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Xiao T, Chen Y, Jiang B, Huang M, Liang Y, Xu Y, Zheng X, Wang W, Chen X, Cai G. Ultrasound-guided renal subcapsular transplantation of mesenchymal stem cells for treatment of acute kidney injury in a minipig model: safety and efficacy evaluation. Stem Cell Res Ther 2025; 16:102. [PMID: 40022148 PMCID: PMC11871648 DOI: 10.1186/s13287-025-04137-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 01/10/2025] [Indexed: 03/03/2025] Open
Abstract
BACKGROUND Acute kidney injury (AKI) is a major global public health concern with limited treatment options. While preclinical studies have suggested the potential of mesenchymal stem cells (MSCs) to repair and protect injured kidneys in AKI, clinical trials using transarterial MSCs transplantation have yielded disappointing results. This study aimed to investigate the feasibility and safety of minimally invasive renal subcapsular transplantation of MSCs for treating AKI in a minipig model, ultimately aiming to facilitate the clinical translation of this approach. METHODS A novel AKI minipig model was established by combining cisplatin with hydration to evaluate the effectiveness of potential therapies. Renal subcapsular catheterization was successfully achieved under ultrasound guidance. Subsequently, the efficacy of renal subcapsular MSCs transplantation was assessed, and the biological role of the tryptophan metabolite kynurenine (Kyn) in AKI was elucidated through both in vivo and in vitro experiments. RESULTS The method of pre-hydration at 4% of body weight, followed by post-cisplatin (3.8 mg/kg) hydration at 2% of body weight, successfully established a cisplatin-induced AKI minipig model with a survival time exceeding 28 days, closely mimicking the clinical characteristics of typical AKI patients. Additionally, we discovered that multiple MSCs transplantations promoted renal function recovery more effectively than single transplantation via the renal subcapsular catheter. Furthermore, elevated levels of Kyn were observed in kidney during AKI, which activated the aryl hydrocarbon receptor (AhR)-mediated NF-κB/NLRP3/IL-1β signaling pathway in tubular epithelial cells, thereby exacerbating inflammatory injury. CONCLUSIONS Ultrasound-guided renal subcapsular transplantation of mesenchymal stem cells is a safe and effective therapeutic approach for AKI, with the potential to bring about significant clinical advancements in the future.
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Affiliation(s)
- Tuo Xiao
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing, 100853, China
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Yuhao Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing, 100853, China
| | - Bo Jiang
- Department of Ultrasound, First Medical Centre of Chinese PLA General Hospital, Beijing, 100853, China
| | - Mengjie Huang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing, 100853, China
| | - Yanjun Liang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing, 100853, China
| | - Yue Xu
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing, 100853, China
| | - Xumin Zheng
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing, 100853, China
| | - Wenjuan Wang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing, 100853, China
| | - Xiangmei Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing, 100853, China.
| | - Guangyan Cai
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing, 100853, China.
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Hodgson-Garms M, Moore MJ, Martino MM, Kelly K, Frith JE. Proteomic profiling of iPSC and tissue-derived MSC secretomes reveal a global signature of inflammatory licensing. NPJ Regen Med 2025; 10:7. [PMID: 39905050 PMCID: PMC11794695 DOI: 10.1038/s41536-024-00382-y] [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: 03/09/2024] [Accepted: 12/03/2024] [Indexed: 02/06/2025] Open
Abstract
Much of the therapeutic potential of mesenchymal stromal cells (MSCs) is underpinned by their secretome which varies significantly with source, donor and microenvironmental cues. Understanding these differences is essential to define the mechanisms of MSC-based tissue repair and optimise cell therapies. This study analysed the secretomes of bone-marrow (BM.MSCs), umbilical-cord (UC.MSCs), adipose-tissue (AT.MSCs) and clinical/commercial-grade induced pluripotent stem cell-derived MSCs (iMSCs), under resting and inflammatory licenced conditions. iMSCs recapitulated the inflammatory licensing process, validating their comparability to tissue-derived MSCs. Overall, resting secretomes were defined by extracellular matrix (ECM) and pro-regenerative proteins, while licensed secretomes were enriched in chemotactic and immunomodulatory proteins. iMSC and UC.MSC secretomes contained proteins indicating proliferative potential and telomere maintenance, whereas adult tissue-derived secretomes contained fibrotic and ECM-related proteins. The data and findings from this study will inform the optimum MSC source for particular applications and underpin further development of MSC therapies.
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Affiliation(s)
- Margeaux Hodgson-Garms
- Department of Materials Science and Engineering, Monash University, Melbourne, VIC, Australia.
- Cynata Therapeutics, Melbourne, VIC, Australia.
| | - Matthew J Moore
- Department of Materials Science and Engineering, Monash University, Melbourne, VIC, Australia
| | - Mikaël M Martino
- Australian Regenerative Medicine Institute, Melbourne, VIC, Australia
- Victorian Heart Institute, Monash University, Melbourne, VIC, Australia
| | | | - Jessica E Frith
- Department of Materials Science and Engineering, Monash University, Melbourne, VIC, Australia.
- Australian Regenerative Medicine Institute, Melbourne, VIC, Australia.
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Osawa T, Yamada D, Takao T, Ming L, Takarada T. PRRX1 upregulates PD-L1 in human mesenchymal stem cells. In Vitro Cell Dev Biol Anim 2024; 60:1132-1137. [PMID: 38664281 PMCID: PMC11655573 DOI: 10.1007/s11626-024-00911-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 04/08/2024] [Indexed: 12/19/2024]
Abstract
Mesenchymal stem cells (MSCs) have been demonstrated to be efficacious in clinical applications for the amelioration of immune disorders, including graft-versus-host disease (GvHD) and Crohn's disease. The immunosuppressive role of Programmed death-ligand 1 (PD-L1) in MSCs is pivotal, yet the regulatory mechanisms governing its expression remain to be fully elucidated. In this study, we explored the influence of paired-related homeobox (PRRX1), a determinant of multipotency and self-renewal in MSCs, on the expression of various surface antigens, notably PD-L1. Multiple isoforms of PRRX1 were found to augment the mRNA levels of MSC markers, such as CD26 and CD317, with all isoforms elevating PD-L1 expression at both mRNA and protein levels. This study reveals that PRRX1 may act as a potential immunomodulatory factor in MSCs by regulating the PD-L1 pathway.
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Affiliation(s)
- Taro Osawa
- Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Daisuke Yamada
- Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Tomoko Takao
- Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Lu Ming
- Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Takeshi Takarada
- Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
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Jo CH, Lee SY, Son YB, Lee WJ, Choe YH, Lee HJ, Oh SJ, Kim TS, Hong CY, Lee SL, Rho GJ. Regulation of Colonic Inflammation and Macrophage Homeostasis of IFN-γ-Primed Canine AMSCs in Experimental Colitis in Mice. Animals (Basel) 2024; 14:3283. [PMID: 39595338 PMCID: PMC11591378 DOI: 10.3390/ani14223283] [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: 09/17/2024] [Revised: 10/24/2024] [Accepted: 11/08/2024] [Indexed: 11/28/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have shown potential in treating immune-mediated diseases due to their immunomodulatory properties, which can be enhanced by priming with inflammatory cytokines like interferon-gamma (IFN-γ). This study evaluates the therapeutic effects of IFN-γ-primed canine adipose tissue-derived MSCs (AMSCs) in a mouse model of inflammatory bowel disease (IBD). Canine AMSCs were primed with 50 ng/mL recombinant canine IFN-γ for 48 h, and the effects were compared to those seen in naïve (unprimed) AMSCs. IBD was induced in mice using dextran sodium sulfate (DSS), and AMSCs were injected intraperitoneally on days 1 and 3. The mice treated with IFN-γ-primed AMSCs showed improved clinical outcomes, including a reduced disease activity index (DAI), less body weight loss, and longer colon length compared to the mice treated with naïve AMSCs. A histological analysis revealed less damage to the intestinal structures and reduced inflammatory cell infiltration. IFN-γ priming led to a shift in the immune cell balance in the gut, decreasing pro-inflammatory macrophages (Ly6Chi) and increasing anti-inflammatory macrophages (Ly6Clo/MHC-IIhi). This was associated with the reduced expression of inflammatory cytokine genes (Il-1β, Il-6, and Il-18) and increased expression of the intestinal stem cell marker Lgr5. These findings suggest that IFN-γ-primed AMSCs offer enhanced therapeutic potential for treating CE in veterinary medicine.
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Affiliation(s)
- Chan-Hee Jo
- College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (C.-H.J.); (S.-Y.L.); (Y.-H.C.); (H.-J.L.); (S.-J.O.); (T.-S.K.); (C.-Y.H.)
| | - Sang-Yun Lee
- College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (C.-H.J.); (S.-Y.L.); (Y.-H.C.); (H.-J.L.); (S.-J.O.); (T.-S.K.); (C.-Y.H.)
| | - Young-Bum Son
- Department of Obstetrics, College of Veterinary Medicine, Chonnam National University, 300 Yonbongdong, Buk-gu, Gwangju 500-757, Republic of Korea;
| | - Won-Jae Lee
- College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Republic of Korea;
| | - Yong-Ho Choe
- College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (C.-H.J.); (S.-Y.L.); (Y.-H.C.); (H.-J.L.); (S.-J.O.); (T.-S.K.); (C.-Y.H.)
| | - Hyeon-Jeong Lee
- College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (C.-H.J.); (S.-Y.L.); (Y.-H.C.); (H.-J.L.); (S.-J.O.); (T.-S.K.); (C.-Y.H.)
| | - Seong-Ju Oh
- College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (C.-H.J.); (S.-Y.L.); (Y.-H.C.); (H.-J.L.); (S.-J.O.); (T.-S.K.); (C.-Y.H.)
| | - Tae-Seok Kim
- College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (C.-H.J.); (S.-Y.L.); (Y.-H.C.); (H.-J.L.); (S.-J.O.); (T.-S.K.); (C.-Y.H.)
| | - Chae-Yeon Hong
- College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (C.-H.J.); (S.-Y.L.); (Y.-H.C.); (H.-J.L.); (S.-J.O.); (T.-S.K.); (C.-Y.H.)
| | - Sung-Lim Lee
- College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (C.-H.J.); (S.-Y.L.); (Y.-H.C.); (H.-J.L.); (S.-J.O.); (T.-S.K.); (C.-Y.H.)
- Research Institute of Life Sciences, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Gyu-Jin Rho
- College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (C.-H.J.); (S.-Y.L.); (Y.-H.C.); (H.-J.L.); (S.-J.O.); (T.-S.K.); (C.-Y.H.)
- Research Institute of Life Sciences, Gyeongsang National University, Jinju 52828, Republic of Korea
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Vaillant L, Akhter W, Nakhle J, Simon M, Villalba M, Jorgensen C, Vignais ML, Hernandez J. The role of mitochondrial transfer in the suppression of CD8 + T cell responses by Mesenchymal stem cells. Stem Cell Res Ther 2024; 15:394. [PMID: 39497203 PMCID: PMC11536934 DOI: 10.1186/s13287-024-03980-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 10/04/2024] [Indexed: 11/07/2024] Open
Abstract
BACKGROUND . CD8+ Cytotoxic T lymphocytes play a key role in the pathogenesis of autoimmune diseases and clinical conditions such as graft versus host disease and graft rejection. Mesenchymal Stromal Cells (MSCs) are multipotent cells with tissue repair and immunomodulatory capabilities. Since they are able to suppress multiple pathogenic immune responses, MSCs have been proposed as a cellular therapy for the treatment of immune-mediated diseases. However, the mechanisms underlying their immunosuppressive properties are not yet fully understood. MSCs have the remarkable ability to sense tissue injury and inflammation and respond by donating their own mitochondria to neighboring cells. Whether mitochondrial transfer has any role in the repression of CD8+ responses is unknown. METHODS AND RESULTS . We have utilized CD8+ T cells from Clone 4 TCR transgenic mice that differentiate into effector cells upon activation in vitro and in vivo to address this question. Allogeneic bone marrow derived MSCs, co-cultured with activated Clone 4 CD8+ T cells, decreased their expansion, the production of the effector cytokine IFNγ and their diabetogenic potential in vivo. Notably, we found that during this interaction leading to suppression, MSCs transferred mitochondria to CD8+ T cells as evidenced by FACS and confocal microscopy. Transfer of MSC mitochondria to Clone 4 CD8+ T cells also resulted in decreased expansion and production of IFNγ upon activation. These effects overlapped and were additive with those of prostaglandin E2 secreted by MSCs. Furthermore, preventing mitochondrial transfer in co-cultures diminished the ability of MSCs to inhibit IFNγ production. Finally, we demonstrated that both MSCs and MSC mitochondria downregulated T-bet and Eomes expression, key transcription factors for CTL differentiation, on activated CD8+ T cells. CONCLUSION . In this report we showed that MSCs are able to interact with CD8+ T cells and transfer them their mitochondria. Mitochondrial transfer contributed to the global suppressive effect of MSCs on CD8+ T cell activation by downregulating T-bet and Eomes expression resulting in impaired IFNγ production of activated CD8+ T cells.
