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Li J, Wu M, He L. Immunomodulatory effects of mesenchymal stem cell therapy in chronic kidney disease: a literature review. BMC Nephrol 2025; 26:107. [PMID: 40033224 PMCID: PMC11874639 DOI: 10.1186/s12882-025-04029-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 02/19/2025] [Indexed: 03/05/2025] Open
Abstract
Chronic kidney disease (CKD) has been a growing public medical concern in recent years which calls for effective interventions. Mesenchymal stem cells (MSCs) have garnered increased interest in past decades due to their potential to repair and regenerate damaged tissues. Many clinical trials have highlighted the safety and effectiveness of kidney disease with this novel cell therapy. MSC infusion can improve renal function indices such as glomerular filtration rate, urine protein, serum creatinine, and blood urea nitrogen, while inhibiting immune response by increasing regulatory T cells. The therapeutic mechanisms may be primarily attributed to a function combined with immunomodulation, anti-inflammation, anti-fibrosis, promoting angiogenesis, anti-oxidation, anti-apoptosis, or tissue healing produced by cell secretsome. However, CKD is a broad concept due to many pathological etiologies including diabetes, hypertension, heart disease, immunological damage, a family history of renal failure, and so on. Furthermore, the therapeutic efficacy of MSCs may be influenced by different cell sources, injection methods, medication dosage, or homing proportion. As a result, it is timely and essential to access recent advancements in the MSC application on CKD.
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Affiliation(s)
- Jipeng Li
- Department of Nephrology, Xijing Hospital, Air Force Medical University, Xi'an, Shaan Xi, China
| | - Mengting Wu
- Department of Nephrology, Xijing Hospital, Air Force Medical University, Xi'an, Shaan Xi, China
| | - Lijie He
- Department of Nephrology, Xijing Hospital, Air Force Medical University, Xi'an, Shaan Xi, China.
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Silva-Carvalho AÉ, Bispo ECI, da Silva IGM, Correa JR, Carvalho JL, Gelfuso GM, Saldanha-Araujo F. Characterization of ibrutinib's effects on the morphology, proliferation, phenotype, viability, and anti-inflammatory potential of adipose-derived mesenchymal stromal cells. Sci Rep 2024; 14:19906. [PMID: 39191849 DOI: 10.1038/s41598-024-71054-6] [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: 01/25/2024] [Accepted: 08/23/2024] [Indexed: 08/29/2024] Open
Abstract
Ibrutinib (IB) is a tyrosine kinase inhibitor (TKI) that has immunomodulatory action and can be used as second-line therapy for steroid-refractory or steroid-resistant chronic Graft versus Host Disease (cGVHD). Mesenchymal stromal cells (MSCs) are distributed throughout the body and their infusion has also been explored as a second-line therapeutic alternative for the treatment of cGVHD. Considering the currently unknown effects of IB on endogenous MSCs, as well as the possible combined use of IB and MSCs for cGVHD, we investigated whether adipose tissue-derived MSCs present IB-targets, as well as the consequences of treating MSCs with this drug, regarding cell viability, proliferation, phenotype, and anti-inflammatory potential. Interestingly, we show for the first time that MSCs express several IB target genes. Also of note, the treatment of such cells with this TKI elevated the levels of CD90 and CD105 surface proteins, as well as VCAM-1. Furthermore, IB-treated MSCs presented increased mRNA expression of the anti-inflammatory genes PD-L1, TSG-6, and IL-10. However, continued exposure to IB, even at low doses, compromised the viability of MSCs. These data indicate that the use of IB can stimulate an anti-inflammatory profile in MSCs, but also that a continued exposure to IB can compromise MSC viability over time.
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Affiliation(s)
- Amandda Évelin Silva-Carvalho
- Laboratório de Hematologia E Células-Tronco, Departamento de Ciências da Saúde, Universidade de Brasília, Campus Darcy Ribeiro, Brasília, DF, Brasil
- Laboratório de Farmacologia Molecular, Universidade de Brasília, Brasília, Brasil
| | - Elizabete Cristina Iseke Bispo
- Laboratório de Hematologia E Células-Tronco, Departamento de Ciências da Saúde, Universidade de Brasília, Campus Darcy Ribeiro, Brasília, DF, Brasil
| | | | - José Raimundo Correa
- Laboratório de Microscopia E Microanálises, Universidade de Brasília, Brasília, Brasil
| | - Juliana Lott Carvalho
- Laboratório Multidisciplinar de Biociências, Universidade de Brasília, Brasília, Brasil
| | | | - Felipe Saldanha-Araujo
- Laboratório de Hematologia E Células-Tronco, Departamento de Ciências da Saúde, Universidade de Brasília, Campus Darcy Ribeiro, Brasília, DF, Brasil.
