed with collagen and administered accordingly. After 12 weeks, the rabbits were sacrificed to evaluate the healing of the bone-to-tendon junction and the fatty degeneration of muscle. Histomorphometric scoring for bone-tendon interface, fatty infiltration (%), and biomechanical tests were performed. Separately, groups of 3 rabbits were assigned to 3 different time points to evaluate maintenance of green fluorescence-labeled EVs with injectable collagen via tracking on the bursal side of the rotator cuff (3 groups: 3 days, 2, and 4 weeks).

RESULTS

The EVs delivered by injectable collagen remained until 4 weeks at the bursal side of the cuff tissue. The RCE group showed a significantly greater histomorphometric total score (P < .001, and P = .013, respectively) and significantly lower fatty degeneration than the RC and R groups (P = .001, and P = .013, respectively). The biomechanical tests revealed significant growing trends in load-to-failure and stiffness (P = .002, and P = .013, respectively), in the R, RC, RCE, and N groups.

CONCLUSIONS

EVs mounted in injectable collagen remained at the repair site for at least 4 weeks after application. Furthermore, they effectively promote bone-to-tendon healing via collagen maturation in bone-tendon interface and preventing fatty degeneration of rotator muscle after RCR as compared with collagen-only or repair-only groups.

CLINICAL RELEVANCE

The combination of collagen with EVs significantly promotes rotator cuff healing demonstrating potential clinical application during partial rotator cuff tear or after RCR.

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Izadi M, Sadr Hashemi Nejad A, Moazenchi M, Masoumi S, Rabbani A, Kompani F, Hedayati Asl AA, Abbasi Kakroodi F, Jaroughi N, Mohseni Meybodi MA, Setoodeh A, Abbasi F, Hosseini SE, Moeini Nia F, Salman Yazdi R, Navabi R, Hajizadeh-Saffar E, Baharvand H. Mesenchymal stem cell transplantation in newly diagnosed type-1 diabetes patients: a phase I/II randomized placebo-controlled clinical trial. Stem Cell Res Ther 2022;13:264. [PMID: 35725652 PMCID: PMC9208234 DOI: 10.1186/s13287-022-02941-w] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 06/04/2022] [Indexed: 01/01/2023] Open

Abstract

Background

Type-1 diabetes (T1D) occurs following autoimmune-induced pancreatic beta cells death. Among several treatment modalities, mesenchymal stem cells (MSCs) transplantation is promising for autoimmune disorders due to immunomodulation, regeneration, and migration to damaged tissue upon systemic injection. This study assessed the safety and efficacy of intravenous injection of autologous bone marrow-derived MSCs in newly diagnosed T1D patients.

Methods

After receiving informed consent, 21 patients who met the study criteria were enrolled and randomly assigned to receive either MSCs or placebo. Each patient in the experimental group received two doses of MSCs and was followed for at least one-year post-transplantation.

Results

The results have shown that this transplantation is safe and significantly reduces the number of hypoglycemic episodes. MSCs transplantation improved glycated hemoglobin (HbA1c), shifted serum cytokine patterns from pro-inflammatory to anti-inflammatory, increased the number of regulatory T-cells in the peripheral blood, and improved quality of life. Early transplantation of MSCs significantly improved HbA1c and C-peptide levels and shifted pro-inflammatory cytokines to anti-inflammatory cytokines. Also, exercise combined with MSCs transplantation improved glycemic and immunologic indices.

Conclusions

Taken together, autologous MSC transplantation is safe and effective, and its early transplantation is a promising treatment in newly diagnosed T1D children suffering from hypoglycemic episodes.

Trial registration: This clinical trial was registered at the Iranian Registry of Clinical Trials (IRCT) with the identifier IRCT ID: IRCT2016070428786N1 registered on August 20, 2016 (Retrospectively registered) (https://en.irct.ir/trial/23256) and at the U.S. National Institutes of Health (ClinicalTrials.gov) with the related identifier NCT04078308 registered on September 6, 2019 (Retrospectively registered). (https://clinicaltrials.gov/ct2/show/NCT04078308).

Supplementary Information

The online version contains supplementary material available at 10.1186/s13287-022-02941-w.

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Affiliation(s)

Mahmoud Izadi Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
Anavasadat Sadr Hashemi Nejad Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
Maedeh Moazenchi Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
Safdar Masoumi Department of Epidemiology and Biostatistics, Tehran University of Medical Sciences, Tehran, Iran
Ali Rabbani Growth and Development Research Center, Children's Medical Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
Farzad Kompani Division of Hematology and Oncology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
Amir Abbas Hedayati Asl Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Hematology-Oncology and Stem Cell Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
Fatemeh Abbasi Kakroodi Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
Neda Jaroughi Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
Mohammad Ali Mohseni Meybodi Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
Aria Setoodeh Division of Pediatrics Endocrinology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
Farzaneh Abbasi Growth and Development Research Center, Children's Medical Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
Seyedeh Esmat Hosseini Department of Medical-Surgical Nursing, School of Nursing and Midwifery, Iran University of Medical Sciences, Tehran, Iran
Fatemeh Moeini Nia Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
Reza Salman Yazdi Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
Roghayeh Navabi Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
Ensiyeh Hajizadeh-Saffar Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. .,Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. .,Department of Diabetes, Obesity, and Metabolism, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
Hossein Baharvand Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. .,Department of Developmental Biology, School of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran.