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Affiliation(s)
- Loic Vaillant
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM U1183, Montpellier, 34295, France
| | - Waseem Akhter
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM U1183, Montpellier, 34295, France
| | - Jean Nakhle
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM U1183, Montpellier, 34295, France
- IGF, Université de Montpellier, CNRS, INSERM, Montpellier, France
- IGMM, Université de Montpellier, CNRS, Montpellier, France
| | - Matthieu Simon
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM U1183, Montpellier, 34295, France
| | - Martin Villalba
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM U1183, Montpellier, 34295, France
| | - Christian Jorgensen
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM U1183, Montpellier, 34295, France
- CHU Montpellier, Montpellier, France
| | - Marie-Luce Vignais
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM U1183, Montpellier, 34295, France
- IGF, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Javier Hernandez
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM U1183, Montpellier, 34295, France.
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Hu L, Sun C, Yuan K, Yang P. Expression, regulation, and function of PD-L1 on non-tumor cells in the tumor microenvironment. Drug Discov Today 2024; 29:104181. [PMID: 39278561 DOI: 10.1016/j.drudis.2024.104181] [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: 07/14/2024] [Revised: 09/03/2024] [Accepted: 09/11/2024] [Indexed: 09/18/2024]
Abstract
Antiprogrammed death ligand 1 (PD-L1) therapy is a leading immunotherapy, but only some patients with solid cancers benefit. Overwhelming evidence has revealed that PD-L1 is expressed on various immune cells in the tumor microenvironment (TME), including macrophages, dendritic cells, and regulatory T cells, modulating tumor immunity and influencing tumor progression. PD-L1 can also be located on tumor cell membranes as well as in exosomes and cytoplasm. Accordingly, the dynamic expression and various forms of PD-L1 might explain the therapy's limited efficacy and resistance. Herein a systematic summary of the expression of PD-L1 on different immune cells and their regulatory mechanisms is provided to offer a solid foundation for future studies.
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Affiliation(s)
- Lingrong Hu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China
| | - Chengliang Sun
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China
| | - Kai Yuan
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China.
| | - Peng Yang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China.
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Jia L, Li N, van Unen V, Zwaginga JJ, Braun J, Hiemstra PS, Koning F, Khedoe PPSJ, Stolk J. Pulmonary and Systemic Immune Profiles Following Lung Volume Reduction Surgery and Allogeneic Mesenchymal Stromal Cell Treatment in Emphysema. Cells 2024; 13:1636. [PMID: 39404398 PMCID: PMC11476308 DOI: 10.3390/cells13191636] [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: 08/12/2024] [Revised: 09/19/2024] [Accepted: 09/20/2024] [Indexed: 10/19/2024] Open
Abstract
Emphysema in patients with chronic obstructive pulmonary disease (COPD) is characterized by progressive inflammation. Preclinical studies suggest that lung volume reduction surgery (LVRS) and mesenchymal stromal cell (MSC) treatment dampen inflammation. We investigated the effects of bone marrow-derived MSC (BM-MSC) and LVRS on circulating and pulmonary immune cell profiles in emphysema patients using mass cytometry. Blood and resected lung tissue were collected at the first LVRS (L1). Following 6-10 weeks of recovery, patients received a placebo or intravenous administration of 2 × 106 cells/kg bodyweight BM-MSC (n = 5 and n = 9, resp.) in week 3 and 4 before the second LVRS (L2), where blood and lung tissue were collected. Irrespective of BM-MSC or placebo treatment, proportions of circulating lymphocytes including central memory CD4 regulatory, effector memory CD8 and γδ T cells were higher, whereas myeloid cell percentages were lower in L2 compared to L1. In resected lung tissue, proportions of Treg (p = 0.0067) and anti-inflammatory CD163- macrophages (p = 0.0001) were increased in L2 compared to L1, while proportions of pro-inflammatory CD163+ macrophages were decreased (p = 0.0004). There were no effects of BM-MSC treatment on immune profiles in emphysema patients. However, we observed alterations in the circulating and pulmonary immune cells upon LVRS, suggesting the induction of anti-inflammatory responses potentially needed for repair processes.
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Affiliation(s)
- Li Jia
- Department of Immunology, Leiden University Medical Center (LUMC), 2333 Leiden, The Netherlands; (L.J.)
- Department of Pulmonology, PulmoScience Lab, Leiden University Medical Center (LUMC), 2333 Leiden, The Netherlands (J.S.)
| | - Na Li
- Department of Immunology, Leiden University Medical Center (LUMC), 2333 Leiden, The Netherlands; (L.J.)
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory of Zoonosis Research of the Ministry of Education, Institute of Zoonosis and College of Veterinary Medicine, Jilin University, Changchun 130012, China
| | - Vincent van Unen
- Department of Immunology, Leiden University Medical Center (LUMC), 2333 Leiden, The Netherlands; (L.J.)
| | - Jaap-Jan Zwaginga
- Department of Hematology, Leiden University Medical Center, 2333 Leiden, The Netherlands
| | - Jerry Braun
- Department of Cardiothoracic Surgery, Leiden University Medical Center, 2333 Leiden, The Netherlands
| | - Pieter S. Hiemstra
- Department of Pulmonology, PulmoScience Lab, Leiden University Medical Center (LUMC), 2333 Leiden, The Netherlands (J.S.)
| | - Frits Koning
- Department of Immunology, Leiden University Medical Center (LUMC), 2333 Leiden, The Netherlands; (L.J.)
| | - P. Padmini S. J. Khedoe
- Department of Pulmonology, PulmoScience Lab, Leiden University Medical Center (LUMC), 2333 Leiden, The Netherlands (J.S.)
| | - Jan Stolk
- Department of Pulmonology, PulmoScience Lab, Leiden University Medical Center (LUMC), 2333 Leiden, The Netherlands (J.S.)
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Kaundal U, Rakha A. Differential effects of TLR3 and TLR4 activation on MSC-mediated immune regulation. Biochem Biophys Rep 2024; 39:101809. [PMID: 39228386 PMCID: PMC11369377 DOI: 10.1016/j.bbrep.2024.101809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 07/31/2024] [Accepted: 08/05/2024] [Indexed: 09/05/2024] Open
Abstract
Mesenchymal stromal cells (MSCs) have evolved as an invaluable therapeutic cell type due to their broad therapeutic properties. Bone marrow-derived MSCs are currently being applied in numerous clinical trials, and the initial results have been encouraging. However, heterogeneous responsiveness amongst patients is also being experienced; therefore, the efficacy of MSCs in vivo is still debatable. Host microenvironment plays an essential role in determining the fate of MSCs in vivo. Recent studies have indicated the role of toll-like receptors (TLR) in modulating the biological properties of MSCs. TLRs are expressed by MSCs, and activation of TLR3 and TLR4 can alter the functionality of MSCs. While MSCs can suppress the effector and memory T cell function by promoting regulatory T cells, the effect of TLR activation on MSC-mediated immune cell induction is still not well understood. This study was performed to understand the TLR licensing of MSCs and its impact on MSC-mediated immunomodulation. We found that TLR3 mediated activation of MSCs (TLR3-MSCs) increased the expression of G-CSF & IL-10 while TLR4-mediated activation of MSCs led to an increase in CXCL-1, CXCL-10, and CXCL-12. To study the immunological aspect, an in vitro co-culture model was established-to imitate the brief in vivo interaction of MSCs and immune cells. We found that TLR3-MSCs led to increase in CD4 and CD8 naive T (TNAI) cells and vice versa for effector (TEFF) and memory T (TMEM) cells, while TLR4-MSCs did not show any effect. Moreover, only TLR3-MSCs led to a non-significant increase in the regulatory T cells (TREGS) and Double negative regulatory cells. No change in B cell profile was evident while TLR3-MSCs depicted an increasing trend in regulatory B cells which was not statistically significant. TLR3 MSCs also inhibited the T cell proliferation in our setup. Our data indicate that TLR3 priming may regulate the function of MSCs through immunomodulation. Understanding the role of TLRs and other microenvironmental factors causing subdued responses of MSCs in vivo would allow the uninhibited use of MSCs for many diseased conditions.
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Affiliation(s)
- Urvashi Kaundal
- Department of Translational and Regenerative Medicine, Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh, 160012, India
- Scleroderma Genomics and Health Disparities Unit, NIAMS, NIH, Bethesda, USA
| | - Aruna Rakha
- Scleroderma Genomics and Health Disparities Unit, NIAMS, NIH, Bethesda, USA
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Wang Y, Huang R, Lu Y, Liu M, Mo R. Immuno-protective vesicle-crosslinked hydrogel for allogenic transplantation. Nat Commun 2024; 15:5176. [PMID: 38890279 PMCID: PMC11189436 DOI: 10.1038/s41467-024-49135-x] [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: 09/16/2023] [Accepted: 05/24/2024] [Indexed: 06/20/2024] Open
Abstract
The longevity of grafts remains a major challenge in allogeneic transplantation due to immune rejection. Systemic immunosuppression can impair graft function and can also cause severe adverse effects. Here, we report a local immuno-protective strategy to enhance post-transplant persistence of allografts using a mesenchymal stem cell membrane-derived vesicle (MMV)-crosslinked hydrogel (MMV-Gel). MMVs are engineered to upregulate expression of Fas ligand (FasL) and programmed death ligand 1 (PD-L1). The MMVs are retained within the hydrogel by crosslinking. The immuno-protective microenvironment of the hydrogel protects allografts by presenting FasL and PD-L1. The binding of these ligands to T effector cells, the dominant contributors to graft destruction and rejection, results in apoptosis of T effector cells and generation of regulatory T cells. We demonstrate that implantation with MMV-Gel prolongs the survival and function of grafts in mouse models of allogeneic pancreatic islet cells and skin transplantation.
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Affiliation(s)
- Yuqian Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and Jiangsu Key Laboratory of Drug Design and Optimization, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
| | - Renqi Huang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and Jiangsu Key Laboratory of Drug Design and Optimization, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
| | - Yougong Lu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and Jiangsu Key Laboratory of Drug Design and Optimization, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
| | - Mingqi Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and Jiangsu Key Laboratory of Drug Design and Optimization, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
| | - Ran Mo
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and Jiangsu Key Laboratory of Drug Design and Optimization, Center of Advanced Pharmaceuticals and Biomaterials, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China.
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10
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Wang C, Yang Y, Jiang C, Xi C, Yin Y, Wu H, Qian C. Exosomes Derived from hucMSCs Primed with IFN-γ Suppress the NF-κB Signal Pathway in LPS-Induced ALI by Modulating the miR-199b-5p/AFTPH Axis. Cell Biochem Biophys 2024; 82:647-658. [PMID: 38216808 DOI: 10.1007/s12013-023-01208-2] [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: 08/03/2023] [Accepted: 11/30/2023] [Indexed: 01/14/2024]
Abstract
Exosomes (exos) are primarily responsible for the process of mesenchymal stem cells (MSCs) treatment for acute lung injury (ALI), but the mechanism remains unclear, particularly in altered microenvironment. Therefore, this study aimed to investigate the potential mechanism of exos derived from human umbilical cord mesenchymal stem cells (hucMSCs) primed with interferon-gamma (IFN-γ) on ALI and to propose a promising and cell-free strategy. This study extracted exos from hucMSCs supernatant primed and unprimed with IFN-γ marked with IFN-γ-exos and CON-exos, which were identified and traced. IFN-γ-exos administration to ALI models suppressed the NF-κB signaling pathway compared to CON-exos, which were quantified through western blot and immunohistochemical staining. Reverse transcription-quantitative polymerase chain reaction validated miR-199b-5p expression in the IFN-γ-exos and CON-exos treatment groups. Data analysis, a dual-luciferase reporter assay, and cell transfection were conducted to investigate the target binding between miR-199b-5p and Aftiphilin (AFTPH), with AFTPH expression analyzed via cell immunofluorescence and western blot. Co-immunoprecipitation was conducted for the interaction between AFTPH and NF-κB p65. The result revealed that miR-199b-5p was down-regulated in the IFN-γ-exos treatment group, which had a target binding site with AFTPH, and an interaction with NF-κB p65. Consequently, IFN-γ-exos inhibited the NF-κB signaling pathway in ALI in vitro and in vivo through the miR-199b-5p/AFTPH axis. Our results demonstrated new directions of novel and targeted treatment for ALI.
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Affiliation(s)
- Chun Wang
- Kunming Medical University, Kunming, Yunnan, China
- Department of Emergency Intensive Care Unit, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yiran Yang
- Kunming Medical University, Kunming, Yunnan, China
| | - Chen Jiang
- Kunming Medical University, Kunming, Yunnan, China
| | - Cheng Xi
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yunxiang Yin
- Department of Emergency Intensive Care Unit, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Haiying Wu
- Department of Emergency, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
| | - Chuanyun Qian
- Department of Emergency, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
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11
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Farzamfar S, Garcia LM, Rahmani M, Bolduc S. Navigating the Immunological Crossroads: Mesenchymal Stem/Stromal Cells as Architects of Inflammatory Harmony in Tissue-Engineered Constructs. Bioengineering (Basel) 2024; 11:494. [PMID: 38790361 PMCID: PMC11118848 DOI: 10.3390/bioengineering11050494] [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: 03/26/2024] [Revised: 04/26/2024] [Accepted: 05/13/2024] [Indexed: 05/26/2024] Open
Abstract
In the dynamic landscape of tissue engineering, the integration of tissue-engineered constructs (TECs) faces a dual challenge-initiating beneficial inflammation for regeneration while avoiding the perils of prolonged immune activation. As TECs encounter the immediate reaction of the immune system upon implantation, the unique immunomodulatory properties of mesenchymal stem/stromal cells (MSCs) emerge as key navigators. Harnessing the paracrine effects of MSCs, researchers aim to craft a localized microenvironment that not only enhances TEC integration but also holds therapeutic promise for inflammatory-driven pathologies. This review unravels the latest advancements, applications, obstacles, and future prospects surrounding the strategic alliance between MSCs and TECs, shedding light on the immunological symphony that guides the course of regenerative medicine.