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Yang H, Cheong S, He Y, Lu F. Mesenchymal stem cell-based therapy for autoimmune-related fibrotic skin diseases-systemic sclerosis and sclerodermatous graft-versus-host disease. Stem Cell Res Ther 2023; 14:372. [PMID: 38111001 PMCID: PMC10729330 DOI: 10.1186/s13287-023-03543-w] [Citation(s) in RCA: 7] [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: 02/10/2023] [Accepted: 10/23/2023] [Indexed: 12/20/2023] Open
Abstract
BACKGROUND Systemic sclerosis (SSc) and sclerodermatous graft-versus-host disease (Scl-GVHD)-characterized by similar developmental fibrosis, vascular abnormalities, and innate and adaptive immune response, resulting in severe skin fibrosis at the late stage-are chronic autoimmune diseases of connective tissue. The significant immune system dysfunction, distinguishing autoimmune-related fibrosis from mere skin fibrosis, should be a particular focus of treating autoimmune-related fibrosis. Recent research shows that innovative mesenchymal stem cell (MSC)-based therapy, with the capacities of immune regulation, inflammation suppression, oxidation inhibition, and fibrosis restraint, shows great promise in overcoming the disease. MAIN BODY This review of recent studies aims to summarize the therapeutic effect and theoretical mechanisms of MSC-based therapy in treating autoimmune-related fibrotic skin diseases, SSc and Scl-GVHD, providing novel insights and references for further clinical applications. It is noteworthy that the efficacy of MSCs is not reliant on their migration into the skin. Working on the immune system, MSCs can inhibit the chemotaxis and infiltration of immune cells to the skin by down-regulating the expression of skin chemokines and chemokine receptors and reducing the inflammatory and pro-fibrotic mediators. Furthermore, to reduce levels of oxidative stress, MSCs may improve vascular abnormalities, and enhance the antioxidant defenses through inducible nitric oxide synthase, thioredoxin 1, as well as other mediators. The oxidative stress environment does not weaken MSCs and may even strengthen certain functions. Regarding fibrosis, MSCs primarily target the transforming growth factor-β signaling pathway to inhibit fibroblast activation. Here, miRNAs may play a critical role in ECM remodeling. Clinical studies have demonstrated the safety of these approaches, though outcomes have varied, possibly owing to the heterogeneity of MSCs, the disorders themselves, and other factors. Nevertheless, the research clearly reveals the immense potential of MSCs in treating autoimmune-related fibrotic skin diseases. CONCLUSION The application of MSCs presents a promising approach for treating autoimmune-related fibrotic skin diseases: SSc and Scl-GVHD. Therapies involving MSCs and MSC extracellular vesicles have been found to operate through three primary mechanisms: rebalancing the immune and inflammatory disorders, resisting oxidant stress, and inhibiting overactivated fibrosis (including fibroblast activation and ECM remodeling). However, the effectiveness of these interventions requires further validation through extensive clinical investigations, particularly randomized control trials and phase III/IV clinical trials. Additionally, the hypothetical mechanism underlying these therapies could be elucidated through further research.
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Affiliation(s)
- Han Yang
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China
| | - Sousan Cheong
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China
| | - Yunfan He
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China.
| | - Feng Lu
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China.
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Husakova J, Echalar B, Kossl J, Palacka K, Fejfarova V, Dubsky M. The Effects of Immunosuppressive Drugs on the Characteristics and Functional Properties of Bone Marrow-Derived Stem Cells Isolated from Patients with Diabetes Mellitus and Peripheral Arterial Disease. Biomedicines 2023; 11:1872. [PMID: 37509511 PMCID: PMC10377428 DOI: 10.3390/biomedicines11071872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/18/2023] [Accepted: 06/28/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Diabetic patients (DPs) with foot ulcers can receive autologous cell therapy (ACT) as a last therapeutic option. Even DPs who have undergone organ transplantation and are using immunosuppressive (IS) drugs can be treated by ACT. The aim of our study was to analyze the effects of IS drugs on the characteristics of bone marrow-derived stem cells (BM-MSCs). METHODS The cells were isolated from the bone marrow of DPs, cultivated for 14-18 days, and phenotypically characterized using flow cytometry. These precursor cells were cultured in the presence of various IS drugs. The impact of IS drugs on metabolic activity was measured using a WST-1 assay, and the expression of genes for immunoregulatory molecules was detected through RT-PCR. Cell death was analyzed through the use of flow cytometry, and the production of cytokines was determined by ELISA. RESULTS The mononuclear fraction of cultured cells contained mesenchymal stem cells (CD45-CD73+CD90+CD105+), myeloid angiogenic cells (CD45+CD146-), and endothelial colony-forming cells (CD45-CD146+). IS drugs inhibited metabolic activity, the expression of genes for immunoregulatory molecules, the production of cytokines, and the viability of the cells. CONCLUSIONS The results indicate that IS drugs in a dose-dependent manner had a negative impact on the properties of BM-MSCs used to treat ischemic diabetic foot ulcers, and that these drugs could affect the therapeutic potential of BM-MSCs.
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Affiliation(s)
- Jitka Husakova
- Diabetes Centre, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
- First Faculty of Medicine, Charles University, 14021 Prague, Czech Republic
| | - Barbora Echalar
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the Czech Academy of Sciences, 14220 Prague, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, 14021 Prague, Czech Republic
| | - Jan Kossl
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the Czech Academy of Sciences, 14220 Prague, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, 14021 Prague, Czech Republic
| | - Katerina Palacka
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the Czech Academy of Sciences, 14220 Prague, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, 14021 Prague, Czech Republic
| | - Vladimira Fejfarova
- Diabetes Centre, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
| | - Michal Dubsky
- Diabetes Centre, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
- First Faculty of Medicine, Charles University, 14021 Prague, Czech Republic
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Shi MY, Liu L, Yang FY. Strategies to improve the effect of mesenchymal stem cell therapy on inflammatory bowel disease. World J Stem Cells 2022; 14:684-699. [PMID: 36188115 PMCID: PMC9516464 DOI: 10.4252/wjsc.v14.i9.684] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/07/2022] [Accepted: 09/07/2022] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis and is an idiopathic, chronic inflammatory disease of the colonic mucosa. The occurrence of IBD, causes irreversible damage to the colon and increases the risk of carcinoma. The routine clinical treatment of IBD includes drug treatment, endoscopic treatment and surgery. The vast majority of patients are treated with drugs and biological agents, but the complete cure of IBD is difficult. Mesenchymal stem cells (MSCs) have become a new type of cell therapy for the treatment of IBD due to their immunomodulatory and nutritional functions, which have been confirmed in many clinical trials. This review discusses some potential mechanisms of MSCs in the treatment of IBD, summarizes the experimental results, and provides new insights to enhance the therapeutic effects of MSCs in future applications.