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Park HS, Chugh RM, Pergande MR, Cetin E, Siblini H, Esfandyari S, Cologna SM, Al-Hendy A. Non-Cytokine Protein Profile of the Mesenchymal Stem Cell Secretome That Regulates the Androgen Production Pathway. Int J Mol Sci 2022;23:ijms23094633. [PMID: 35563028 PMCID: PMC9101816 DOI: 10.3390/ijms23094633] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/15/2022] [Accepted: 04/20/2022] [Indexed: 02/04/2023] Open

Hussein MAA, Hussein HAM, Thabet AA, Selim KM, Dawood MA, El-Adly AM, Wardany AA, Sobhy A, Magdeldin S, Osama A, Anwar AM, Abdel-Wahab M, Askar H, Bakhiet EK, Sultan S, Ezzat AA, Abdel Raouf U, Afifi MM. Human Wharton's Jelly Mesenchymal Stem Cells Secretome Inhibits Human SARS-CoV-2 and Avian Infectious Bronchitis Coronaviruses. Cells 2022;11:1408. [PMID: 35563714 PMCID: PMC9101656 DOI: 10.3390/cells11091408] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/19/2022] [Accepted: 04/20/2022] [Indexed: 02/04/2023] Open

Abstract

Human SARS-CoV-2 and avian infectious bronchitis virus (IBV) are highly contagious and deadly coronaviruses, causing devastating respiratory diseases in humans and chickens. The lack of effective therapeutics exacerbates the impact of outbreaks associated with SARS-CoV-2 and IBV infections. Thus, novel drugs or therapeutic agents are highly in demand for controlling viral transmission and disease progression. Mesenchymal stem cells (MSC) secreted factors (secretome) are safe and efficient alternatives to stem cells in MSC-based therapies. This study aimed to investigate the antiviral potentials of human Wharton’s jelly MSC secretome (hWJ-MSC-S) against SARS-CoV-2 and IBV infections in vitro and in ovo. The half-maximal inhibitory concentrations (IC50), cytotoxic concentration (CC50), and selective index (SI) values of hWJ-MSC-S were determined using Vero-E6 cells. The virucidal, anti-adsorption, and anti-replication antiviral mechanisms of hWJ-MSC-S were evaluated. The hWJ-MSC-S significantly inhibited infection of SARS-CoV-2 and IBV, without affecting the viability of cells and embryos. Interestingly, hWJ-MSC-S reduced viral infection by >90%, in vitro. The IC50 and SI of hWJ-MSC secretome against SARS-CoV-2 were 166.6 and 235.29 µg/mL, respectively, while for IBV, IC50 and SI were 439.9 and 89.11 µg/mL, respectively. The virucidal and anti-replication antiviral effects of hWJ-MSC-S were very prominent compared to the anti-adsorption effect. In the in ovo model, hWJ-MSC-S reduced IBV titer by >99%. Liquid chromatography-tandem mass spectrometry (LC/MS-MS) analysis of hWJ-MSC-S revealed a significant enrichment of immunomodulatory and antiviral proteins. Collectively, our results not only uncovered the antiviral potency of hWJ-MSC-S against SARS-CoV-2 and IBV, but also described the mechanism by which hWJ-MSC-S inhibits viral infection. These findings indicate that hWJ-MSC-S could be utilized in future pre-clinical and clinical studies to develop effective therapeutic approaches against human COVID-19 and avian IB respiratory diseases.

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Affiliation(s)