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Affiliation(s)
- Saeed Farzamfar
- Centre de Recherche en Organogénèse Expérimentale/LOEX, Regenerative Medicine Division, CHU de Québec-Université Laval Research Center, Québec, QC G1V 4G2, Canada; (S.F.); (M.R.)
| | - Luciana Melo Garcia
- Department of Medicine, Université Laval, Québec, QC G1V 0A6, Canada;
- Hematology-Oncology Service, CHU de Québec—Université Laval, Québec, QC G1V 0A6, Canada
| | - Mahya Rahmani
- Centre de Recherche en Organogénèse Expérimentale/LOEX, Regenerative Medicine Division, CHU de Québec-Université Laval Research Center, Québec, QC G1V 4G2, Canada; (S.F.); (M.R.)
| | - Stephane Bolduc
- Centre de Recherche en Organogénèse Expérimentale/LOEX, Regenerative Medicine Division, CHU de Québec-Université Laval Research Center, Québec, QC G1V 4G2, Canada; (S.F.); (M.R.)
- Department of Surgery, Faculty of Medicine, Université Laval, Québec, QC G1V 0A6, Canada
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12
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Chen S, Liang B, Xu J. Unveiling heterogeneity in MSCs: exploring marker-based strategies for defining MSC subpopulations. J Transl Med 2024; 22:459. [PMID: 38750573 PMCID: PMC11094970 DOI: 10.1186/s12967-024-05294-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 05/11/2024] [Indexed: 05/19/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) represent a heterogeneous cell population distributed throughout various tissues, demonstrating remarkable adaptability to microenvironmental cues and holding immense promise for disease treatment. However, the inherent diversity within MSCs often leads to variability in therapeutic outcomes, posing challenges for clinical applications. To address this heterogeneity, purification of MSC subpopulations through marker-based isolation has emerged as a promising approach to ensure consistent therapeutic efficacy. In this review, we discussed the reported markers of MSCs, encompassing those developed through candidate marker strategies and high-throughput approaches, with the aim of explore viable strategies for addressing the heterogeneity of MSCs and illuminate prospective research directions in this field.
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Affiliation(s)
- Si Chen
- Shenzhen University Medical School, Shenzhen University, Shenzhen, 518000, People's Republic of China
| | - Bowei Liang
- Shenzhen University Medical School, Shenzhen University, Shenzhen, 518000, People's Republic of China
| | - Jianyong Xu
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-Implantation, Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-Implantation, Shenzhen Zhongshan Obstetrics & Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital), Fuqiang Avenue 1001, Shenzhen, 518060, Guangdong, People's Republic of China.
- Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-Implantation, Shenzhen, 518000, People's Republic of China.
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13
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Kurawaki S, Nakashima A, Ishiuchi N, Kanai R, Maeda S, Sasaki K, Masaki T. Mesenchymal stem cells pretreated with interferon-gamma attenuate renal fibrosis by enhancing regulatory T cell induction. Sci Rep 2024; 14:10251. [PMID: 38704512 PMCID: PMC11069572 DOI: 10.1038/s41598-024-60928-4] [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: 05/22/2023] [Accepted: 04/29/2024] [Indexed: 05/06/2024] Open
Abstract
Mesenchymal stem cells (MSCs) exert their anti-inflammatory and anti-fibrotic effects by secreting various humoral factors. Interferon-gamma (IFN-γ) can enhance these effects of MSCs, and enhancement of regulatory T (Treg) cell induction is thought to be an underlying mechanism. However, the extent to which Treg cell induction by MSCs pretreated with IFN-γ (IFN-γ MSCs) ameliorates renal fibrosis remains unknown. In this study, we investigated the effects of Treg cell induction by IFN-γ MSCs on renal inflammation and fibrosis using an siRNA knockdown system. Administration of IFN-γ MSCs induced Treg cells and inhibited infiltration of inflammatory cells in ischemia reperfusion injury (IRI) rats more drastically than control MSCs without IFN-γ pretreatment. In addition, administration of IFN-γ MSCs more significantly attenuated renal fibrosis compared with control MSCs. Indoleamine 2,3-dioxygenase (IDO) expression levels in conditioned medium from MSCs were enhanced by IFN-γ pretreatment. Moreover, IDO1 knockdown in IFN-γ MSCs reduced their anti-inflammatory and anti-fibrotic effects in IRI rats by reducing Treg cell induction. Our findings suggest that the increase of Treg cells induced by enhanced secretion of IDO by IFN-γ MSCs played a pivotal role in their anti-fibrotic effects. Administration of IFN-γ MSCs may potentially be a useful therapy to prevent renal fibrosis progression.
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Affiliation(s)
- So Kurawaki
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Ayumu Nakashima
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
| | - Naoki Ishiuchi
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Ryo Kanai
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Satoshi Maeda
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
- TWOCELLS Company, Limited, 16-35 Hijiyama-honmachi, Minami-ku, Hiroshima, 732-0816, Japan
| | - Kensuke Sasaki
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Takao Masaki
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
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14
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Barrère-Lemaire S, Vincent A, Jorgensen C, Piot C, Nargeot J, Djouad F. Mesenchymal stromal cells for improvement of cardiac function following acute myocardial infarction: a matter of timing. Physiol Rev 2024; 104:659-725. [PMID: 37589393 DOI: 10.1152/physrev.00009.2023] [Citation(s) in RCA: 29] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 07/05/2023] [Accepted: 08/16/2023] [Indexed: 08/18/2023] Open
Abstract
Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery, i.e., reperfusion, is the only way to save the myocardium. However, the expected benefits of reducing infarct size are disappointing due to the reperfusion paradox, which also induces specific cell death. These ischemia-reperfusion (I/R) lesions can account for up to 50% of final infarct size, a major determinant for both mortality and the risk of heart failure (morbidity). In this review, we provide a detailed description of the cell death and inflammation mechanisms as features of I/R injury and cardioprotective strategies such as ischemic postconditioning as well as their underlying mechanisms. Due to their biological properties, the use of mesenchymal stromal/stem cells (MSCs) has been considered a potential therapeutic approach in AMI. Despite promising results and evidence of safety in preclinical studies using MSCs, the effects reported in clinical trials are not conclusive and even inconsistent. These discrepancies were attributed to many parameters such as donor age, in vitro culture, and storage time as well as injection time window after AMI, which alter MSC therapeutic properties. In the context of AMI, future directions will be to generate MSCs with enhanced properties to limit cell death in myocardial tissue and thereby reduce infarct size and improve the healing phase to increase postinfarct myocardial performance.
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Affiliation(s)
- Stéphanie Barrère-Lemaire
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Anne Vincent
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Christian Jorgensen
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
| | - Christophe Piot
- Département de Cardiologie Interventionnelle, Clinique du Millénaire, Montpellier, France
| | - Joël Nargeot
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Farida Djouad
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
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15
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Hazrati A, Malekpour K, Khorramdelazad H, Rajaei S, Hashemi SM. Therapeutic and immunomodulatory potentials of mesenchymal stromal/stem cells and immune checkpoints related molecules. Biomark Res 2024; 12:35. [PMID: 38515166 PMCID: PMC10958918 DOI: 10.1186/s40364-024-00580-2] [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: 01/05/2024] [Accepted: 03/07/2024] [Indexed: 03/23/2024] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) are used in many studies due to their therapeutic potential, including their differentiative ability and immunomodulatory properties. These cells perform their therapeutic functions by using various mechanisms, such as the production of anti-inflammatory cytokines, growth factors, direct cell-to-cell contact, extracellular vesicles (EVs) production, and mitochondrial transfer. However, mechanisms related to immune checkpoints (ICPs) and their effect on the immunomodulatory ability of MSCs are less discussed. The main function of ICPs is to prevent the initiation of unwanted responses and to regulate the immune system responses to maintain the homeostasis of these responses. ICPs are produced by various types of immune system regulatory cells, and defects in their expression and function may be associated with excessive responses that can ultimately lead to autoimmunity. Also, by expressing different types of ICPs and their ligands (ICPLs), tumor cells prevent the formation and durability of immune responses, which leads to tumors' immune escape. ICPs and ICPLs can be produced by MSCs and affect immune cell responses both through their secretion into the microenvironment or direct cell-to-cell interaction. Pre-treatment of MSCs in inflammatory conditions leads to an increase in their therapeutic potential. In addition to the effect that inflammatory environments have on the production of anti-inflammatory cytokines by MSCs, they can increase the expression of various types of ICPLs. In this review, we discuss different types of ICPLs and ICPs expressed by MSCs and their effect on their immunomodulatory and therapeutic potential.
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Affiliation(s)
- Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Khorramdelazad
- Department of Immunology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Samira Rajaei
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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16
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Su Z, Li J, Lin J, Li Z, Che Y, Zhang Z, Zheng G, Ye G, Yu W, Zeng Y, Xu P, Xu X, Xie Z, Wu Y, Shen H. TNF-α-Induced KAT2A Impedes BMMSC Quiescence by Mediating Succinylation of the Mitophagy-Related Protein VCP. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2303388. [PMID: 38145956 PMCID: PMC10933659 DOI: 10.1002/advs.202303388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 12/07/2023] [Indexed: 12/27/2023]
Abstract
Regular quiescence and activation are important for the function of bone marrow mesenchymal stem cells (BMMSC), multipotent stem cells that are widely used in the clinic due to their capabilities in tissue repair and inflammatory disease treatment. TNF-α is previously reported to regulate BMMSC functions, including multilineage differentiation and immunoregulation. The present study demonstrates that TNF-α impedes quiescence and promotes the activation of BMMSC in vitro and in vivo. Mechanistically, the TNF-α-induced expression of KAT2A promotes the succinylation of VCP at K658, which inhibits the interaction between VCP and MFN1 and thus inhibits mitophagy. Furthermore, activated BMMSC exhibits stronger fracture repair and immunoregulation functions in vivo. This study contributes to a better understanding of the mechanisms of BMMSC quiescence and activation and to improving the effectiveness of BMMSC in clinical applications.
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Affiliation(s)
- Zepeng Su
- Department of OrthopedicsThe Eighth Affiliated Hospital of Sun Yat‐Sen UniversityShenzhen518000China
| | - Jinteng Li
- Department of OrthopedicsThe Eighth Affiliated Hospital of Sun Yat‐Sen UniversityShenzhen518000China
| | - Jiajie Lin
- Department of OrthopedicsThe Eighth Affiliated Hospital of Sun Yat‐Sen UniversityShenzhen518000China
| | - Zhikun Li
- Department of OrthopedicsThe Eighth Affiliated Hospital of Sun Yat‐Sen UniversityShenzhen518000China
| | - Yunshu Che
- Department of OrthopedicsThe Eighth Affiliated Hospital of Sun Yat‐Sen UniversityShenzhen518000China
| | - Zhaoqiang Zhang
- Department of OrthopedicsThe Eighth Affiliated Hospital of Sun Yat‐Sen UniversityShenzhen518000China
| | - Guan Zheng
- Department of OrthopedicsThe Eighth Affiliated Hospital of Sun Yat‐Sen UniversityShenzhen518000China
| | - Guiwen Ye
- Department of OrthopedicsThe Eighth Affiliated Hospital of Sun Yat‐Sen UniversityShenzhen518000China
| | - Wenhui Yu
- Department of OrthopedicsThe Eighth Affiliated Hospital of Sun Yat‐Sen UniversityShenzhen518000China
| | - Yipeng Zeng
- Department of OrthopedicsThe Eighth Affiliated Hospital of Sun Yat‐Sen UniversityShenzhen518000China
| | - Peitao Xu
- Department of OrthopedicsThe Eighth Affiliated Hospital of Sun Yat‐Sen UniversityShenzhen518000China
| | - Xiaojun Xu
- Department of OrthopedicsThe Eighth Affiliated Hospital of Sun Yat‐Sen UniversityShenzhen518000China
| | - Zhongyu Xie
- Department of OrthopedicsThe Eighth Affiliated Hospital of Sun Yat‐Sen UniversityShenzhen518000China
| | - Yanfeng Wu
- Center for BiotherapyThe Eighth Affiliated Hospital of Sun Yat‐Sen UniversityShenzhen518000China
| | - Huiyong Shen
- Department of OrthopedicsThe Eighth Affiliated Hospital of Sun Yat‐Sen UniversityShenzhen518000China
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17
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Vukotić M, Kapor S, Simon F, Cokic V, Santibanez JF. Mesenchymal stromal cells in myeloid malignancies: Immunotherapeutic opportunities. Heliyon 2024; 10:e25081. [PMID: 38314300 PMCID: PMC10837636 DOI: 10.1016/j.heliyon.2024.e25081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 01/18/2024] [Accepted: 01/19/2024] [Indexed: 02/06/2024] Open
Abstract
Myeloid malignancies are clonal disorders of the progenitor cells or hematopoietic stem cells, including acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative malignancies, and chronic myelomonocytic leukemia. Myeloid neoplastic cells affect the proliferation and differentiation of other hematopoietic lineages in the bone marrow and peripheral blood, leading to severe and life-threatening complications. Mesenchymal stromal cells (MSCs) residing in the bone marrow exert immunosuppressive functions by suppressing innate and adaptive immune systems, thus creating a supportive and tolerant microenvironment for myeloid malignancy progression. This review summarizes the significant features of MSCs in myeloid malignancies, including their role in regulating cell growth, cell death, and antineoplastic resistance, in addition to their immunosuppressive contributions. Understanding the implications of MSCs in myeloid malignancies could pave the path for potential use in immunotherapy.