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Affiliation(s)
- Meng-Yue Shi
- School of Medicine, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Lian Liu
- Department of Pharmacology, Medical School of Yangtze University, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Fu-Yuan Yang
- Health Science Center, Yangtze University, Jingzhou 434020, Hubei Province, China
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Mizuno T, Inoue M, Kubo T, Iwaki Y, Kawamoto K, Itamoto K, Kambayashi S, Igase M, Baba K, Okuda M. Improvement of anemia in five dogs with nonregenerative anemia treated with allogeneic adipose-derived stem cells. Vet Anim Sci 2022; 17:100264. [PMID: 35898238 PMCID: PMC9310121 DOI: 10.1016/j.vas.2022.100264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 07/08/2022] [Accepted: 07/12/2022] [Indexed: 10/31/2022] Open
Abstract
Five canine cases with nonregenerative anemia were included in this study. All were treated with allogeneic adipose-derived stem cells (ADSCs). All cases showed improvement of anemia by ADSCs treatment. Background Objectives Methods Results Conclusions
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Wise RM, Al-Ghadban S, Harrison MAA, Sullivan BN, Monaco ER, Aleman SJ, Donato UM, Bunnell BA. Short-Term Autophagy Preconditioning Upregulates the Expression of COX2 and PGE2 and Alters the Immune Phenotype of Human Adipose-Derived Stem Cells In Vitro. Cells 2022; 11:cells11091376. [PMID: 35563682 PMCID: PMC9101706 DOI: 10.3390/cells11091376] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/28/2022] [Accepted: 04/07/2022] [Indexed: 12/28/2022] Open
Abstract
Human adipose-derived stem cells (hASCs) are potent modulators of inflammation and promising candidates for the treatment of inflammatory and autoimmune diseases. Strategies to improve hASC survival and immunoregulation are active areas of investigation. Autophagy, a homeostatic and stress-induced degradative pathway, plays a crucial role in hASC paracrine signaling—a primary mechanism of therapeutic action. Therefore, induction of autophagy with rapamycin (Rapa), or inhibition with 3-methyladenine (3-MA), was examined as a preconditioning strategy to enhance therapeutic efficacy. Following preconditioning, both Rapa and 3-MA-treated hASCs demonstrated preservation of stemness, as well as upregulated transcription of cyclooxygenase-2 (COX2) and interleukin-6 (IL-6). Rapa-ASCs further upregulated TNFα-stimulated gene-6 (TSG-6) and interleukin-1 beta (IL-1β), indicating additional enhancement of immunomodulatory potential. Preconditioned cells were then stimulated with the inflammatory cytokine interferon-gamma (IFNγ) and assessed for immunomodulatory factor production. Rapa-pretreated cells, but not 3-MA-pretreated cells, further amplified COX2 and IL-6 transcripts following IFNγ exposure, and both groups upregulated secretion of prostaglandin-E2 (PGE2), the enzymatic product of COX2. These findings suggest that a 4-h Rapa preconditioning strategy may bestow the greatest improvement to hASC expression of cytokines known to promote tissue repair and regeneration and may hold promise for augmenting the therapeutic potential of hASCs for inflammation-driven pathological conditions.
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Affiliation(s)
- Rachel M. Wise
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70118, USA; (R.M.W.); (M.A.A.H.); (B.N.S.); (E.R.M.); (S.J.A.); (U.M.D.)
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA;
| | - Sara Al-Ghadban
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA;
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Mark A. A. Harrison
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70118, USA; (R.M.W.); (M.A.A.H.); (B.N.S.); (E.R.M.); (S.J.A.); (U.M.D.)
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA;
| | - Brianne N. Sullivan
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70118, USA; (R.M.W.); (M.A.A.H.); (B.N.S.); (E.R.M.); (S.J.A.); (U.M.D.)
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA;
| | - Emily R. Monaco
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70118, USA; (R.M.W.); (M.A.A.H.); (B.N.S.); (E.R.M.); (S.J.A.); (U.M.D.)
| | - Sarah J. Aleman
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70118, USA; (R.M.W.); (M.A.A.H.); (B.N.S.); (E.R.M.); (S.J.A.); (U.M.D.)
| | - Umberto M. Donato
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70118, USA; (R.M.W.); (M.A.A.H.); (B.N.S.); (E.R.M.); (S.J.A.); (U.M.D.)
| | - Bruce A. Bunnell
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA;
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Correspondence:
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Wu X, Mu Y, Yao J, Lin F, Wu D, Ma Z. Adipose-Derived Stem Cells From Patients With Ulcerative Colitis Exhibit Impaired Immunosuppressive Function. Front Cell Dev Biol 2022; 10:822772. [PMID: 35252190 PMCID: PMC8894714 DOI: 10.3389/fcell.2022.822772] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 01/17/2022] [Indexed: 12/15/2022] Open
Abstract
Adipose-derived stem cells (ADSCs) are able to modulate the immune response and are used for treating ulcerative colitis (UC). However, it is possible that ADSCs from patients with inflammatory or autoimmune disorders may show defective immunosuppression. We investigated the use of ADSCs from UC patients for autologous cell treatment, specifically, ADSCs from healthy donors (H-ADSCs) and UC patients (P-ADSCs) in terms of various functions, including differentiation, proliferation, secretion, and immunosuppression. The efficacy of P-ADSCs for treating UC was examined in mouse models of acute or chronic colitis. Both H-ADSCs and P-ADSCs were similar in cell morphology, size, adipogenic differentiation capabilities, and cell surface markers. We found that P-ADSCs had lower proliferative capacity, cloning ability, and osteogenic and chondrogenic differentiation potential than H-ADSCs. P-ADSCs exhibited a diminished capacity to inhibit peripheral blood mononuclear cell proliferation, suppress CD25 and CD69 marker expression, decrease the production of inflammation-associated cytokines interferon-γ and tumor necrosis factor-α, and reduce their cytotoxic effect on A549 cells. When primed with inflammatory cytokines, P-ADSCs secreted lower levels of prostaglandin E2, indoleamine 2, 3-dioxygenase, and tumor necrosis factor-α–induced protein 6, which mediated their reduced immunopotency. Moreover, P-ADSCs exhibited weaker therapeutic effects than H-ADSCs, determined by disease activity, histology, myeloperoxidase activity, and body weight. These findings indicate that the immunosuppressive properties of ASCs are affected by donor metabolic characteristics. This study shows, for the first time, the presence of defective ADSC immunosuppression in UC, indicating that autologous transplantation of ADSCs may be inappropriate for patients with UC.