Mohamed A. A. Hussein Department of Microbiology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt; (M.A.A.H.); (A.M.E.-A.); (A.A.W.); (E.K.B.); (M.M.A.)
Hosni A. M. Hussein Department of Microbiology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt; (M.A.A.H.); (A.M.E.-A.); (A.A.W.); (E.K.B.); (M.M.A.)
Ali A. Thabet Department of Zoology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt; (A.A.T.); (M.A.-W.); (H.A.)
Karim M. Selim Reference Laboratory for Veterinary Quality Control on Poultry Production, Animal Health Research Institute, Agricultural Research Center, Dokki, Giza 12618, Egypt;
Mervat A. Dawood Clinical Pathology, Mansoura Research Center for Cord Stem Cells (MARC-CSC), Faculty of Medicine, Mansoura University, El Mansoura 35516, Egypt;
Ahmed M. El-Adly Department of Microbiology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt; (M.A.A.H.); (A.M.E.-A.); (A.A.W.); (E.K.B.); (M.M.A.)
Ahmed A. Wardany Department of Microbiology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt; (M.A.A.H.); (A.M.E.-A.); (A.A.W.); (E.K.B.); (M.M.A.)
Ali Sobhy Department of Clinical Pathology, Faculty of Medicine, Al-Azhar University, Assiut 71524, Egypt;
Sameh Magdeldin Proteomics and Metabolomics Research Program, Basic Research Department, Children’s Cancer Hospital, (CCHE-57357), Cairo 57357, Egypt; (S.M.); (A.O.); (A.M.A.) Department of Physiology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
Aya Osama Proteomics and Metabolomics Research Program, Basic Research Department, Children’s Cancer Hospital, (CCHE-57357), Cairo 57357, Egypt; (S.M.); (A.O.); (A.M.A.)
Ali M. Anwar Proteomics and Metabolomics Research Program, Basic Research Department, Children’s Cancer Hospital, (CCHE-57357), Cairo 57357, Egypt; (S.M.); (A.O.); (A.M.A.)
Mohammed Abdel-Wahab Department of Zoology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt; (A.A.T.); (M.A.-W.); (H.A.)
Hussam Askar Department of Zoology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt; (A.A.T.); (M.A.-W.); (H.A.)
Elsayed K. Bakhiet Department of Microbiology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt; (M.A.A.H.); (A.M.E.-A.); (A.A.W.); (E.K.B.); (M.M.A.)
Serageldeen Sultan Department of Microbiology, Virology Division, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt;
Amgad A. Ezzat Department of Medical Microbiology and Immunology, Faculty of Medicine, Al-Azhar University, Assiut 71524, Egypt;
Usama Abdel Raouf Department of Botany and Microbiology, Faculty of Science, Aswan University, Aswan 81528, Egypt;
Magdy M. Afifi Department of Microbiology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt; (M.A.A.H.); (A.M.E.-A.); (A.A.W.); (E.K.B.); (M.M.A.)

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Yang Y, Lei T, Bi W, Xiao Z, Zhang X, Du H. The combined therapy of mesenchymal stem cell transplantation and resveratrol for diabetes: Future applications and challenges. Life Sci 2022;301:120563. [PMID: 35460708 DOI: 10.1016/j.lfs.2022.120563] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/07/2022] [Accepted: 04/14/2022] [Indexed: 12/22/2022]

Effects of bone marrow‐derived mesenchymal stem cells on doxorubicin‐induced liver injury in rats. J Biochem Mol Toxicol 2022;36:e22985. [DOI: 10.1002/jbt.22985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 11/25/2021] [Accepted: 01/04/2022] [Indexed: 11/07/2022]

Harness EM, Mohamad-Fauzi N, Murray JD. MSC therapy in livestock models. Transl Anim Sci 2022;6:txac012. [PMID: 35356233 PMCID: PMC8962450 DOI: 10.1093/tas/txac012] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 01/24/2022] [Indexed: 11/25/2022] Open

Abstract

Mesenchymal stem cells (MSCs) have great value as therapeutic tools in a wide array of applications in regenerative medicine. The wide repertoire of cell functions regarding tissue regeneration, immunomodulation, and antimicrobial activity makes MSC-based therapy a strong candidate for treatment options in a variety of clinical conditions and should be studied to expand the current breadth of knowledge surrounding their physiological properties and therapeutic benefits. Livestock models are an appropriate resource for testing the efficacy of MSC therapies for their use in biomedical research and can be used to improve both human health and animal agriculture. Agricultural animal models such as pigs, cattle, sheep, and goats have grown in popularity for in vivo research relative to small animal models due to their overlapping similarities in structure and function that more closely mimic the human body. Cutaneous wound healing, bone regeneration, osteoarthritis, ischemic reperfusion injury, and mastitis recovery represent a few examples of the types of disease states that may be investigated in livestock using MSC-based therapy. Although the cost of agricultural animals is greater than small animal models, the information gained using livestock as a model holds great value for human applications, and in some cases, outcompetes the weight of information gained from rodent models. With emerging fields such as exosome-based therapy, proper in vivo models will be needed for testing efficacy and translational practice, i.e., livestock models should be strongly considered as candidates. The potential for capitalizing on areas that have crossover benefits for both agricultural economic gain and improved health of the animals while minimizing the gap between translational research and clinical practice are what make livestock great choices for experimental MSC models.