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Affiliation(s)
- Milica Vukotić
- Molecular Oncology Group, Institute for Medical Research, University of Belgrade, Belgrade, Serbia
| | - Suncica Kapor
- Department of Hematology, Clinical Hospital Center “Dr. Dragisa Misovic-Dedinje,” University of Belgrade, Serbia
| | - Felipe Simon
- Laboratory of Integrative Physiopathology, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Millennium Nucleus of Ion Channel-Associated Diseases, Universidad de Chile, Santiago, Chile
| | - Vladan Cokic
- Molecular Oncology Group, Institute for Medical Research, University of Belgrade, Belgrade, Serbia
| | - Juan F. Santibanez
- Molecular Oncology Group, Institute for Medical Research, University of Belgrade, Belgrade, Serbia
- Centro Integrativo de Biología y Química Aplicada (CIBQA), Universidad Bernardo O'Higgins, Santiago, Chile
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18
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Tao X, Wang J, Liu B, Cheng P, Mu D, Du H, Niu B. Plasticity and crosstalk of mesenchymal stem cells and macrophages in immunomodulation in sepsis. Front Immunol 2024; 15:1338744. [PMID: 38352879 PMCID: PMC10861706 DOI: 10.3389/fimmu.2024.1338744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 01/10/2024] [Indexed: 02/16/2024] Open
Abstract
Sepsis is a multisystem disease characterized by dysregulation of the host immune response to infection. Immune response kinetics play a crucial role in the pathogenesis and progression of sepsis. Macrophages, which are known for their heterogeneity and plasticity, actively participate in the immune response during sepsis. These cells are influenced by the ever-changing immune microenvironment and exhibit two-sided immune regulation. Recently, the immunomodulatory function of mesenchymal stem cells (MSCs) in sepsis has garnered significant attention. The immune microenvironment can profoundly impact MSCs, prompting them to exhibit dual immunomodulatory functions akin to a double-edged sword. This discovery holds great importance for understanding sepsis progression and devising effective treatment strategies. Importantly, there is a close interrelationship between macrophages and MSCs, characterized by the fact that during sepsis, these two cell types interact and cooperate to regulate inflammatory processes. This review summarizes the plasticity of macrophages and MSCs within the immune microenvironment during sepsis, as well as the intricate crosstalk between them. This remains an important concern for the future use of these cells for immunomodulatory treatments in the clinic.
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Affiliation(s)
- Xingyu Tao
- Department of Critical Care Medicine, Chongqing Key Laboratory of Emergency Medicine, School of Medicine, Chongqing University Central Hospital, Chongqing University, Chongqing, China
| | - Jialian Wang
- Department of Critical Care Medicine, Chongqing Key Laboratory of Emergency Medicine, School of Medicine, Chongqing University Central Hospital, Chongqing University, Chongqing, China
| | - Bin Liu
- Department of Critical Care Medicine, Chongqing Key Laboratory of Emergency Medicine, School of Medicine, Chongqing University Central Hospital, Chongqing University, Chongqing, China
| | - Peifeng Cheng
- Department of Critical Care Medicine, Chongqing Key Laboratory of Emergency Medicine, School of Medicine, Chongqing University Central Hospital, Chongqing University, Chongqing, China
| | - Dan Mu
- Department of Critical Care Medicine, Chongqing Key Laboratory of Emergency Medicine, School of Medicine, Chongqing University Central Hospital, Chongqing University, Chongqing, China
| | - Huimin Du
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bailin Niu
- Department of Critical Care Medicine, Chongqing Key Laboratory of Emergency Medicine, School of Medicine, Chongqing University Central Hospital, Chongqing University, Chongqing, China
- Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
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19
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Chen Z, Yao MW, Ao X, Gong QJ, Yang Y, Liu JX, Lian QZ, Xu X, Zuo LJ. The expression mechanism of programmed cell death 1 ligand 1 and its role in immunomodulatory ability of mesenchymal stem cells. Chin J Traumatol 2024; 27:1-10. [PMID: 38065706 PMCID: PMC10859298 DOI: 10.1016/j.cjtee.2023.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 10/30/2023] [Accepted: 11/13/2023] [Indexed: 02/05/2024] Open
Abstract
Programmed cell death 1 ligand 1 (PD-L1) is an important immunosuppressive molecule, which inhibits the function of T cells and other immune cells by binding to the receptor programmed cell death-1. The PD-L1 expression disorder plays an important role in the occurrence, development, and treatment of sepsis or other inflammatory diseases, and has become an important target for the treatment of these diseases. Mesenchymal stem cells (MSCs) are a kind of pluripotent stem cells with multiple differentiation potential. In recent years, MSCs have been found to have a strong immunosuppressive ability and are used to treat various inflammatory insults caused by hyperimmune diseases. Moreover, PD-L1 is deeply involved in the immunosuppressive events of MSCs and plays an important role in the treatment of various diseases. In this review, we will summarize the main regulatory mechanism of PD-L1 expression, and discuss various biological functions of PD-L1 in the immune regulation of MSCs.
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Affiliation(s)
- Zhuo Chen
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, 400042, China; College of Basic Medical Sciences, Army Medical University, Chongqing, 400038, China
| | - Meng-Wei Yao
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Xiang Ao
- Department of Orthopedics, 953 Hospital of PLA, Shigatse Branch of Xinqiao Hospital, Army Medical University, Shigatse, 857000, Tibet Autonomous Region, China
| | - Qing-Jia Gong
- College of Basic Medical Sciences, Army Medical University, Chongqing, 400038, China
| | - Yi Yang
- Department of Rheumatology and Immunology, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Jin-Xia Liu
- Department of Obstetrics and Gynecology, Chongqing People's Hospital, Chongqing, 401121, China
| | - Qi-Zhou Lian
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Xiang Xu
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, 400042, China.
| | - Ling-Jing Zuo
- Department of Nuclear Medicine, The First People's Hospital of Yunnan province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650034, China.
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20
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Mahajan A, Bhattacharyya S. Immunomodulation by mesenchymal stem cells during osteogenic differentiation: Clinical implications during bone regeneration. Mol Immunol 2023; 164:143-152. [PMID: 38011783 DOI: 10.1016/j.molimm.2023.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 11/08/2023] [Accepted: 11/12/2023] [Indexed: 11/29/2023]
Abstract
Critical bone defects resulting in delayed and non-union are a major concern in the field of orthopedics. Over the past decade, mesenchymal stem cells (MSCs) have become a promising frontier for bone repair and regeneration owing to their high expansion rate and osteogenic differentiation potential ex vivo. MSCs have also long been associated with their ability to modulate immune response in the recipients. These can even skew the immune response towards pro-inflammatory or anti-inflammatory type by sensing their local microenvironment. MSCs adopt anti-inflammatory phenotype at bone injury site and secrete various immunomodulatory factors such as IDO, NO, TGFβ1 and PGE-2 which have redundant role in osteoblast differentiation and bone formation. As such, several studies have also sought to decipher the immunomodulatory effects of osteogenically differentiated MSCs. The present review discusses the immunomodulatory status of MSCs during their osteogenic differentiation and summarizes few mechanisms that cause immunosuppression by osteogenically differentiated MSCs and its implication during bone healing.
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Affiliation(s)
- Aditi Mahajan
- Department of Biophysics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Shalmoli Bhattacharyya
- Department of Biophysics, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
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21
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Simon L, Lapinte V, Morille M. Exploring the role of polymers to overcome ongoing challenges in the field of extracellular vesicles. J Extracell Vesicles 2023; 12:e12386. [PMID: 38050832 PMCID: PMC10696644 DOI: 10.1002/jev2.12386] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 11/03/2023] [Accepted: 11/09/2023] [Indexed: 12/07/2023] Open
Abstract
Extracellular vesicles (EVs) are naturally occurring nanoparticles released from all eucaryotic and procaryotic cells. While their role was formerly largely underestimated, EVs are now clearly established as key mediators of intercellular communication. Therefore, these vesicles constitute an attractive topic of study for both basic and applied research with great potential, for example, as a new class of biomarkers, as cell-free therapeutics or as drug delivery systems. However, the complexity and biological origin of EVs sometimes complicate their identification and therapeutic use. Thus, this rapidly expanding research field requires new methods and tools for the production, enrichment, detection, and therapeutic application of EVs. In this review, we have sought to explain how polymer materials actively contributed to overcome some of the limitations associated to EVs. Indeed, thanks to their infinite diversity of composition and properties, polymers can act through a variety of strategies and at different stages of EVs development. Overall, we would like to emphasize the importance of multidisciplinary research involving polymers to address persistent limitations in the field of EVs.
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Affiliation(s)
| | | | - Marie Morille
- ICGM, Univ Montpellier, CNRS, ENSCMMontpellierFrance
- Institut universitaire de France (IUF)ParisFrance
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22
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Walewska A, Janucik A, Tynecka M, Moniuszko M, Eljaszewicz A. Mesenchymal stem cells under epigenetic control - the role of epigenetic machinery in fate decision and functional properties. Cell Death Dis 2023; 14:720. [PMID: 37932257 PMCID: PMC10628230 DOI: 10.1038/s41419-023-06239-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 10/12/2023] [Accepted: 10/20/2023] [Indexed: 11/08/2023]
Abstract
Mesenchymal stem cells (mesenchymal stromal cells, MSC) are multipotent stem cells that can differentiate into cells of at least three mesodermal lineages, namely adipocytes, osteoblasts, and chondrocytes, and have potent immunomodulatory properties. Epigenetic modifications are critical regulators of gene expression and cellular differentiation of mesenchymal stem cells (MSCs). Epigenetic machinery controls MSC differentiation through direct modifications to DNA and histones. Understanding the role of epigenetic machinery in MSC is crucial for the development of effective cell-based therapies for degenerative and inflammatory diseases. In this review, we summarize the current understanding of the role of epigenetic control of MSC differentiation and immunomodulatory properties.
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Affiliation(s)
- Alicja Walewska
- Centre of Regenerative Medicine, Medical University of Bialystok, ul. Waszyngtona 15B, 15-269, Bialystok, Poland
| | - Adrian Janucik
- Centre of Regenerative Medicine, Medical University of Bialystok, ul. Waszyngtona 15B, 15-269, Bialystok, Poland
| | - Marlena Tynecka
- Centre of Regenerative Medicine, Medical University of Bialystok, ul. Waszyngtona 15B, 15-269, Bialystok, Poland
| | - Marcin Moniuszko
- Centre of Regenerative Medicine, Medical University of Bialystok, ul. Waszyngtona 15B, 15-269, Bialystok, Poland
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, ul. Waszyngtona 13, 15-269, Bialystok, Poland
- Department of Allergology and Internal Medicine, Medical University of Bialystok, ul. M. Sklodowskiej-Curie 24A, 15-276, Bialystok, Poland
| | - Andrzej Eljaszewicz
- Centre of Regenerative Medicine, Medical University of Bialystok, ul. Waszyngtona 15B, 15-269, Bialystok, Poland.
- Tissue and Cell Bank, Medical University of Bialystok Clinical Hospital, ul. Waszyngtona 13, 15-069, Bialystok, Poland.
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23
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Hudakova N, Mudronova D, Marcincakova D, Slovinska L, Majerova P, Maloveska M, Petrouskova P, Humenik F, Cizkova D. The role of primed and non-primed MSC-derived conditioned media in neuroregeneration. Front Mol Neurosci 2023; 16:1241432. [PMID: 38025267 PMCID: PMC10656692 DOI: 10.3389/fnmol.2023.1241432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 10/16/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction With growing significance in nervous system repair, mesenchymal stem cell-derived conditioned media (MSCCM) have been used in cell-free therapies in regenerative medicine. However, the immunomodulatory and neuroregenerative effects of MSCCM and the influence of priming on these effects are still poorly understood. Methods In this study, by various methods focused on cell viability, proliferation, neuron-like differentiation, neurite outgrowth, cell migration and regrowth, we demonstrated that MSCCM derived from adipose tissue (AT-MSCCM) and amniotic membrane (AM-MSCCM) had different effects on SH-SY5Y cells. Results and discussion AT-MSCCM was found to have a higher proliferative capacity and the ability to impact neurite outgrowth during differentiation, while AM-MSCCM showed more pronounced immunomodulatory activity, migration, and re-growth of SH-SY5Y cells in the scratch model. Furthermore, priming of MSC with pro-inflammatory cytokine (IFN-γ) resulted in different proteomic profiles of conditioned media from both sources, which had the highest effect on SH-SY5Y proliferation and neurite outgrowth in terms of the length of neurites (pAT-MSCCM) compared to the control group (DMEM). Altogether, our results highlight the potential of primed and non-primed MSCCM as a therapeutic tool for neurodegenerative diseases, although some differences must be considered.