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Affiliation(s)
- Xiaoyun Wu
- Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China
- Department of Technology, Research Center for Hua-Da Precision Medicine of Inner Mongolia Autonomous Region, Hohhot, China
- Department of Interventional, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Yongxu Mu
- Department of Interventional, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Jingyi Yao
- Experimental Center, Beijing Clinical Research Institute, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, China
| | - Fuhong Lin
- Department of Neurology, Affiliated Hospital of Chifeng College, Chifeng, China
| | - Daocheng Wu
- Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China
- *Correspondence: Daocheng Wu, ; Zhijie Ma,
| | - Zhijie Ma
- Department of Pharmacy, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, China
- *Correspondence: Daocheng Wu, ; Zhijie Ma,
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Salimiyan S, Mohammadi M, Aliakbari S, Kazemi R, Amini AA, Rahmani MR. Hydrocortisone Long-term Treatment Effect on Immunomodulatory Properties of Human Adipose-Derived Mesenchymal Stromal/Stem Cells. J Interferon Cytokine Res 2022; 42:72-81. [PMID: 35171704 DOI: 10.1089/jir.2021.0120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Cortisol is secreted in prolonged stress and has therapeutic effects in inflammatory diseases. Considering the immunomodulatory effects of mesenchymal stem cells, here we investigated the effect of hydrocortisone (HC) long-term treatment on immunomodulatory properties of human adipose-derived mesenchymal stromal/stem cells (ASCs). Isolated ASCs from healthy subjects were treated with different HC concentrations for 14 days. The effect of HC-treated ASCs on the proliferative response of peripheral blood mononuclear cells (PBMCs) was evaluated in ASCs/2-way mixed leukocyte reaction coculture using 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT)-assay. HC-treated ASCs were further divided into interferon gamma (IFN-γ) stimulated and unstimulated groups. Transforming growth factor beta 1 (TGF-β1) and interleukin (IL)-6 levels were measured in culture supernatants by enzyme-linked immunosorbent assay. Relative expression of cyclooxygenase-2 (COX-2), hepatocyte growth factor, indoleamine dioxygenase, and programmed death-ligand 1 genes was assessed by real-time PCR. Levels of TGF-β1 and COX-2 expression were elevated in unstimulated ASCs, while exposure to high concentration of HC significantly increased TGF-β1 levels and reduced COX-2 expression. Unstimulated HC-5-μM-treated ASCs increased PBMC proliferation ratio on day 2 of coculture compared to the control group (P = 0.05). In IFN-γ stimulated condition, pretreatment with HC-5 μM resulted in a significantly increased IL-6 and significantly decreased COX-2 expression compared to the HC untreated control group. In conclusion, our results showed various alterations of ASC immunomodulatory related features as a result of long-term exposure of different concentrations of HC. It seems that HC at low concentration pushed the balance toward extended immune response in ASCs, while this observation wasn't persistent in ASCs treated with higher concentrations of HC.
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Affiliation(s)
- Samira Salimiyan
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran.,Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mobin Mohammadi
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.,Cancer and Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Sara Aliakbari
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran.,Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Romina Kazemi
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran.,Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Abbas Ali Amini
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.,Cancer and Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mohammad Reza Rahmani
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.,Zoonosis Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
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Mukherjee S, Yun JW. Prednisone stimulates white adipocyte browning via β3-AR/p38 MAPK/ERK signaling pathway. Life Sci 2022; 288:120204. [PMID: 34864064 DOI: 10.1016/j.lfs.2021.120204] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/26/2021] [Accepted: 11/30/2021] [Indexed: 02/08/2023]
Abstract
AIMS Prednisone is a corticosteroid-derived drug which is widely used for its role in immunosuppression and treatment of lung disorders. The current study reports, for the first time, the critical role of prednisone in the induction of white fat browning, thereby promoting thermogenic effect in cultured white adipocytes. MAIN METHODS The fat-browning activity of prednisone was evaluated in 3T3-L1 cells by quantitative real-time PCR, immunoblot analysis, immunofluorescence, and molecular docking techniques. KEY FINDINGS Exposure to prednisone stimulated browning in 3T3-L1 white adipocytes by increasing the expressions of core fat browning marker proteins (UCP1, PGC-1α and PRDM16) as well as beige-specific genes (Cd137, Cidea, Cited1, and Tbx1) via ATF2 and CREB activation mediated by p38 MAPK and ERK signaling, respectively. Prednisone exposure also resulted in the robust activation of lipolytic and fatty acid oxidation marker proteins, thereby increasing mitochondrial biogenesis. In addition, prednisone treatment resulted in reduced expression levels of adipogenic transcription factors while elevating SIRT1, as well as attenuation of lipogenesis and lipid droplets formation. Furthermore, molecular docking and mechanistic studies demonstrated the recruitment of beige fat by prednisone via the β3-AR/p38 MAPK/ERK signaling pathway. SIGNIFICANCE Taken together, these results indicate the unique role of prednisone as a fat-browning stimulant, and demonstrate its therapeutic potential in the treatment of obesity by enhancing thermogenesis.
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Affiliation(s)
- Sulagna Mukherjee
- Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk 38453, Republic of Korea
| | - Jong Won Yun
- Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk 38453, Republic of Korea.