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Ezzat SM, Abdel Rahman MF, Salama MM, Mahrous EA, El Bariary A. Non-polar metabolites of green beans (Phaseolus vulgaris L.) potentiate the antidiabetic activity of mesenchymal stem cells in streptozotocin-induced diabetes in rats. J Food Biochem 2022;46:e14083. [PMID: 35034354 DOI: 10.1111/jfbc.14083] [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: 09/18/2021] [Revised: 11/04/2021] [Accepted: 12/13/2021] [Indexed: 11/28/2022]

Abstract

Green beans (Phaseolus vulgaris L.) are consumed as pods or mature seeds (common beans). The pods were extracted with 95% ethanol and processed to prepare non-polar and polar fractions. Comparing the antihyperglycemic activity of both fractions, non-polar fraction (NPF, 200 mg kg^-1 day^-1 ) lowered blood glucose in streptozotocin diabetic rats by 65% compared to 57% for the polar fraction at the same dose. When NPF treatment was combined with injection of mesenchymal stem cells (MSC) a 4.4-fold increase in serum insulin and a 73.6% reduction in blood glucose were observed compared to untreated control. Additionally, a significant decrease in malondialdehyde (76.2%), nitric oxide (68.2%), cholesterol (76.1%), and triglycerides (69.5%) and a 1.75-fold increase in HDL concentrations were observed in the group treated with this combination compared to diabetic animals. Interestingly, NPF increased homing of MSC in pancreas potentiating their antidiabetic activity. Finally, 26 compounds were identified in NPF using LC/MS analysis and four were isolated in pure form. The isolated compounds namely calotroproceryl acetate, fridelin, calotroproceryl A, and stigmasterol showed good inhibitory activity against pancreatic lipase with IC₅₀ at 1.93, 1.07, 1.34 and 1.44-1 μg/ml, respectively. Additionally, these compounds inhibited α-amylase, albeit at higher concentration, with IC₅₀ at 248, 212, 254, and 155 μg/ml for calotroproceryl acetate, fridelin, calotroproceryl A, and stigmasterol, respectively. Our results suggest that green beans extract can potentiate effect of MSC in diabetes directly due to its own antidiabetic effect and indirectly by increasing MSC homing in pancreatic tissues. PRACTICAL APPLICATIONS: It has been suggested in this study that green beans can improve hyperglycemia, oxidative balance in diabetes, so green beans can be promoted as a healthy nutrient for diabetic patients. Green beans also can enhance homing and differentiation of mesnchymal stem cells in the pancreas for future stem cell therapy of type I diabetes.

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Forskolin-Loaded Halloysite Nanotubes as Osteoconductive Additive for the Biopolymer Tissue Engineering Scaffolds. Polymers (Basel) 2021;13:polym13223949. [PMID: 34833247 PMCID: PMC8619346 DOI: 10.3390/polym13223949] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/03/2021] [Accepted: 11/10/2021] [Indexed: 01/22/2023] Open

Matheakakis A, Batsali A, Papadaki HA, Pontikoglou CG. Therapeutic Implications of Mesenchymal Stromal Cells and Their Extracellular Vesicles in Autoimmune Diseases: From Biology to Clinical Applications. Int J Mol Sci 2021;22:10132. [PMID: 34576296 PMCID: PMC8468750 DOI: 10.3390/ijms221810132] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 12/11/2022] Open

Wang M, Zhou T, Zhang Z, Liu H, Zheng Z, Xie H. Current therapeutic strategies for respiratory diseases using mesenchymal stem cells. MedComm (Beijing) 2021;2:351-380. [PMID: 34766151 PMCID: PMC8554668 DOI: 10.1002/mco2.74] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 03/15/2021] [Accepted: 03/18/2021] [Indexed: 02/06/2023] Open

Mesenchymal Stem Cell-Conditioned Media Regulate Steroidogenesis and Inhibit Androgen Secretion in a PCOS Cell Model via BMP-2. Int J Mol Sci 2021;22:ijms22179184. [PMID: 34502090 PMCID: PMC8431467 DOI: 10.3390/ijms22179184] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/19/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open

Frontino G, Guercio Nuzio S, Scaramuzza AE, D'Annunzio G, Toni S, Citriniti F, Bonfanti R. Prevention of type 1 diabetes: where we are and where we are going. Minerva Pediatr (Torino) 2021;73:486-503. [PMID: 34286946 DOI: 10.23736/s2724-5276.21.06529-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]

Ma Y, Wang L, Yang S, Liu D, Zeng Y, Lin L, Qiu L, Lu J, Chang J, Li Z. The tissue origin of human mesenchymal stem cells dictates their therapeutic efficacy on glucose and lipid metabolic disorders in type II diabetic mice. Stem Cell Res Ther 2021;12:385. [PMID: 34233739 PMCID: PMC8261817 DOI: 10.1186/s13287-021-02463-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 06/15/2021] [Indexed: 12/12/2022] Open

Abstract

Background

The therapeutic efficacy of mesenchymal stem cells (MSCs) of different tissue origins on metabolic disorders can be varied in many ways but remains poorly defined. Here we report a comprehensive comparison of human MSCs derived from umbilical cord Wharton’s jelly (UC-MSCs), dental pulp (PU-MSCs), and adipose tissue (AD-MSCs) on the treatment of glucose and lipid metabolic disorders in type II diabetic mice.