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Affiliation(s)
- Nikola Hudakova
- Centre of Experimental and Clinical Regenerative Medicine, University of Veterinary Medicine and Pharmacy in Kosice, Košice, Slovakia
| | - Dagmar Mudronova
- Department of Microbiology and Immunology, University of Veterinary Medicine and Pharmacy in Kosice, Košice, Slovakia
| | - Dana Marcincakova
- Department of Pharmacology and Toxicology, University of Veterinary Medicine and Pharmacy in Kosice, Košice, Slovakia
| | - Lucia Slovinska
- Associated Tissue Bank, Faculty of Medicine, Pavol Jozef Safarik University and Luis Pasteur University Hospital, Košice, Slovakia
| | - Petra Majerova
- Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Marcela Maloveska
- Centre of Experimental and Clinical Regenerative Medicine, University of Veterinary Medicine and Pharmacy in Kosice, Košice, Slovakia
| | - Patricia Petrouskova
- Centre of Experimental and Clinical Regenerative Medicine, University of Veterinary Medicine and Pharmacy in Kosice, Košice, Slovakia
| | - Filip Humenik
- Centre of Experimental and Clinical Regenerative Medicine, University of Veterinary Medicine and Pharmacy in Kosice, Košice, Slovakia
| | - Dasa Cizkova
- Centre of Experimental and Clinical Regenerative Medicine, University of Veterinary Medicine and Pharmacy in Kosice, Košice, Slovakia
- Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
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24
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Sionov RV, Ahdut-HaCohen R. A Supportive Role of Mesenchymal Stem Cells on Insulin-Producing Langerhans Islets with a Specific Emphasis on The Secretome. Biomedicines 2023; 11:2558. [PMID: 37761001 PMCID: PMC10527322 DOI: 10.3390/biomedicines11092558] [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: 08/15/2023] [Revised: 09/06/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Type 1 Diabetes (T1D) is a chronic autoimmune disease characterized by a gradual destruction of insulin-producing β-cells in the endocrine pancreas due to innate and specific immune responses, leading to impaired glucose homeostasis. T1D patients usually require regular insulin injections after meals to maintain normal serum glucose levels. In severe cases, pancreas or Langerhans islet transplantation can assist in reaching a sufficient β-mass to normalize glucose homeostasis. The latter procedure is limited because of low donor availability, high islet loss, and immune rejection. There is still a need to develop new technologies to improve islet survival and implantation and to keep the islets functional. Mesenchymal stem cells (MSCs) are multipotent non-hematopoietic progenitor cells with high plasticity that can support human pancreatic islet function both in vitro and in vivo and islet co-transplantation with MSCs is more effective than islet transplantation alone in attenuating diabetes progression. The beneficial effect of MSCs on islet function is due to a combined effect on angiogenesis, suppression of immune responses, and secretion of growth factors essential for islet survival and function. In this review, various aspects of MSCs related to islet function and diabetes are described.
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Affiliation(s)
- Ronit Vogt Sionov
- The Institute of Biomedical and Oral Research (IBOR), Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Ronit Ahdut-HaCohen
- Department of Medical Neurobiology, Institute of Medical Research, Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel;
- Department of Science, The David Yellin Academic College of Education, Jerusalem 9103501, Israel
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25
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Mendiratta M, Mendiratta M, Mohanty S, Sahoo RK, Prakash H. Breaking the graft-versus-host-disease barrier: Mesenchymal stromal/stem cells as precision healers. Int Rev Immunol 2023; 43:95-112. [PMID: 37639700 DOI: 10.1080/08830185.2023.2252007] [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: 03/07/2023] [Revised: 08/08/2023] [Accepted: 08/21/2023] [Indexed: 08/31/2023]
Abstract
Mesenchymal Stromal/Stem Cells (MSCs) are multipotent, non-hematopoietic progenitor cells with a wide range of immune modulation and regenerative potential which qualify them as a potential component of cell-based therapy for various autoimmune/chronic inflammatory ailments. Their immunomodulatory properties include the secretion of immunosuppressive cytokines, the ability to suppress T-cell activation and differentiation, and the induction of regulatory T-cells. Considering this and our interest, we here discuss the significance of MSC for the management of Graft-versus-Host-Disease (GvHD), one of the autoimmune manifestations in human. In pre-clinical models, MSCs have been shown to reduce the severity of GvHD symptoms, including skin and gut damage, which are the most common and debilitating manifestations of this disease. While initial clinical studies of MSCs in GvHD cases were promising, the results were variable in randomized studies. So, further studies are warranted to fully understand their potential benefits, safety profile, and optimal dosing regimens. Owing to these inevitable issues, here we discuss various mechanisms, and how MSCs can be employed in managing GvHD, as a cellular therapeutic approach for this disease.
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Affiliation(s)
- Mohini Mendiratta
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | | | - Sujata Mohanty
- Stem Cell Facility, All India Institute of Medical Sciences, New Delhi, India
| | - Ranjit Kumar Sahoo
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Hridayesh Prakash
- Amity Centre for Translational Research, Amity University, Noida, India
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26
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Rosado-Galindo H, Domenech M. Substrate topographies modulate the secretory activity of human bone marrow mesenchymal stem cells. Stem Cell Res Ther 2023; 14:208. [PMID: 37605275 PMCID: PMC10441765 DOI: 10.1186/s13287-023-03450-0] [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: 09/15/2022] [Accepted: 08/11/2023] [Indexed: 08/23/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) secrete a diversity of factors with broad therapeutic potential, yet current culture methods limit potency outcomes. In this study, we used topographical cues on polystyrene films to investigate their impact on the secretory profile and potency of bone marrow-derived MSCs (hBM-MSCs). hBM-MSCs from four donors were cultured on topographic substrates depicting defined roughness, curvature, grooves and various levels of wettability. METHODS The topographical PS-based array was developed using razor printing, polishing and plasma treatment methods. hBM-MSCs from four donors were purchased from RoosterBio and used in co-culture with peripheral blood mononuclear cells (PBMCs) from Cell Applications Inc. in an immunopotency assay to measure immunosuppressive capacity. Cells were cultured on low serum (2%) for 24-48 h prior to analysis. Image-based analysis was used for cell quantification and morphology assessment. Metabolic activity of BM-hMSCs was measured as the mitochondrial oxygen consumption rate using an extracellular flux analyzer. Conditioned media samples of BM-hMSCs were used to quantify secreted factors, and the data were analyzed using R statistics. Enriched bioprocesses were identify using the Gene Ontology tool enrichGO from the clusterprofiler. One-way and two-way ANOVAs were carried out to identify significant changes between the conditions. Results were deemed statistically significant for combined P < 0.05 for at least three independent experiments. RESULTS Cell viability was not significantly affected in the topographical substrates, and cell elongation was enhanced at least twofold in microgrooves and surfaces with a low contact angle. Increased cell elongation correlated with a metabolic shift from oxidative phosphorylation to a glycolytic state which is indicative of a high-energy state. Differential protein expression and gene ontology analyses identified bioprocesses enriched across donors associated with immune modulation and tissue regeneration. The growth of peripheral blood mononuclear cells (PBMCs) was suppressed in hBM-MSCs co-cultures, confirming enhanced immunosuppressive potency. YAP/TAZ levels were found to be reduced on these topographies confirming a mechanosensing effect on cells and suggesting a potential role in the immunomodulatory function of hMSCs. CONCLUSIONS This work demonstrates the potential of topographical cues as a culture strategy to improve the secretory capacity and enrich for an immunomodulatory phenotype in hBM-MSCs.
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Affiliation(s)
- Heizel Rosado-Galindo
- Bioengineering Program, University of Puerto Rico-Mayagüez, Road 108, KM 1.1., Mayagüez, PR, 00680, USA
| | - Maribella Domenech
- Bioengineering Program, University of Puerto Rico-Mayagüez, Road 108, KM 1.1., Mayagüez, PR, 00680, USA.
- Department of Chemical Engineering, University of Puerto Rico-Mayagüez, Road 108, KM 1.1., Mayagüez, PR, 00680, USA.
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27
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Gao Y, Chi Y, Chen Y, Wang W, Li H, Zheng W, Zhu P, An J, Duan Y, Sun T, Liu X, Xue F, Liu W, Fu R, Han Z, Zhang Y, Yang R, Cheng T, Wei J, Zhang L, Zhang X. Multi-omics analysis of human mesenchymal stem cells shows cell aging that alters immunomodulatory activity through the downregulation of PD-L1. Nat Commun 2023; 14:4373. [PMID: 37474525 PMCID: PMC10359415 DOI: 10.1038/s41467-023-39958-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Accepted: 07/06/2023] [Indexed: 07/22/2023] Open
Abstract
Mesenchymal stem cells (MSCs) possess potent immunomodulatory activity and have been extensively investigated for their therapeutic potential in treating inflammatory disorders. However, the mechanisms underlying the immunosuppressive function of MSCs are not fully understood, hindering the development of standardized MSC-based therapies for clinical use. In this study, we profile the single-cell transcriptomes of MSCs isolated from adipose tissue (AD), bone marrow (BM), placental chorionic membrane (PM), and umbilical cord (UC). Our results demonstrate that MSCs undergo a progressive aging process and that the cellular senescence state influences their immunosuppressive activity by downregulating PD-L1 expression. Through integrated analysis of single-cell transcriptomic and proteomic data, we identify GATA2 as a regulator of MSC senescence and PD-L1 expression. Overall, our findings highlight the roles of cell aging and PD-L1 expression in modulating the immunosuppressive efficacy of MSCs and implicating perinatal MSC therapy for clinical applications in inflammatory disorders.
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Affiliation(s)
- Yuchen Gao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, 300020, China
| | - Ying Chi
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, 300020, China
| | - Yunfei Chen
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, 300020, China
| | - Wentian Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, 300020, China
| | - Huiyuan Li
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, 300020, China
| | - Wenting Zheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, 300020, China
| | - Ping Zhu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, 300020, China
| | - Jinying An
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China
| | - Yanan Duan
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China
| | - Ting Sun
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, 300020, China
| | - Xiaofan Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, 300020, China
| | - Feng Xue
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, 300020, China
| | - Wei Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, 300020, China
| | - Rongfeng Fu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, 300020, China
| | - Zhibo Han
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, 300020, China
| | - Yingchi Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, 300020, China
| | - Renchi Yang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, 300020, China
| | - Tao Cheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, 300020, China
| | - Jun Wei
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, 300020, China.
| | - Lei Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, 300020, China.
- Tianjin Institutes of Health Science, Tianjin, 301600, China.
| | - Xiaomin Zhang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China.
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Yoon J, Lee SK, Park A, Lee J, Jung I, Song KB, Choi EJ, Kim S, Yu J. Exosome from IFN-γ-Primed Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Improved Skin Inflammation and Barrier Function. Int J Mol Sci 2023; 24:11635. [PMID: 37511392 PMCID: PMC10380988 DOI: 10.3390/ijms241411635] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/09/2023] [Accepted: 07/15/2023] [Indexed: 07/30/2023] Open
Abstract
The pathogenesis of atopic dermatitis (AD) is multifactorial, including immune dysregulation and epidermal barrier defects, and a novel therapeutic modality that can simultaneously target multiple pathways is needed. We investigated the therapeutic effects of exosomes (IFN-γ-iExo) secreted from IFN-γ-primed induced pluripotent stem cell-derived mesenchymal stem cells (iMSC) in mice with Aspergillus fumigatus-induced AD. IFN-γ-iExo was epicutaneously administered to mice with AD-like skin lesions. The effects of IFN-γ-iExo treatment were investigated through clinical scores, transepidermal water loss (TEWL) measurements, and histopathology. To elucidate the therapeutic mechanism, we used an in vitro model of human keratinocyte HaCaT cells stimulated with IL-4 and IL-13 and performed extensive bioinformatics analysis of skin mRNA from mice. The expression of indoleamine 2,3-dioxygenase was higher in IFN-γ primed iMSCs than in iMSCs. In human keratinocyte HaCaT cells, treatment with IFN-γ-iExo led to decreases in the mRNA expression of thymic stromal lymphopoietin, IL-25, and IL-33 and increases in keratin 1, keratin 10, desmoglein 1, and ceramide synthase 3. IFN-γ-iExo treatment significantly improved clinical and histological outcomes in AD mice, including clinical scores, TEWL, inflammatory cell infiltration, and epidermal thickness. Bioinformatics analysis of skin mRNA from AD mice showed that IFN-γ-iExo treatment is predominantly involved in skin barrier function and T cell immune response. Treatment with IFN-γ-iExo improved the clinical and histological outcomes of AD mice, which were likely mediated by restoring proper skin barrier function and suppressing T cell-mediated immune response.