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11
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Ranjbar A, Hassanzadeh H, Jahandoust F, Miri R, Bidkhori HR, Monzavi SM, Sanjar-Moussavi N, Matin MM, Shariati-Sarabi Z. Allogeneic adipose-derived mesenchymal stromal cell transplantation for refractory lupus nephritis: Results of a phase I clinical trial. Curr Res Transl Med 2021; 70:103324. [PMID: 34979487 DOI: 10.1016/j.retram.2021.103324] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 10/13/2021] [Accepted: 12/06/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Mesenchymal stromal/stem cells (MSCs) are known for their immunomodulatory properties. This study was performed to analyse the effects of MSC transplantation on treatment-resistant lupus nephritis (LN). METHODS In this phase I trial, nine biopsy-proven LN patients refractory to standard treatments underwent systemic infusion of 2 × 106 allogeneic adipose-derived (AD) MSCs/kg and were followed for 12 months post-intervention. RESULTS The treatment protocol resulted in no major adverse events. Urine protein levels significantly decreased during the first month post-intervention (baseline vs. month 1 (median): 1800 vs. 1020, P = 0.008), followed by a gradual increase but remained significantly lower than baseline only up to the 3rd month. During the first 3 months post-intervention, complete renal response (proteinuria < 0.5 g/24 h) and partial response (proteinuria > 0.5 g/24 h, but > 50% decrease in proteinuria) were observed in 33.3% and 44.4% of the patients, respectively, though these rates declined thereafter. Median score of Systemic Lupus Erythematosus Disease Activity Index decreased significantly from 16 at the baseline to 6 at sixth months post-treatment (P = 0.007), though it slightly increased at the 12th month follow-up. CONCLUSIONS Allogenic AD-MSC transplantation was associated with favourable safety and efficient to reduce urine protein excretion and disease activity; however, the maximum effect (greatest improvement in outcomes) was observed at 1 month based on the proteinuria, and 6 months post-intervention based on disease activity scores. A single dose of AD-MSCs may not be adequate to maintain long-term remission of refractory LN, and so, additional doses may be required.
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Affiliation(s)
- Amin Ranjbar
- Department of Internal Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Halimeh Hassanzadeh
- Stem Cell and Regenerative Medicine Research Group, Academic Center for Education, Culture and Research (ACECR)-Khorasan Razavi, Mashhad, Iran; Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Vakilabad Blvd., Mashhad, Iran
| | - Faezeh Jahandoust
- Department of Internal Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Raheleh Miri
- Blood Borne Infections Research Center, Academic Center for Education, Culture and Research (ACECR)-Khorasan Razavi, Mashhad, Iran
| | - Hamid Reza Bidkhori
- Stem Cell and Regenerative Medicine Research Group, Academic Center for Education, Culture and Research (ACECR)-Khorasan Razavi, Mashhad, Iran
| | - Seyed Mostafa Monzavi
- Center of Excellence for Stem Cell Research and Regenerative Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nasser Sanjar-Moussavi
- Department of General Surgery, Faculty of Medicine, Islamic Azad University-Mashhad Branch, Mashhad, Iran
| | - Maryam M Matin
- Stem Cell and Regenerative Medicine Research Group, Academic Center for Education, Culture and Research (ACECR)-Khorasan Razavi, Mashhad, Iran; Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Vakilabad Blvd., Mashhad, Iran; Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran.
| | - Zhaleh Shariati-Sarabi
- Department of Internal Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Center of Excellence for Stem Cell Research and Regenerative Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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12
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Chen Y, Yan G, Ma Y, Zhong M, Yang Y, Guo J, Wang C, Han W, Zhang L, Xu S, Huang J, Dai H, Qi Z. Combination of mesenchymal stem cells and FK506 prolongs heart allograft survival by inhibiting TBK1/IRF3-regulated-IFN-γ production. Immunol Lett 2021; 238:21-28. [PMID: 34228988 DOI: 10.1016/j.imlet.2021.06.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 06/04/2021] [Accepted: 06/29/2021] [Indexed: 10/20/2022]
Abstract
Lifelong immunosuppression use presents many serious side effects to transplant recipients. Previous studies have shown that mesenchymal stem cells (MSC) regulate the progress of inflammation and protect allograft function. However, the benefits of MSC combined with low-dose tacrolimus (FK506) has not been investigated in heart transplant recipients, and its mechanism deserves further investigation. SD Rat bone marrow-derived MSC were infused into recipient mouse (C57BL/6, B6) through the tail vein, followed by a BALB/c donor cervical ectopic heart transplantation on the next day of infusion. T-lymphocyte subsets and their functions were determined using flow cytometry, ELISA, and qPCR. Thereafter, in vitro and in vivo experiments were conducted to identify the mechanisms regarding MSC and FK506 combination (MF group) use in regulating IFN-γ signaling. MF group in the allogeneic heart transplantation mouse model inhibited acute rejection and prolonged mean survival time (MST) of grafts from 7 days (d) to 22d. Pathological examination of heart grafts suggested that inflammatory cell infiltration decreased, and tissue damage was significantly reduced in the MF group. IFN-γ mRNA expression levels in the grafts and recipients decreased, while IL-4 and TGF-β mRNA expression increased in the MF group. Phosphorylation of TBK1/IRF3 in recipient immune cells decreased under donor antigen stimulation. Combination use of MSC and FK506 can prolong graft survival, possibly by down-regulating TBK1/IRF3 phosphorylation, thus reducing IFN-γ production to prevent infiltration of inflammatory cells in the graft and extend graft survival. The findings provide a potential new approach to immunosuppression selection.