Methods

Fourteen-to-fifteen-week-old male C57BL/6 db/db mice were intravenously administered with human UC-MSCs, PU-MSCs, and AD-MSCs at various doses or vehicle control once every 2 weeks for 6 weeks. Metformin (MET) was given orally to animals in a separate group once a day at weeks 4 to 6 as a positive control. Body weight, blood glucose, and insulin levels were measured every week. Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were performed every 2 weeks. All the animals were sacrificed at week 6 and the blood and liver tissues were collected for biochemical and histological examinations.

Results

UC-MSCs showed the strongest efficacy in reducing fasting glucose levels, increasing fasting insulin levels, and improving GTT and ITT in a dose-dependent manner, whereas PU-MSCs showed an intermediate efficacy and AD-MSCs showed the least efficacy on these parameters. Moreover, UC-MSCs also reduced the serum low-density lipoprotein cholesterol (LDL-C) levels with the most prominent potency and AD-MSCs had only very weak effect on LDL-C. In contrast, AD-MSCs substantially reduced the lipid content and histological lesion of liver and accompanying biomarkers of liver injury such as serum aspartate transaminase (AST) and alanine aminotransferase (ALT) levels, whereas UC-MSCs and PU-MSCs displayed no or modest effects on these parameters, respectively.

Conclusions

Taken together, our results demonstrated that MSCs of different tissue origins can confer substantially different therapeutic efficacy in ameliorating glucose and lipid metabolic disorders in type II diabetes. MSCs with different therapeutic characteristics could be selected according to the purpose of the treatment in the future clinical practice.

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Affiliation(s)

Yinzhong Ma SIAT-GHMSCB Biomedical Laboratory for Major Diseases, Dongguan Enlife Stem Cell Biotechnology Institute, Dongguan Avenue 430, Dongguan, Guangdong, China.,Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Xueyuan Blvd 1068, Shenzhen, Guangdong, China
Lisha Wang SIAT-GHMSCB Biomedical Laboratory for Major Diseases, Dongguan Enlife Stem Cell Biotechnology Institute, Dongguan Avenue 430, Dongguan, Guangdong, China
Shilun Yang Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Xueyuan Blvd 1068, Shenzhen, Guangdong, China
Dongyu Liu SIAT-GHMSCB Biomedical Laboratory for Major Diseases, Dongguan Enlife Stem Cell Biotechnology Institute, Dongguan Avenue 430, Dongguan, Guangdong, China
Yi Zeng Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Xueyuan Blvd 1068, Shenzhen, Guangdong, China
Lilong Lin SIAT-GHMSCB Biomedical Laboratory for Major Diseases, Dongguan Enlife Stem Cell Biotechnology Institute, Dongguan Avenue 430, Dongguan, Guangdong, China
Linhui Qiu Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Xueyuan Blvd 1068, Shenzhen, Guangdong, China
Jiahao Lu SIAT-GHMSCB Biomedical Laboratory for Major Diseases, Dongguan Enlife Stem Cell Biotechnology Institute, Dongguan Avenue 430, Dongguan, Guangdong, China
Junlei Chang Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Xueyuan Blvd 1068, Shenzhen, Guangdong, China.
Zhihuan Li SIAT-GHMSCB Biomedical Laboratory for Major Diseases, Dongguan Enlife Stem Cell Biotechnology Institute, Dongguan Avenue 430, Dongguan, Guangdong, China.

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Human umbilical cord mesenchymal stem cells in type 2 diabetes mellitus: the emerging therapeutic approach. Cell Tissue Res 2021;385:497-518. [PMID: 34050823 DOI: 10.1007/s00441-021-03461-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 04/11/2021] [Indexed: 12/14/2022]

Vieira CP, McCarrel TM, Grant MB. Novel Methods to Mobilize, Isolate, and Expand Mesenchymal Stem Cells. Int J Mol Sci 2021;22:ijms22115728. [PMID: 34072061 PMCID: PMC8197893 DOI: 10.3390/ijms22115728] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/12/2021] [Accepted: 05/20/2021] [Indexed: 12/11/2022] Open

Pi C, Ma C, Wang H, Sun H, Yu X, Gao X, Yang Y, Sun Y, Zhang H, Shi Y, Li Y, Li Y, He X. MiR-34a suppression targets Nampt to ameliorate bone marrow mesenchymal stem cell senescence by regulating NAD⁺-Sirt1 pathway. Stem Cell Res Ther 2021;12:271. [PMID: 33957971 PMCID: PMC8101138 DOI: 10.1186/s13287-021-02339-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 04/19/2021] [Indexed: 12/13/2022] Open

Abstract

BACKGROUND

Expansion-mediated replicative senescence and age-related natural senescence have adverse effects on mesenchymal stem cell (MSC) regenerative capability and functionality, thus severely impairing the extensive applications of MSC-based therapies. Emerging evidences suggest that microRNA-34a (miR-34a) has been implicated in the process of MSC senescence; however, the molecular mechanisms with regard to how miR-34a influencing MSC senescence remain largely undetermined.