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Affiliation(s)
- Jin Yoon
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea; (J.Y.); (A.P.); (J.L.)
| | - Seul Ki Lee
- Brexogen Research Center, Brexogen Inc., Seoul 05855, Republic of Korea;
| | - Arum Park
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea; (J.Y.); (A.P.); (J.L.)
| | - Jiho Lee
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea; (J.Y.); (A.P.); (J.L.)
| | - Inuk Jung
- School of Computer Science and Engineering, Kyungpook National University, Daegu 41566, Republic of Korea;
| | - Kun Baek Song
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea; (K.B.S.); (E.J.C.)
| | - Eom Ji Choi
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea; (K.B.S.); (E.J.C.)
| | - Soo Kim
- Brexogen Research Center, Brexogen Inc., Seoul 05855, Republic of Korea;
| | - Jinho Yu
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea; (K.B.S.); (E.J.C.)
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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: 19] [Impact Index Per Article: 9.5] [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
Abstract
Polycystic ovary syndrome (PCOS) is known as the most common endocrine disorder in women. Previously, we suggested that human mesenchymal stem cells (MSCs) can reverse the PCOS condition by secreting factors. Here, we evaluated the therapeutic capability of MSC-derived extracellular vesicles (EVs), also known as exosomes, in both in vitro and in vivo PCOS models. Exosomes were used to treat androgen-producing H293R cells and injected in a mouse model through intraovarian and intravenous injection into a letrozole (LTZ)-induced PCOS mouse model. We assessed the effects of the exosomes on androgen-producing cells or the PCOS mouse model by analyzing steroidogenic gene expression (quantitative real-time polymerase chain reaction (qRT-PCR)), body weight change, serum hormone levels, and fertility by pup delivery. Our data show the therapeutic effect of MSC-derived EVs for reversing PCOS conditions, including fertility issues. Interestingly, intravenous injection was more effective for serum glucose regulation, and an intraovarian injection was more effective for ovary restoration. Our study suggests that MSC-derived exosomes can be promising biopharmaceutics for treating PCOS conditions as a novel therapeutic option. Despite the fact that we need more validation in human patients, we may evaluate this novel treatment option for PCOS with the following clinical trials.
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Affiliation(s)
- Hang-Soo Park
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | - Esra Cetin
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | - Hiba Siblini
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | - Jin Seok
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | - Hiba Alkelani
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | - Samar Alkhrait
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | - Farzana Liakath Ali
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | | | - Analea Beckman
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | - Ayman Al-Hendy
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
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30
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Yang G, Fan X, Liu Y, Jie P, Mazhar M, Liu Y, Dechsupa N, Wang L. Immunomodulatory Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells. Stem Cell Rev Rep 2023; 19:1214-1231. [PMID: 37058201 PMCID: PMC10103048 DOI: 10.1007/s12015-023-10539-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/29/2023] [Indexed: 04/15/2023]
Abstract
Mesenchymal stem cells (MSCs) are regarded as highly promising cells for allogeneic cell therapy, owing to their multipotent nature and ability to display potent and varied functions in different diseases. The functions of MSCs, including native immunomodulation, high self-renewal characteristic, and secretory and trophic properties, can be employed to improve the immune-modulatory functions in diseases. MSCs impact most immune cells by directly contacting and/or secreting positive microenvironmental factors to influence them. Previous studies have reported that the immunomodulatory role of MSCs is basically dependent on their secretion ability from MSCs. This review discusses the immunomodulatory capabilities of MSCs and the promising strategies to successfully improve the potential utilization of MSCs in clinical research.
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Affiliation(s)
- Guoqiang Yang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- Acupuncture and Rehabilitation Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Xuehui Fan
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention of Cardiovascular Diseases, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany
| | - Yingchun Liu
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Pingping Jie
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Maryam Mazhar
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Yong Liu
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China.
| | - Nathupakorn Dechsupa
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.
| | - Li Wang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China.
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China.
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31
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Gornostaeva AN, Buravkova LB. Changes Induced by Inflammatory-Activated Immune Cell Microenvironment in the Paracrine Profile of MSC. Bull Exp Biol Med 2023; 174:544-548. [PMID: 36894814 DOI: 10.1007/s10517-023-05745-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Indexed: 03/11/2023]
Abstract
We studied the influence of activated innate and adaptive immune cells on the production of growth factors by human adipose tissue multipotent mesenchymal stromal cells (MSC). MSC showed immunosuppressive properties in vitro: decreased activation and proliferation of stimulated immune cells. T-cell interaction with MSC resulted with increased secretion of EGF, PDGF-AB/BB, FGF-2, and VEGF growth factors. Co-culturing with natural killer cells also stimulated TGFα production. The intensity of the effect varied depending on the type of immune cells. Natural killer caused a more significant increase in PDGF-AB/BB and FGF-2 secretion, while VEGF secretion increased stronger after co-culturing with T cells. The obtained data indicate the possibility of increasing reparative potential of MSC under the influence of inflammatory microenvironment.
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Affiliation(s)
- A N Gornostaeva
- Institute of Biomedical Problems, State Research Center, Russian Academy of Sciences, Moscow, Russia.
| | - L B Buravkova
- Institute of Biomedical Problems, State Research Center, Russian Academy of Sciences, Moscow, Russia
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32
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Ju H, Yun H, Kim Y, Nam YJ, Lee S, Lee J, Jeong SM, Heo J, Kwon H, Cho YS, Jeong G, Ryu CM, Shin DM. Activating transcription factor-2 supports the antioxidant capacity and ability of human mesenchymal stem cells to prevent asthmatic airway inflammation. Exp Mol Med 2023; 55:413-425. [PMID: 36765266 PMCID: PMC9981582 DOI: 10.1038/s12276-023-00943-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 11/09/2022] [Accepted: 12/04/2022] [Indexed: 02/12/2023] Open
Abstract
Glutathione (GSH), an abundant nonprotein thiol antioxidant, participates in several biological processes and determines the functionality of stem cells. A detailed understanding of the molecular network mediating GSH dynamics is still lacking. Here, we show that activating transcription factor-2 (ATF2), a cAMP-response element binding protein (CREB), plays a crucial role in maintaining the level and activity of GSH in human mesenchymal stem cells (MSCs) by crosstalking with nuclear factor erythroid-2 like-2 (NRF2), a well-known master regulator of cellular redox homeostasis. Priming with ascorbic acid 2-glucoside (AA2G), a stable vitamin C derivative, increased the expression and activity of ATF2 in MSCs derived from human embryonic stem cells and umbilical cord. Subsequently, activated ATF2 crosstalked with the CREB1-NRF2 pathway to preserve the GSH dynamics of MSCs through the induction of genes involved in GSH synthesis (GCLC and GCLM) and redox cycling (GSR and PRDX1). Accordingly, shRNA-mediated silencing of ATF2 significantly impaired the self-renewal, migratory, proangiogenic, and anti-inflammatory capacities of MSCs, and these defects were rescued by supplementation of the cells with GSH. In addition, silencing ATF2 attenuated the ability of MSCs to alleviate airway inflammatory responses in an ovalbumin-induced mouse model of allergic asthma. Consistently, activation of ATF2 by overexpression or the AA2G-based priming procedure enhanced the core functions of MSCs, improving the in vivo therapeutic efficacy of MSCs for treating asthma. Collectively, our findings suggest that ATF2 is a novel modulator of GSH dynamics that determines the core functionality and therapeutic potency of MSCs used to treat allergic asthma.
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Affiliation(s)
- Hyein Ju
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - HongDuck Yun
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - YongHwan Kim
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Yun Ji Nam
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Seungun Lee
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Jinwon Lee
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Seon Min Jeong
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Jinbeom Heo
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Hyungu Kwon
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - You Sook Cho
- Division of Allergy and Clinical Immunology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Gowun Jeong
- AI Recommendation, T3K, SK Telecom, Seoul, 04539, South Korea
| | - Chae-Min Ryu
- Center for Cell Therapy, Asan Medical Center, Seoul, 05505, South Korea.
| | - Dong-Myung Shin
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea.
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea.
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33
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Park HY, Kim CE, Lee SM, Ahn JM, Yoon EH, Yoo M, Kim JM, Back J, Park DH, Jang WH, Kwon B, Seo SK. Priming Mesenchymal Stem/Stromal Cells with a Combination of a Low Dose of IFN-γ and Bortezomib Results in Potent Suppression of Pathogenic Th17 Immunity Through the IDO1-AHR Axis. Stem Cells 2023; 41:64-76. [PMID: 36242771 DOI: 10.1093/stmcls/sxac075] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 08/26/2022] [Indexed: 02/02/2023]
Abstract
Preconditioning of mesenchymal stem/stromal cells (MSCs) with the inflammatory cytokine IFN-γ enhances not only their immunosuppressive activity but also their expression of HLA and proinflammatory genes. We hypothesized that prevention of the upregulation of inflammatory cytokines and HLA molecules in IFN-γ-primed MSCs would render these cells more immunosuppressive and less immunogenic. In this study, we discovered the following findings supporting this hypothesis: (1) activated human T cells induced the expression of IDO1 in MSCs via IFN-γ secretion and those MSCs in turn inhibited T-cell proliferation in an AHR-dependent fashion; (2) there was no difference in the expression of IDO1 and HLA-DR in MSCs after priming with a low dose (25 IU/mL) versus a high dose (100 IU/mL) of IFN-γ; (3) the transient addition of bortezomib, a proteasome inhibitor, to culture MSCs after IFN-γ priming decreased the expression of HLA-DR, inflammatory cytokine genes and Vcam1 while increasing the expression of IDO1 and the production of L-kynurenine; finally, MSCs primed with a combination of a low dose of IFN-γ and bortezomib were more effective in inhibiting Th17-mediated idiopathic pneumonia syndrome (IPS) and chronic colitis than unprimed MSCs. Our results suggest that bortezomib significantly eliminates the unfavorable effects of IFN-γ priming of MSCs (increased expression of MHC molecules and inflammatory cytokines and cell aggregation genes) and simultaneously increases their immunosuppressive activity by upregulating IDO1. Taken together, our newly established MSC priming method may contribute to MSC-based cell therapy for inflammatory diseases.
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Affiliation(s)
- Ha Young Park
- Department of Microbiology and Immunology, College of Medicine Inje University, Busan, Republic of Korea
| | - Chae Eun Kim
- Department of Microbiology and Immunology, College of Medicine Inje University, Busan, Republic of Korea
| | - Soung-Min Lee
- Department of Microbiology and Immunology, College of Medicine Inje University, Busan, Republic of Korea
| | - Joo Mi Ahn
- Department of Microbiology and Immunology, College of Medicine Inje University, Busan, Republic of Korea
| | - Eun Hye Yoon
- Department of Microbiology and Immunology, College of Medicine Inje University, Busan, Republic of Korea
| | - Minjoo Yoo
- Cell Therapy Research Center, GC Cell, Gyeonggi-do, Republic of Korea
| | - Jung-Mi Kim
- Cell Therapy Research Center, GC Cell, Gyeonggi-do, Republic of Korea
| | - Jiyeon Back
- School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea
| | - Dae Hwi Park
- Cell Therapy Research Center, GC Cell, Gyeonggi-do, Republic of Korea
| | - Won Hee Jang
- Department of Biochemistry, College of Medicine Inje University, Busan, Republic of Korea
| | - Byungsuk Kwon
- School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea
| | - Su-Kil Seo
- Department of Microbiology and Immunology, College of Medicine Inje University, Busan, Republic of Korea
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34
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Akhter W, Nakhle J, Vaillant L, Garcin G, Le Saout C, Simon M, Crozet C, Djouad F, Jorgensen C, Vignais ML, Hernandez J. Transfer of mesenchymal stem cell mitochondria to CD4 + T cells contributes to repress Th1 differentiation by downregulating T-bet expression. Stem Cell Res Ther 2023; 14:12. [PMID: 36694226 PMCID: PMC9875419 DOI: 10.1186/s13287-022-03219-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 12/08/2022] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Mesenchymal stem/stromal cells (MSCs) are multipotent cells with strong tissue repair and immunomodulatory properties. Due to their ability to repress pathogenic immune responses, and in particular T cell responses, they show therapeutic potential for the treatment of autoimmune diseases, organ rejection and graft versus host disease. MSCs have the remarkable ability to export their own mitochondria to neighboring cells in response to injury and inflammation. However, whether mitochondrial transfer occurs and has any role in the repression of CD4+ Th1 responses is unknown. METHODS AND RESULTS In this report we have utilized CD4+ T cells from HNT TCR transgenic mice that develop Th1-like responses upon antigenic stimulation in vitro and in vivo. Allogeneic bone marrow-derived MSCs reduced the diabetogenic potential of HNT CD4+ T cells in vivo in a transgenic mouse model of disease. In co-culture experiments, we have shown that MSCs were able to reduce HNT CD4+ T cell expansion, expression of key effector markers and production of the effector cytokine IFNγ after activation. This was associated with the ability of CD4+ T cells to acquire mitochondria from MSCs as evidenced by FACS and confocal microscopy. Remarkably, transfer of isolated MSC mitochondria to CD4+ T cells resulted in decreased T cell proliferation and IFNγ production. These effects were additive with those of prostaglandin E2 secreted by MSCs. Finally, we demonstrated that both co-culture with MSCs and transfer of isolated MSC mitochondria prevent the upregulation of T-bet, the master Th1 transcription factor, on activated CD4+ T cells. CONCLUSION The present study demonstrates that transfer of MSC mitochondria to activated CD4+ T cells results in the suppression of Th1 responses in part by downregulating T-bet expression. Furthermore, our studies suggest that MSC mitochondrial transfer might represent a general mechanism of MSC-dependent immunosuppression.