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Affiliation(s)
- Yingyu Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China; Organ Transplantation institute, School of Medicine, Xiamen University, Xiamen, Fujian, China; Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, China; School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Guoliang Yan
- Organ Transplantation institute, School of Medicine, Xiamen University, Xiamen, Fujian, China; Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, China; School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Yunhan Ma
- Organ Transplantation institute, School of Medicine, Xiamen University, Xiamen, Fujian, China; Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, China; School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Mengya Zhong
- Organ Transplantation institute, School of Medicine, Xiamen University, Xiamen, Fujian, China; Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, China; School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Yan Yang
- Organ Transplantation institute, School of Medicine, Xiamen University, Xiamen, Fujian, China; Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, China; School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Junjun Guo
- School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Chenxi Wang
- School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Weimin Han
- School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Liyi Zhang
- Organ Transplantation institute, School of Medicine, Xiamen University, Xiamen, Fujian, China; Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, China; School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Shuangyue Xu
- Organ Transplantation institute, School of Medicine, Xiamen University, Xiamen, Fujian, China; Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, China; School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Jinjin Huang
- School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Helong Dai
- Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China; Clinical Research Center for Organ Transplantation in Hunan Province, Changsha, China; Clinical Immunology Center, Central South University, Changsha, China.
| | - Zhongquan Qi
- Organ Transplantation institute, School of Medicine, Xiamen University, Xiamen, Fujian, China; Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, China; Medical College, Guangxi University, Nanning, Guangxi, China.
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13
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Bojanic C, To K, Hatoum A, Shea J, Seah KTM, Khan W, Malata CM. Mesenchymal stem cell therapy in hypertrophic and keloid scars. Cell Tissue Res 2021; 383:915-930. [PMID: 33386995 PMCID: PMC7960584 DOI: 10.1007/s00441-020-03361-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 11/19/2020] [Indexed: 12/20/2022]
Abstract
Scars are the normal outcome of wound repair and involve a co-ordinated inflammatory and fibrotic process. When a scar does not resolve, uncontrolled chronic inflammation can persist and elicits excessive scarring that leads to a range of abnormal phenotypes such as hypertrophic and keloid scars. These pathologies result in significant impairment of quality of life over a long period of time. Existing treatment options are generally unsatisfactory, and there is mounting interest in innovative cell-based therapies. Despite the interest in mesenchymal stem cells (MSCs), there is yet to be a human clinical trial that investigates the potential of MSCs in treating abnormal scarring. A synthesis of existing evidence of animal studies may therefore provide insight into the barriers to human application. The aim of this PRISMA systematic review was to evaluate the effectiveness of MSC transplantation in the treatment of hypertrophic and keloid scars in in vivo models. A total of 11 case-control studies were identified that treated a total of 156 subjects with MSCs or MSC-conditioned media. Ten studies assessed hypertrophic scars, and one looked at keloid scars. All studies evaluated scars in terms of macroscopic and histological appearances and most incorporated immunohistochemistry. The included studies all found improvements in the above outcomes with MSC or MSC-conditioned media without complications. The studies reviewed support a role for MSC therapy in treating scars that needs further exploration. The transferability of these findings to humans is limited by factors such as the reliability and validity of the disease model, the need to identify the optimal MSC cell source, and the outcome measures employed.
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Affiliation(s)
- Christine Bojanic
- Plastic & Reconstructive Surgery Department, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Kendrick To
- Division of Trauma and Orthopaedics, Department of Surgery, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Adam Hatoum
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Jessie Shea
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - K T Matthew Seah
- Division of Trauma and Orthopaedics, Department of Surgery, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Wasim Khan
- Division of Trauma and Orthopaedics, Department of Surgery, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
| | - Charles M Malata
- Plastic & Reconstructive Surgery Department, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- School of Medicine, Anglia Ruskin University, Cambridge & Chelmsford, UK
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14
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Wise RM, Harrison MAA, Sullivan BN, Al-Ghadban S, Aleman SJ, Vinluan AT, Monaco ER, Donato UM, Pursell IA, Bunnell BA. Short-Term Rapamycin Preconditioning Diminishes Therapeutic Efficacy of Human Adipose-Derived Stem Cells in a Murine Model of Multiple Sclerosis. Cells 2020; 9:E2218. [PMID: 33008073 PMCID: PMC7600854 DOI: 10.3390/cells9102218] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 09/16/2020] [Accepted: 09/28/2020] [Indexed: 01/22/2023] Open
Abstract
Human adipose-derived stem cells (ASCs) show immense promise for treating inflammatory diseases, attributed primarily to their potent paracrine signaling. Previous investigations demonstrated that short-term Rapamycin preconditioning of bone marrow-derived stem cells (BMSCs) elevated secretion of prostaglandin E2, a pleiotropic molecule with therapeutic effects in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), and enhanced immunosuppressive capacity in vitro. However, this has yet to be examined in ASCs. The present study examined the therapeutic potential of short-term Rapamycin-preconditioned ASCs in the EAE model. Animals were treated at peak disease with control ASCs (EAE-ASCs), Rapa-preconditioned ASCs (EAE-Rapa-ASCs), or vehicle control (EAE). Results show that EAE-ASCs improved clinical disease scores and elevated intact myelin compared to both EAE and EAE-Rapa-ASC animals. These results correlated with augmented CD4+ T helper (Th) and T regulatory (Treg) cell populations in the spinal cord, and increased gene expression of interleukin-10 (IL-10), an anti-inflammatory cytokine. Conversely, EAE-Rapa-ASC mice showed no improvement in clinical disease scores, reduced myelin levels, and significantly less Th and Treg cells in the spinal cord. These findings suggest that short-term Rapamycin preconditioning reduces the therapeutic efficacy of ASCs when applied to late-stage EAE.
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Affiliation(s)
- Rachel M. Wise
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70118, USA; (R.M.W.); (M.A.A.H.); (B.N.S.); (S.J.A.); (A.T.V.); (E.R.M.); (U.M.D.)
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA; (S.A.-G.); (I.A.P.)
| | - Mark A. A. Harrison
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70118, USA; (R.M.W.); (M.A.A.H.); (B.N.S.); (S.J.A.); (A.T.V.); (E.R.M.); (U.M.D.)
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA; (S.A.-G.); (I.A.P.)
| | - Brianne N. Sullivan
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70118, USA; (R.M.W.); (M.A.A.H.); (B.N.S.); (S.J.A.); (A.T.V.); (E.R.M.); (U.M.D.)