METHODS

MiR-34a expression in MSCs was evaluated utilizing RT-qPCR. The functional effects of miR-34a exerting on MSC senescence were investigated via gene manipulation. Relevant gene and protein expression levels were analyzed by RT-qPCR and western blot. Luciferase reporter assays were applied to confirm that Nampt is a direct target of miR-34a. The underlying regulatory mechanism of miR-34a targeting Nampt in MSC senescence was further explored by measuring intracellular NAD⁺ content, NAD⁺/NADH ratio and Sirt1 activity.

RESULTS

In contrast to Nampt expression, miR-34a expression incremented in senescent MSCs. MiR-34a overexpression in young MSCs resulted in senescence-associated characteristics as displayed by senescence-like morphology, prolonged cell proliferation, declined osteogenic differentiation potency, heightened senescence-associated-β-galactosidase activity, and upregulated expression levels of the senescence-associated factors. Conversely, miR-34a suppression in replicative senescent and natural senescent MSCs contributed to diminished senescence-related phenotypic features. We identified Nampt as a direct target gene of miR-34a. In addition, miR-34a repletion resulted in prominent reductions in Nampt expression levels, NAD⁺ content, NAD⁺/NADH ratio, and Sirt1 activity, whereas anti-miR-34a treatment exerted the opposite effects. Furthermore, miR-34a-mediated MSC senescence was evidently rescued following the co-treatment with Nampt overexpression.

CONCLUSION

This study identifies a significant role of miR-34a playing in MSC replicative senescence and natural senescence via targeting Nampt and further mediating by NAD⁺-Sirt1 pathway, carrying great implications for optimal strategies for MSC therapeutic applications.

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Affiliation(s)

Chenchen Pi The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xin Min Street, Changchun, Jilin Province, People's Republic of China.,The First Hospital, and Institute of Immunology, Jilin University, Changchun, 130021, China
Cao Ma Department of Pathology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China
Huan Wang Department of Pathology, The First Affiliated Hospital, Henan University of Chinese Medicine, Henan, 450000, China
Hui Sun The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xin Min Street, Changchun, Jilin Province, People's Republic of China
Xiao Yu The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xin Min Street, Changchun, Jilin Province, People's Republic of China
Xingyu Gao The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xin Min Street, Changchun, Jilin Province, People's Republic of China
Yue Yang Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, 610072, China
Yanan Sun The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xin Min Street, Changchun, Jilin Province, People's Republic of China
Haiying Zhang The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xin Min Street, Changchun, Jilin Province, People's Republic of China
Yingai Shi The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xin Min Street, Changchun, Jilin Province, People's Republic of China
Yan Li Division of Orthopedics and Biotechnology, Department for Clinical Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden
Yulin Li The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xin Min Street, Changchun, Jilin Province, People's Republic of China
Xu He The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xin Min Street, Changchun, Jilin Province, People's Republic of China.

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Ahamad N, Singh BB. Calcium channels and their role in regenerative medicine. World J Stem Cells 2021;13:260-280. [PMID: 33959218 PMCID: PMC8080543 DOI: 10.4252/wjsc.v13.i4.260] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/22/2021] [Accepted: 03/30/2021] [Indexed: 02/06/2023] Open

Abstract

Stem cells hold indefinite self-renewable capability that can be differentiated into all desired cell types. Based on their plasticity potential, they are divided into totipotent (morula stage cells), pluripotent (embryonic stem cells), multipotent (hematopoietic stem cells, multipotent adult progenitor stem cells, and mesenchymal stem cells [MSCs]), and unipotent (progenitor cells that differentiate into a single lineage) cells. Though bone marrow is the primary source of multipotent stem cells in adults, other tissues such as adipose tissues, placenta, amniotic fluid, umbilical cord blood, periodontal ligament, and dental pulp also harbor stem cells that can be used for regenerative therapy. In addition, induced pluripotent stem cells also exhibit fundamental properties of self-renewal and differentiation into specialized cells, and thus could be another source for regenerative medicine. Several diseases including neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, virus infection (also coronavirus disease 2019) have limited success with conventional medicine, and stem cell transplantation is assumed to be the best therapy to treat these disorders. Importantly, MSCs, are by far the best for regenerative medicine due to their limited immune modulation and adequate tissue repair. Moreover, MSCs have the potential to migrate towards the damaged area, which is regulated by various factors and signaling processes. Recent studies have shown that extracellular calcium (Ca²⁺) promotes the proliferation of MSCs, and thus can assist in transplantation therapy. Ca²⁺signaling is a highly adaptable intracellular signal that contains several components such as cell-surface receptors, Ca²⁺ channels/pumps/exchangers, Ca²⁺ buffers, and Ca²⁺ sensors, which together are essential for the appropriate functioning of stem cells and thus modulate their proliferative and regenerative capacity, which will be discussed in this review.