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Affiliation(s)
- Waseem Akhter
- grid.121334.60000 0001 2097 0141Institute for Regenerative Medicine and Biotherapy (IRMB), INSERM U1183, Université de Montpellier, 34295 Montpellier, France
| | - Jean Nakhle
- grid.121334.60000 0001 2097 0141Institute for Regenerative Medicine and Biotherapy (IRMB), INSERM U1183, Université de Montpellier, 34295 Montpellier, France ,grid.121334.60000 0001 2097 0141IGF, CNRS, INSERM, Université de Montpellier, Montpellier, France ,grid.121334.60000 0001 2097 0141IGMM, CNRS, Université de Montpellier, Montpellier, France
| | - Loïc Vaillant
- grid.121334.60000 0001 2097 0141Institute for Regenerative Medicine and Biotherapy (IRMB), INSERM U1183, Université de Montpellier, 34295 Montpellier, France
| | - Geneviève Garcin
- grid.121334.60000 0001 2097 0141Institute for Regenerative Medicine and Biotherapy (IRMB), INSERM U1183, Université de Montpellier, 34295 Montpellier, France
| | - Cécile Le Saout
- grid.121334.60000 0001 2097 0141Institute for Regenerative Medicine and Biotherapy (IRMB), INSERM U1183, Université de Montpellier, 34295 Montpellier, France
| | - Matthieu Simon
- grid.121334.60000 0001 2097 0141Institute for Regenerative Medicine and Biotherapy (IRMB), INSERM U1183, Université de Montpellier, 34295 Montpellier, France
| | - Carole Crozet
- grid.121334.60000 0001 2097 0141Institute for Regenerative Medicine and Biotherapy (IRMB), INSERM U1183, Université de Montpellier, 34295 Montpellier, France ,grid.121334.60000 0001 2097 0141INM, INSERM, Université de Montpellier, Montpellier, France
| | - Farida Djouad
- grid.121334.60000 0001 2097 0141Institute for Regenerative Medicine and Biotherapy (IRMB), INSERM U1183, Université de Montpellier, 34295 Montpellier, France
| | - Christian Jorgensen
- grid.121334.60000 0001 2097 0141Institute for Regenerative Medicine and Biotherapy (IRMB), INSERM U1183, Université de Montpellier, 34295 Montpellier, France ,grid.157868.50000 0000 9961 060XCHU Montpellier, Montpellier, France
| | - Marie-Luce Vignais
- grid.121334.60000 0001 2097 0141Institute for Regenerative Medicine and Biotherapy (IRMB), INSERM U1183, Université de Montpellier, 34295 Montpellier, France ,grid.121334.60000 0001 2097 0141IGF, CNRS, INSERM, Université de Montpellier, Montpellier, France
| | - Javier Hernandez
- Institute for Regenerative Medicine and Biotherapy (IRMB), INSERM U1183, Université de Montpellier, 34295, Montpellier, France.
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35
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Sheikholeslami A, Fazaeli H, Kalhor N, Khoshandam M, Eshagh Hoseini SJ, Sheykhhasan M. Use of Mesenchymal Stem Cells in Crohn's Disease and Perianal Fistulas: A Narrative Review. Curr Stem Cell Res Ther 2023; 18:76-92. [PMID: 34530720 DOI: 10.2174/1574888x16666210916145717] [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: 04/01/2021] [Revised: 06/08/2021] [Accepted: 06/15/2021] [Indexed: 11/22/2022]
Abstract
Crohn's Disease (CD), which usually leads to anal fistulas among patients, is the most important inflammatory bowel disease that causes morbidity in many people around the world. This review article proposes using MSCs as a hopeful therapeutic strategy for CD and anal fistula treatment in both preclinical and clinical conditions. Finally, darvadstrocel, a cell-based medication to treat complex anal fistulas in adults, as the only European Medicines Agency (EMA)-approved product for the treatment of anal fistulas in CD is addressed. Although several common therapies, such as surgery and anti-tumor necrosis factor-alpha (TNF-α) drugs as well as a combination of these methods is used to improve this disease, however, due to the low effectiveness of these treatments, the use of new strategies with higher efficiency is still recommended. Cell therapy is among the new emerging therapeutic strategies that have attracted great attention from clinicians due to its unique capabilities. One of the most widely used cell sources administrated in cell therapy is mesenchymal stem cell (MSC). This review article will discuss preclinical and clinical studies about MSCs as a potent and promising therapeutic option in the treatment of CD and anal fistula.
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Affiliation(s)
- Azar Sheikholeslami
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | - Hoda Fazaeli
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom,Iran
| | - Naser Kalhor
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | - Mohadeseh Khoshandam
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | | | - Mohsen Sheykhhasan
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
- Department of Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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36
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Park SJ, Kim DS, Choi M, Han KH, Han JS, Yoo KH, Moon KS. Preclinical Evaluation of interferon-gamma primed human Wharton's jelly-derived mesenchymal stem cells. Hum Exp Toxicol 2023; 42:9603271231171650. [PMID: 37092667 DOI: 10.1177/09603271231171650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
The potential of human mesenchymal stem cells (MSCs) for cell therapy has been investigated in numerous immune-mediated conditions; MSCs are considered one of the most promising cellular therapeutics to treat intractable diseases. Recently, approaches to prime MSCs have been investigated, thereby generating cellular products with enhanced potential for a variety of clinical applications. Interferon-gamma (IFN-γ) priming is a current approach used to increase the therapeutic efficacy of MSCs. In this study, we determined the systemic toxicity, tumorigenicity and biodistribution of IFN-γ-primed Wharton's jelly-derived (WJ)-MSCs in male and female BALB/c-nu/nu mice. There were no deaths or pathologic lesions in the mice treated with 5 × 106 cells/kg IFN-γ-primed MSCs in the repeated dose study. In the tumorigenicity study, one of the subcutaneously treated mice showed bronchioloalveolar adenoma in the lung but tested negative for human-specific anti-mitochondrial antibody, suggesting the spontaneous murine origin of the adenoma. A biodistribution study using real-time quantitative polymerase chain reaction demonstrated the systemic IFN-γ-primed MSC clearance by day 28. Based on the toxicity, biodistribution, and tumorigenicity studies, we concluded that IFN-γ-primed MSCs at 5 × 106 cells/kg do not induce tumor formation and adverse changes.
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Affiliation(s)
- Sang-Jin Park
- Korea Institute of Toxicology, Daejeon, Republic of Korea
| | - Dae Seong Kim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Seoul, Republic of Korea
- Division of Clinical Development, CELLnLIFE Research Center, CELLnLIFE Inc., Seoul, Republic of Korea
| | - Myeongjin Choi
- Korea Institute of Toxicology, Daejeon, Republic of Korea
| | - Kang-Hyun Han
- Korea Institute of Toxicology, Daejeon, Republic of Korea
| | - Ji-Seok Han
- Korea Institute of Toxicology, Daejeon, Republic of Korea
| | - Keon Hee Yoo
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Seoul, Republic of Korea
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37
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Kim J, Lee SK, Jung M, Jeong SY, You H, Won JY, Han SD, Cho HJ, Park S, Park J, Kim TM, Kim S. Extracellular vesicles from IFN-γ-primed mesenchymal stem cells repress atopic dermatitis in mice. J Nanobiotechnology 2022; 20:526. [PMID: 36496385 PMCID: PMC9741801 DOI: 10.1186/s12951-022-01728-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/28/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by immune dysregulation, pruritus, and abnormal epidermal barrier function. Compared with conventional mesenchymal stem cell (MSC), induced pluripotent stem cell (iPSC)-derived mesenchymal stem cell (iMSC) is recognized as a unique source for producing extracellular vesicles (EVs) because it can be obtained in a scalable manner with an enhanced homogeneity. Stimulation of iMSCs with inflammatory cytokines can improve the immune-regulatory, anti-inflammatory, and tissue-repairing potential of iMSC-derived EVs. RESULTS Proteome analysis showed that IFN-γ-iMSC-EVs are enriched with protein sets that are involved in regulating interferon responses and inflammatory pathways. In AD mice, expression of interleukin receptors for Th2 cytokines (IL-4Rα/13Rα1/31Rα) and activation of their corresponding intracellular signaling molecules was reduced. IFN-γ-iMSC-EVs decreased itching, which was supported by reduced inflammatory cell infiltration and mast cells in AD mouse skin; reduced IgE receptor expression and thymic stromal lymphopoietin and NF-kB activation; and recovered impaired skin barrier, as evidenced by upregulation of key genes of epidermal differentiation and lipid synthesis. CONCLUSIONS IFN-γ-iMSC-EVs inhibit Th2-induced immune responses, suppress inflammation, and facilitate skin barrier restoration, contributing to AD improvement.
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Affiliation(s)
- Jimin Kim
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Seul Ki Lee
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Minyoung Jung
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Seon-Yeong Jeong
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Haedeun You
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Ji-Yeon Won
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Sang-Deok Han
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Hye Jin Cho
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Somi Park
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Joonghoon Park
- grid.31501.360000 0004 0470 5905Graduate School of International Agricultural Technology, Seoul National University, Pyeongchang, Gangwon-do 25354 South Korea ,grid.31501.360000 0004 0470 5905Institutes of Green-Bio Science and Technology, Seoul National University, Pyeongchang, Gangwon-do 25354 South Korea
| | - Tae Min Kim
- grid.31501.360000 0004 0470 5905Graduate School of International Agricultural Technology, Seoul National University, Pyeongchang, Gangwon-do 25354 South Korea ,grid.31501.360000 0004 0470 5905Institutes of Green-Bio Science and Technology, Seoul National University, Pyeongchang, Gangwon-do 25354 South Korea
| | - Soo Kim
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
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Zheng L, Zhang L, Guo Y, Xu X, Liu Z, Yan Z, Fu R. The immunological role of mesenchymal stromal cells in patients with myelodysplastic syndrome. Front Immunol 2022; 13:1078421. [PMID: 36569863 PMCID: PMC9767949 DOI: 10.3389/fimmu.2022.1078421] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 11/24/2022] [Indexed: 12/13/2022] Open
Abstract
Myelodysplastic syndrome (MDS) is a common hematological malignant disease, characterized by malignant hematopoietic stem cell proliferation in the bone marrow (BM); clinically, it mainly manifests clinically mainly by as pathological hematopoiesis, hemocytopenia, and high-risk transformation to acute leukemia. Several studies have shown that the BM microenvironment plays a critical role in the progression of MDS. In this study, we specifically evaluated mesenchymal stromal cells (MSCs) that exert immunomodulatory effects in the BM microenvironment. This immunomodulatory effect occurs through direct cell-cell contact and the secretion of soluble cytokines or micro vesicles. Several researchers have compared MSCs derived from healthy donors to low-risk MDS-associated bone mesenchymal stem cells (BM-MSCs) and have found no significant abnormalities in the MDS-MSC phenotype; however, these cells have been observed to exhibit altered function, including a decline in osteoblastic function. This altered function may promote MDS progression. In patients with MDS, especially high-risk patients, MSCs in the BM microenvironment regulate immune cell function, such as that of T cells, B cells, natural killer cells, dendritic cells, neutrophils, myeloid-derived suppressor cells (MDSCs), macrophages, and Treg cells, thereby enabling MDS-associated malignant cells to evade immune cell surveillance. Alterations in MDS-MSC function include genomic instability, microRNA production, histone modification, DNA methylation, and abnormal signal transduction and cytokine secretion.
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Affiliation(s)
- Likun Zheng
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China,Department of Hematology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei, China
| | - Lei Zhang
- Department of Orthopedics, Kailuan General Hospital, Tangshan, Hebei, China
| | - Yixuan Guo
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xintong Xu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhaoyun Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhenyu Yan
- Department of Hematology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei, China
| | - Rong Fu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China,*Correspondence: Rong Fu,
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hUC-MSCs Attenuate Acute Graft-Versus-Host Disease through Chi3l1 Repression of Th17 Differentiation. Stem Cells Int 2022; 2022:1052166. [PMID: 36277038 PMCID: PMC9582900 DOI: 10.1155/2022/1052166] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 06/04/2022] [Indexed: 11/23/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have already demonstrated definitive evidence of their clinical benefits in acute graft-versus-host disease (aGvHD) and other inflammatory diseases. However, the comprehensive mechanism of MSCs' immunomodulation properties has not been elucidated. To reveal their potential immunosuppressive molecules, we used RNA sequencing to analyze gene expression in different tissue-derived MSCs, including human bone marrow, umbilical cord, amniotic membrane, and placenta, and found that chitinase-3-like protein 1 (Chi3l1) was highly expressed in human umbilical cord mesenchymal stem cells (hUC-MSCs). We found that hUC-MSCs treated with interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) exhibited increased expression of Chi3l1 and concurrently repressed T-helper 17 cell (Th17) differentiation through inhibition of signal transducer and activator of transcription 3 (STAT3) activation. Furthermore, Chi3l1 knockdown hUC-MSCs exhibited impaired therapeutic efficacy in aGvHD mice with an increased inflammatory response by promoting Th17 cell differentiation, including an increase in IL-17A in the spleen, intestine, and serum. Collectively, these results reveal a new immunosuppressive molecule, Chi3l1, in hUC-MSCs in the treatment of aGvHD that regulates Th17 differentiation and inhibits STAT3 activation. These novel insights into the mechanisms of hUC-MSC immunoregulation may lead to the consistent production of hUC-MSCs with strong immunosuppressive functions and thus improved clinical utility.