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA; (S.A.-G.); (I.A.P.)
| | - Sara Al-Ghadban
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA; (S.A.-G.); (I.A.P.)
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Sarah J. Aleman
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70118, USA; (R.M.W.); (M.A.A.H.); (B.N.S.); (S.J.A.); (A.T.V.); (E.R.M.); (U.M.D.)
| | - Amber T. Vinluan
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70118, USA; (R.M.W.); (M.A.A.H.); (B.N.S.); (S.J.A.); (A.T.V.); (E.R.M.); (U.M.D.)
| | - Emily R. Monaco
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70118, USA; (R.M.W.); (M.A.A.H.); (B.N.S.); (S.J.A.); (A.T.V.); (E.R.M.); (U.M.D.)
| | - Umberto M. Donato
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70118, USA; (R.M.W.); (M.A.A.H.); (B.N.S.); (S.J.A.); (A.T.V.); (E.R.M.); (U.M.D.)
| | - India A. Pursell
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA; (S.A.-G.); (I.A.P.)
| | - Bruce A. Bunnell
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA; (S.A.-G.); (I.A.P.)
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA
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15
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Mesenchymal Stem/Progenitor Cells: The Prospect of Human Clinical Translation. Stem Cells Int 2020; 2020:8837654. [PMID: 33953753 PMCID: PMC8063852 DOI: 10.1155/2020/8837654] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/19/2020] [Accepted: 07/20/2020] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem/progenitor cells (MSCs) are key players in regenerative medicine, relying principally on their differentiation/regeneration potential, immunomodulatory properties, paracrine effects, and potent homing ability with minimal if any ethical concerns. Even though multiple preclinical and clinical studies have demonstrated remarkable properties for MSCs, the clinical applicability of MSC-based therapies is still questionable. Several challenges exist that critically hinder a successful clinical translation of MSC-based therapies, including but not limited to heterogeneity of their populations, variability in their quality and quantity, donor-related factors, discrepancies in protocols for isolation, in vitro expansion and premodification, and variability in methods of cell delivery, dosing, and cell homing. Alterations of MSC viability, proliferation, properties, and/or function are also affected by various drugs and chemicals. Moreover, significant safety concerns exist due to possible teratogenic/neoplastic potential and transmission of infectious diseases. Through the current review, we aim to highlight the major challenges facing MSCs' human clinical translation and shed light on the undergoing strategies to overcome them.
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16
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Sergeant E, Buysse M, Devos T, Sprangers B. Multipotent mesenchymal stromal cells in kidney transplant recipients: The next big thing? Blood Rev 2020; 45:100718. [PMID: 32507576 DOI: 10.1016/j.blre.2020.100718] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 04/13/2020] [Accepted: 05/11/2020] [Indexed: 12/20/2022]
Abstract
Bone marrow-derived multipotent mesenchymal stromal cells (BM-MSCs) are non-haematopoietic cells present in the bone marrow stroma. They have the potential to modulate immune responses and exhibit a capacity to promote immune tolerance. Although the efficacy of immunosuppressive drugs has improved significantly, thereby ameliorating renal graft outcome, the use of these drugs still carries an increased risk of malignancies and opportunistic infections, and sometimes fail to prevent chronic allograft rejection or recurrence of the original kidney disease. As such, there is strong interest in ways to induce immune tolerance and thereby tempering or avoiding conventional immunosuppressive drugs. Cellular immunomodulation by MSCs can create a new way to induce transplant tolerance. This review will give a critical overview of the use of BM-MSCs as a cell-based immunosuppressive therapy in kidney transplant recipients. In vitro studies revealed several mechanisms that can clarify the immunomodulatory potential of BM-MSCs. Several clinical studies showed that BM-MSCs can modulate T-cell proliferation and can alter the ratio of T-cell subsets, favoring immune tolerance. However, this immunomodulation was often not associated with better clinical outcome during follow-up when compared to control groups. Some clinical studies found that BM-MSCs allow a reduction in dose of conventional immunosuppressive drugs and prevent acute graft dysfunction. Most clinical studies emphasized that BM-MSC infusion was safe. This review suggests that the use of BM-MSCs as cell-based immunosuppression therapy in kidney transplant recipients has potential, however some caution regarding their clinical use is appropriate. Mechanisms by which BM-MSCs induce transplant tolerance and factors that can alter their functionality need to be analyzed in more detail before clinical use.
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Affiliation(s)
- Elien Sergeant
- Division of Internal Medicine, University Hospitals Leuven, Leuven, Belgium.
| | - Malicorne Buysse
- Division of Hematology, University Hospitals Ghent, Ghent, Belgium.
| | - Timothy Devos
- Department of Microbiology and Immunology, Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Leuven, Belgium; Division of Hematology, University Hospitals Leuven, Leuven, Belgium.
| | - Ben Sprangers
- Department of Microbiology and Immunology, Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Leuven, Belgium; Division of Nephrology, University Hospitals Leuven, Leuven, Belgium.
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17
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Cyclosporine A promotes the therapeutic effect of mesenchymal stem cells on transplantation reaction. Clin Sci (Lond) 2020; 133:2143-2157. [PMID: 31654074 DOI: 10.1042/cs20190294] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 10/15/2019] [Accepted: 10/17/2019] [Indexed: 12/15/2022]
Abstract
The successful application of mesenchymal stem cells (MSCs) remains a major challenge in stem cell therapy. Currently, several in vitro studies have indicated potentially beneficial interactions of MSCs with immunosuppressive drugs. These interactions can be even more complex in vivo, and it is in this setting that we investigate the effect of MSCs in combination with Cyclosporine A (CsA) on transplantation reaction and allogeneic cell survival. Using an in vivo mouse model, we found that CsA significantly promoted the survival of MSCs in various organs and tissues of the recipients. In addition, compared to treatment with CsA or MSCs alone, the survival of transplanted allogeneic cells was significantly improved after the combined application of MSCs with CsA. We further observed that the combinatory treatment suppressed immune response to the alloantigen challenge and modulated the immune balance by harnessing proinflammatory CD4+T-bet+ and CD4+RORγt+ cell subsets. These changes were accompanied by a significant decrease in IL-17 production along with an elevated level of IL-10. Co-cultivation of purified naive CD4+ cells with peritoneal macrophages isolated from mice treated with MSCs and CsA revealed that MSC-educated macrophages play an important role in the immunomodulatory effect observed on distinct T-cell subpopulations. Taken together, our findings suggest that CsA promotes MSC survival in vivo and that the therapeutic efficacy of the combination of MSCs with CsA is superior to each monotherapy. This combinatory treatment thus represents a promising approach to reducing immunosuppressant dosage while maintaining or even improving the outcome of therapy.