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Paracrine interleukin-8 affects mesenchymal stem cells through the Akt pathway and enhances human umbilical vein endothelial cell proliferation and migration. Biosci Rep 2021;41:228273. [PMID: 33843989 PMCID: PMC8493446 DOI: 10.1042/bsr20210198] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/06/2021] [Accepted: 04/08/2021] [Indexed: 11/17/2022] Open

Liu J, Ting JP, Al-Azzam S, Ding Y, Afshar S. Therapeutic Advances in Diabetes, Autoimmune, and Neurological Diseases. Int J Mol Sci 2021;22:ijms22062805. [PMID: 33802091 PMCID: PMC8001105 DOI: 10.3390/ijms22062805] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/02/2021] [Accepted: 03/06/2021] [Indexed: 02/08/2023] Open

Chen J, Zheng CX, Jin Y, Hu CH. Mesenchymal stromal cell-mediated immune regulation: A promising remedy in the therapy of type 2 diabetes mellitus. STEM CELLS (DAYTON, OHIO) 2021;39:838-852. [PMID: 33621403 DOI: 10.1002/stem.3357] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 02/03/2021] [Indexed: 11/09/2022]

Chen MT, Zhao YT, Zhou LY, Li M, Zhang Q, Han Q, Xiao XH. Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Enhance Insulin Sensitivity in Insulin Resistant Human Adipocytes. Curr Med Sci 2021;41:87-93. [PMID: 33582911 DOI: 10.1007/s11596-021-2323-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 11/19/2020] [Indexed: 12/17/2022]

Affiliation(s)

Mei-Ting Chen Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Diabetes Research Center of Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
Yi-Ting Zhao Department of PET-CT Center, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
Li-Yuan Zhou Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Diabetes Research Center of Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
Ming Li Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Diabetes Research Center of Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
Qian Zhang Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Diabetes Research Center of Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
Qin Han Center of Excellence in Tissue Engineering, Key Laboratory of Beijing, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
Xin-Hua Xiao Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Diabetes Research Center of Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.

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Khatri R, Petry SF, Linn T. Intrapancreatic MSC transplantation facilitates pancreatic islet regeneration. Stem Cell Res Ther 2021;12:121. [PMID: 33579357 PMCID: PMC7881671 DOI: 10.1186/s13287-021-02173-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 01/19/2021] [Indexed: 12/11/2022] Open

Abstract

Background

Type 1 diabetes mellitus (T1D) is characterized by the autoimmune destruction of the pancreatic β cells. The transplantation of mesenchymal stromal/stem cells (MSC) was reported to rescue the damaged pancreatic niche. However, there is an ongoing discussion on whether direct physical contact between MSC and pancreatic islets results in a superior outcome as opposed to indirect effects of soluble factors released from the MSC entrapped in the lung microvasculature after systemic administration. Hence, MSC were studied in direct contact (DC) and indirect contact (IDC) with murine pancreatic β cell line MIN6-cells damaged by nitrosourea derivative streptozotocin (STZ) in vitro. Further, the protective and antidiabetic outcome of MSC transplantation was evaluated through the intrapancreatic route (IPR) and intravenous route (IVR) in STZ-induced diabetic NMRI nude mice.

Methods

MSC were investigated in culture with STZ-damaged MIN6-cells, either under direct contact (DC) or separated through a semi-permeable membrane (IDC). Moreover, multiple low doses of STZ were administered to NMRI nude mice for the induction of hyperglycemia. 0.5 × 10⁶ adipose-derived mesenchymal stem cells (ADMSC) were transferred through direct injection into the pancreas (IPR) or the tail vein (IVR), respectively. Bromodeoxyuridine (BrdU) was injected for the detection of proliferating islet cells in vivo, and real-time polymerase chain reaction (RT-PCR) was employed for the measurement of the expression of growth factor and immunomodulatory genes in the murine pancreas and human MSC. Phosphorylation of AKT and ERK was analyzed with Western blotting.

Results

The administration of MSC through IPR ameliorated hyperglycemia in contrast to IVR, STZ, and non-diabetic control in a 30-day window. IPR resulted in a higher number of replicating islet cells, number of islets, islet area, growth factor (EGF), and balancing of the Th1/Th2 response in vivo. Physical contact also provided a superior protection to MIN6-cells from STZ through the AKT and ERK pathway in vitro in comparison with IDC.

Conclusion

Our study suggests that the physical contact between MSC and pancreatic islet cells is required to fully unfold their protective potential.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13287-021-02173-4.

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Bao Y, Zhao Z, Gao H. Effect of hTIMP-1 overexpression in human umbilical cord mesenchymal stem cells on the repair of pancreatic islets in type-1 diabetic mice. Cell Biol Int 2021;45:1038-1049. [PMID: 33404139 DOI: 10.1002/cbin.11548] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 12/23/2020] [Accepted: 01/03/2021] [Indexed: 12/28/2022]

Kumar P, Sah AK, Tripathi G, Kashyap A, Tripathi A, Rao R, Mishra PC, Mallick K, Husain A, Kashyap MK. Role of ACE2 receptor and the landscape of treatment options from convalescent plasma therapy to the drug repurposing in COVID-19. Mol Cell Biochem 2021;476:553-574. [PMID: 33029696 PMCID: PMC7539757 DOI: 10.1007/s11010-020-03924-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 09/19/2020] [Indexed: 02/06/2023]

Abstract

Since the first case reports in Wuhan, China, the SARS-CoV-2 has caused a pandemic and took lives of > 8,35,000 people globally. This single-stranded RNA virus uses Angiotensin-converting enzyme 2 (ACE2) as a receptor for entry into the host cell. Overexpression of ACE2 is mainly observed in hypertensive, diabetic and heart patients that make them prone to SARS-CoV-2 infection. Mitigations strategies were opted globally by the governments to minimize transmission of SARS-CoV-2 via the implementation of social distancing norms, wearing the facemasks, and spreading awareness using digital platforms. The lack of an approved drug treatment regimen, and non-availability of a vaccine, collectively posed a challenge for mankind to fight against the SARS-CoV-2 pandemic. In this scenario, repurposing of existing drugs and old treatment options like convalescent plasma therapy can be one of the potential alternatives to treat the disease. The drug repurposing provides a selection of drugs based on the scientific rationale and with a shorter cycle of clinical trials, while plasma isolated from COVID-19 recovered patients can be a good source of neutralizing antibody to provide passive immunity. In this review, we provide in-depth analysis on these two approaches currently opted all around the world to treat COVID-19 patients. For this, we used "Boolean Operators" such as AND, OR & NOT to search relevant research articles/reviews from the PUBMED for the repurposed drugs and the convalescent plasma in the COVID-19 treatment. The repurposed drugs like Chloroquine and Hydroxychloroquine, Tenofovir, Remdesivir, Ribavirin, Darunavir, Oseltamivir, Arbidol (Umifenovir), Favipiravir, Anakinra, and Baricitinib are already being used in clinical trials to treat the COVID-19 patients. These drugs have been approved for a different indication and belong to a diverse category such as anti-malarial/anti-parasitic, anti-retroviral/anti-viral, anti-cancer, or against rheumatoid arthritis. Although, the vaccine would be an ideal option for providing active immunity against the SARS-CoV-2, but considering the current situation, drug repurposing and convalescent plasma therapy and repurposed drugs are the most viable option against SARS-CoV-2.

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Harman RM, Patel RS, Fan JC, Park JE, Rosenberg BR, Van de Walle GR. Single-cell RNA sequencing of equine mesenchymal stromal cells from primary donor-matched tissue sources reveals functional heterogeneity in immune modulation and cell motility. Stem Cell Res Ther 2020;11:524. [PMID: 33276815 PMCID: PMC7716481 DOI: 10.1186/s13287-020-02043-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 11/23/2020] [Indexed: 02/08/2023] Open

Abstract

BACKGROUND

The efficacy of mesenchymal stromal cell (MSC) therapy is thought to depend on the intrinsic heterogeneity of MSC cultures isolated from different tissue sources as well as individual MSCs isolated from the same tissue source, neither of which is well understood. To study this, we used MSC cultures isolated from horses. The horse is recognized as a physiologically relevant large animal model appropriate for translational MSC studies. Moreover, due to its large size the horse allows for the simultaneous collection of adequate samples from multiple tissues of the same animal, and thus, for the unique collection of donor matched MSC cultures from different sources. The latter is much more challenging in mice and humans due to body size and ethical constraints, respectively.

METHODS

In the present study, we performed single-cell RNA sequencing (scRNA-seq) on primary equine MSCs that were collected from three donor-matched tissue sources; adipose tissue (AT), bone marrow (BM), and peripheral blood (PB). Based on transcriptional differences detected with scRNA-seq, we performed functional experiments to examine motility and immune regulatory function in distinct MSC populations.

RESULTS

We observed both inter- and intra-source heterogeneity across the three sources of equine MSCs. Functional experiments demonstrated that transcriptional differences correspond with phenotypic variance in cellular motility and immune regulatory function. Specifically, we found that (i) differential expression of junctional adhesion molecule 2 (JAM2) between MSC cultures from the three donor-matched tissue sources translated into altered cell motility of BM-derived MSCs when RNA interference was used to knock down this gene, and (ii) differences in C-X-C motif chemokine ligand 6 (CXCL6) expression in clonal MSC lines derived from the same tissue source correlated with the chemoattractive capacity of PB-derived MSCs.

CONCLUSIONS

Ultimately, these findings will enhance our understanding of MSC heterogeneity and will lead to improvements in the therapeutic potential of MSCs, accelerating the transition from bench to bedside.

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