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18
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Sávio-Silva C, Soinski-Sousa PE, Balby-Rocha MTA, Lira ÁDO, Rangel ÉB. Mesenchymal stem cell therapy in acute kidney injury (AKI): review and perspectives. REVISTA DA ASSOCIAÇÃO MÉDICA BRASILEIRA 2020; 66:s45-s54. [DOI: 10.1590/1806-9282.66.s1.45] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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19
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Lohan P, Murphy N, Treacy O, Lynch K, Morcos M, Chen B, Ryan AE, Griffin MD, Ritter T. Third-Party Allogeneic Mesenchymal Stromal Cells Prevent Rejection in a Pre-sensitized High-Risk Model of Corneal Transplantation. Front Immunol 2018; 9:2666. [PMID: 30515159 PMCID: PMC6255848 DOI: 10.3389/fimmu.2018.02666] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 10/29/2018] [Indexed: 12/16/2022] Open
Abstract
High-risk cornea transplant recipients represent a patient population with significant un-met medical need for more effective therapies to prevent immunological graft rejection due to heightened anti-donor immune response. In this study, a rat model of pre-existing anti-donor immunity was developed in which corneal allografts were rejected earlier than in non-pre-sensitized recipients. In this model, third-party (non-donor, non-recipient strain) allogeneic mesenchymal stromal cells (allo-MSC) were administered intravenously 7 and 1 days prior to transplantation. Rejection-free graft survival to 30 days post-transplant improved from 0 to 63.6% in MSC-treated compared to vehicle-treated control animals (p = < 0.0001). Pre-sensitized animals that received third-party allo-MSC prior to transplantation had significantly higher proportions of CD45+CD11b+ B220+ monocytes in the lungs 24 h after the second MSC injection and significantly higher proportions of CD4+ FoxP3+ regulatory T cells in the graft-draining lymph nodes at the average day of rejection of control animals. In in vitro experiments, third-party allo-MSC polarized primary lung-derived CD11b/c+ myeloid cells to a more anti-inflammatory phenotype, as determined by cytokine profile and conferred them with the capacity to suppress T cell activation via prostaglandin E2 and TGFβ1. In experiments designed to further validate the clinical potential of the protocol, thawed cryopreserved, third-party allo-MSC were shown to be similarly potent at prolonging rejection-free corneal allograft survival as their freshly-cultured counterparts in the pre-sensitized high-risk model. Furthermore, thawed cryopreserved third-party allo-MSC could be co-administered with mycophenolate mofetil without adversely affecting their immunomodulatory function. In conclusion, a clinically-relevant protocol consisting of two intravenous infusions of third-party allo-MSC during the week prior to transplantation, exerts a potent anti-rejection effect in a pre-sensitized rat model of high-risk corneal allo-transplantation. This immune regulatory effect is likely to be mediated in the immediate post-transplant period through the promotion, by allo-MSC, of alternatively-activated macrophages in the lung and, later, by enhanced regulatory T-cell numbers.
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Affiliation(s)
- Paul Lohan
- Regenerative Medicine Institute, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Nick Murphy
- Regenerative Medicine Institute, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Oliver Treacy
- Regenerative Medicine Institute, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.,Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Kevin Lynch
- Regenerative Medicine Institute, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.,Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Maurice Morcos
- Regenerative Medicine Institute, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Bingling Chen
- Regenerative Medicine Institute, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Aideen E Ryan
- Regenerative Medicine Institute, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.,Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.,CÚRAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Matthew D Griffin
- Regenerative Medicine Institute, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.,CÚRAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Thomas Ritter
- Regenerative Medicine Institute, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.,CÚRAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
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20
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Effect of a Combination of Prednisone or Mycophenolate Mofetil and Mesenchymal Stem Cells on Lupus Symptoms in MRL. Faslpr Mice. Stem Cells Int 2018; 2018:4273107. [PMID: 30057623 PMCID: PMC6051060 DOI: 10.1155/2018/4273107] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 05/10/2018] [Accepted: 06/03/2018] [Indexed: 01/27/2023] Open
Abstract
The combination of immunosuppressants and mesenchymal stem cells (MSCs) is a promising therapeutic strategy for systemic lupus erythematosus, since this approach reduces doses of immunosuppressants while maintaining the same therapeutic outcome. However, it is unavoidable for MSCs to be exposed to immunosuppressants. Here, we examined the combination effect of prednisone (PD) or mycophenolate mofetil (MMF) and MSCs. We showed that PD or MMF in combination with MSCs showed better therapeutic effect than single therapy in lupus-prone MRL.Faslpr mice, as assessed by using the following readouts: prolongation of survival, decrease in anti-dsDNA and total IgG levels in serum, decrease in cytokine gene expression in spleen cells, and decrease in inflammatory cell infiltration into the kidney. In vitro, immunosuppressants and MSCs inhibited T cell proliferation in a synergistic manner. However, immunosuppressants did not affect MSC viability and functions such as TGF-β1 and PGE2 production, migration, and immunosuppressive capacity. In summary, our study demonstrates that a combination of immunosuppressants and MSCs is a good strategy to reduce the side effects of PD and MMF without the loss of therapeutic outcome.
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