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Small extracellular vesicles of hypoxic endothelial cells regulate the therapeutic potential of adipose-derived mesenchymal stem cells via miR-486-5p/PTEN in a limb ischemia model. J Nanobiotechnology 2022; 20:422. [PMID: 36153544 PMCID: PMC9509557 DOI: 10.1186/s12951-022-01632-1] [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: 06/23/2022] [Accepted: 09/12/2022] [Indexed: 11/29/2022] Open
Abstract
Background Patients with critical limb ischemia (CLI) are at great risk of major amputation and cardiovascular events. Adipose-derived mesenchymal stem cell (ADSC) therapy is a promising therapeutic strategy for CLI, but the poor engraftment and insufficient angiogenic ability of ADSCs limit their regenerative potential. Herein, we explored the potential of human umbilical vein endothelial cells (HUVECs)-derived small extracellular vesicles (sEVs) for enhancing the therapeutic efficacy of ADSCs in CLI. Results sEVs derived from hypoxic HUVECs enhanced the resistance of ADSCs to reactive oxygen species (ROS) and further improved the proangiogenic ability of ADSCs in vitro. We found that the hypoxic environment altered the composition of sEVs from HUVECs and that hypoxia increased the level of miR-486-5p in sEVs. Compared to normoxic sEVs (nsEVs), hypoxic sEVs (hsEVs) of HUVECs significantly downregulated the phosphatase and tensin homolog (PTEN) via direct targeting of miR-486-5p, therefore activating the AKT/MTOR/HIF-1α pathway and influencing the survival and pro-angiogenesis ability of ADSCs. In a hindlimb ischemia model, we discovered that hsEVs-primed ADSCs exhibited superior cell engraftment, and resulted in better angiogenesis and tissue repair. Conclusion hsEVs could be used as a therapeutic booster to improve the curative potential of ADSCs in a limb ischemia model. This finding offers new insight for CLI treatment. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s12951-022-01632-1.
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Singhatanadgit W, Kitpakornsanti S, Toso M, Pavasant P. IFNγ-primed periodontal ligament cells regulate T-cell responses via IFNγ-inducible mediators and ICAM-1-mediated direct cell contact. ROYAL SOCIETY OPEN SCIENCE 2022; 9:220056. [PMID: 35911203 PMCID: PMC9326268 DOI: 10.1098/rsos.220056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 07/04/2022] [Indexed: 06/15/2023]
Abstract
Periodontal ligament (PDL) cells help maintain tissue homeostasis by balancing PDL tissue inflammation and regeneration. However, the mechanisms by which interferon γ (IFNγ) modulate this process are not yet fully understood. The present study aimed to examine the effect of primed and non-primed PDL cells with IFNγ on the viability and differentiation of T lymphocytes and its functional consequences. The results showed that IFNγ-primed PDL cells possessed enhanced immunosuppression by suppressing T-lymphocyte viability and directing T-lymphocyte differentiation towards a higher T helper (Th) Th2/Th1 ratio. Suppression of T-cell viability was mainly mediated by IFNγ-inducible secreted mediators, which was prevented in the presence of direct cell contact, probably by intercellular adhesion molecule-1 (ICAM-1)-induced PI3 K-mediated transforming growth factor β1 expression in PDL cells. By contrast, ICAM-1 activation augmented IFNγ-induced IFNγ and interleukin-6 expression in PDL cells, which in turn modulated T-cell differentiation. The resulting interaction between these two cell types activated macrophage and suppressed osteoclast differentiation. In conclusion, the results have shown, for the first time to our knowledge, that primed and non-primed PDL cells with IFNγ differentially control T-cell responses via IFNγ-inducible mediators and ICAM-1-mediated direct cell contact, suggesting the role of PDL cells in shifting an inflammatory phase towards a regenerative phase.
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Affiliation(s)
- Weerachai Singhatanadgit
- Oral and Maxillofacial Surgery Unit, Faculty of Dentistry, Thammasat University, Rangsit Campus, Pathumthani, Thailand
- Research Unit in Mineralized Tissue Reconstruction, Thammasat University, Rangsit Campus, Pathumthani, Thailand
| | - Setthawut Kitpakornsanti
- Research Unit in Mineralized Tissue Reconstruction, Thammasat University, Rangsit Campus, Pathumthani, Thailand
| | - Montree Toso
- Research Unit in Mineralized Tissue Reconstruction, Thammasat University, Rangsit Campus, Pathumthani, Thailand
- Stem Cell for Life Research Center, Greater Pharma Manufacturing Co. Ltd, Nakhon Pathom, Thailand
| | - Prasit Pavasant
- Center of Excellence in Regenerative Dentistry, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
- Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
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Nozari P, Mokhtari P, Nemati M, Zainodini N, Taghipour Z, Asadi F, Ayoobi F, Jafarzadeh A. Investigation of the effect of IFN-γ/TNF-α-treated mesenchymal stem cells on Th9- and Treg cell-related parameters in a mouse model of ovalbumin-induced allergic asthma. Immunopharmacol Immunotoxicol 2022; 44:773-785. [PMID: 35620857 DOI: 10.1080/08923973.2022.2082977] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Th9- and regulatory T (Treg) cells exert pro- and anti-allergic activity, respectively. Mesenchymal stem cell (MSC)-related immunomodulatory impacts can be enhanced by inflammatory cytokines. Here, the modulatory effects of IFN-γ/TNF-α-induced MSCs on Th9- and Treg cell-related parameters were investigated using an asthma model. METHODS Allergic asthma was induced in BALB/c mice using sensitized and challenging with ovalbumin (OVA). The asthmatic groups were treated intraperitoneally with PBS, MSCs, IFN-γ-induced MSCs, TNF-α-induced MSCs and "IFN-γ + TNF-α"-induced MSCs before the challenge phase. The mice were sacrificed 24 hours after challenge. The serum IL-9 and IL-35 levels, as well as gene expression of IL-9, PU.1, IL-35-EBI3 and FOXP3 in the lung tissues were assessed using ELISA and real time-PCR, respectively. RESULTS The differences of Th9 and Treg-related parameters were not significant between untreated asthmatic mice and those treated with non-induced MSCs. In comparison with untreated asthmatic group, treatment with IFN-γ-induced MSCs significantly reduced serum IL-9 levels, reduced lung expression of IL-9 and PU.1, while increasing serum IL-35 levels as well as lung expression of FOXP3; treatment with TNF-α-induced MSCs significantly reduced serum IL-9 levels as well as lung expression of IL-9, and treatment with "IFN-γ + TNF-α"-induced MSCs significantly modulated all investigated Th9 and Treg-related parameters. In comparison to mice treated with non-induced MSCs, serum IL-9 levels were remarkably decreased in mice treated with IFN-γ-induced and "IFN-γ + TNF-α"-induced MSCs. CONCLUSIONS IFN-γ-and "IFN-γ + TNF-α" treated MSCs exerted almost comparable impacts, but were more efficient than TNF-α-exposed MSCs. Thus, IFN-γ alone can be sufficient to promote immunomodulatory effects of MSCs.
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Affiliation(s)
- Parvin Nozari
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Pejman Mokhtari
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Maryam Nemati
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.,Department of Haematology and Laboratory Sciences, School of Para-Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Nahid Zainodini
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Zahra Taghipour
- Department of Histology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Fatemeh Asadi
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Fatemeh Ayoobi
- Non-Communicable Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Abdollah Jafarzadeh
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.,Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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Gilazieva Z, Ponomarev A, Rizvanov A, Solovyeva V. The Dual Role of Mesenchymal Stromal Cells and Their Extracellular Vesicles in Carcinogenesis. BIOLOGY 2022; 11:biology11060813. [PMID: 35741334 PMCID: PMC9220333 DOI: 10.3390/biology11060813] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 02/07/2023]
Abstract
Simple Summary Extracellular vesicles (EVs) are membrane structures that play the role of intermediaries between tumor cells and the tumor microenvironment (TME) because they have the ability to transport lipids, transcription factors, mRNA, and proteins. Mesenchymal stem cells (MSCs) are a major component of the TME and may have different effects on tumor progression using EVs. This review includes information about various studies which have reported that EVs from MSCs can have either antitumor or pro-tumor effects, depending on both the tumor type and developmental stage. It provides an overview of the published data on EV MSCs and their effect on tumor cells. In addition, the use of EV MSCs for the development of new methods for treating oncological diseases is described. Abstract Mesenchymal stem cells (MSCs) are a major component of the tumor microenvironment (TME) and play an important role in tumor progression. MSCs remodel the extracellular matrix, participate in the epithelial–mesenchymal transition, promote the spread of metastases, and inhibit antitumor immune responses in the TME; however, there are also data pertaining to the antitumor effects of MSCs. MSCs activate the cell death mechanism by modulating the expression of proteins involved in the regulation of the cell cycle, angiogenesis receptors, and proapoptotic proteins. One of the main ways in which MSCs and TME interact is through the production of extracellular vesicles (EVs) by cells. Currently, data on the effects of both MSCs and their EVs on tumor cells are rather contradictory. Various studies have reported that EVs from MSCs can have either antitumor or pro-tumor effects, depending on both the tumor type and developmental stage. In this review, we discuss published data on EV MSCs and their effect on tumor cells. The molecular composition of vesicles obtained from MSCs is also presented in the review. In addition, the use of EV MSCs for the development of new methods for treating oncological diseases is described.
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Srinivasan A, Sathiyanathan P, Yin L, Liu TM, Lam A, Ravikumar M, Smith RAA, Loh HP, Zhang Y, Ling L, Ng SK, Yang YS, Lezhava A, Hui J, Oh S, Cool SM. Strategies to enhance immunomodulatory properties and reduce heterogeneity in mesenchymal stromal cells during ex vivo expansion. Cytotherapy 2022; 24:456-472. [PMID: 35227601 DOI: 10.1016/j.jcyt.2021.11.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 10/24/2021] [Accepted: 11/08/2021] [Indexed: 02/06/2023]
Abstract
Therapies using mesenchymal stromal cells (MSCs) to treat immune and inflammatory conditions are now at an exciting stage of development, with many MSC-based products progressing to phase II and III clinical trials. However, a major bottleneck in the clinical translation of allogeneic MSC therapies is the variable immunomodulatory properties of MSC products due to differences in their tissue source, donor heterogeneity and processes involved in manufacturing and banking. This variable functionality of MSC products likely contributes to the substantial inconsistency observed in the clinical outcomes of phase III trials of MSC therapies; several trials have failed to reach the primary efficacy endpoint. In this review, we discuss various strategies to consistently maintain or enhance the immunomodulatory potency of MSCs during ex vivo expansion, which will enable the manufacture of allogeneic MSC banks that have high potency and low variability. Biophysical and biochemical priming strategies, the use of culture additives such as heparan sulfates, and genetic modification can substantially enhance the immunomodulatory properties of MSCs during in vitro expansion. Furthermore, robust donor screening, the use of biomarkers to select for potent MSC subpopulations, and rigorous quality testing to improve the release criteria for MSC banks have the potential to reduce batch-to-batch heterogeneity and enhance the clinical efficacy of the final MSC product. Machine learning approaches to develop predictive models of individual patient response can enable personalized therapies and potentially establish correlations between in vitro potency measurements and clinical outcomes in human trials.
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Affiliation(s)
- Akshaya Srinivasan
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | - Lu Yin
- Bioprocessing Technology Institute, A*STAR, Singapore
| | - Tong Ming Liu
- Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Alan Lam
- Bioprocessing Technology Institute, A*STAR, Singapore
| | - Maanasa Ravikumar
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Molecular and Cell Biology, A*STAR, Singapore
| | | | - Han Ping Loh
- Bioprocessing Technology Institute, A*STAR, Singapore
| | - Ying Zhang
- Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Ling Ling
- Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Say Kong Ng
- Bioprocessing Technology Institute, A*STAR, Singapore
| | | | - Alexander Lezhava
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
| | - James Hui
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Steve Oh
- Bioprocessing Technology Institute, A*STAR, Singapore.
| | - Simon M Cool
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Molecular and Cell Biology, A*STAR, Singapore.
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Bergmann CA, Beltran S, Vega-Letter AM, Murgas P, Hernandez MF, Gomez L, Labrador L, Cortés BI, Poblete C, Quijada C, Carrion F, Woehlbier U, Manque PA. The Autophagy Protein Pacer Positively Regulates the Therapeutic Potential of Mesenchymal Stem Cells in a Mouse Model of DSS-Induced Colitis. Cells 2022; 11:cells11091503. [PMID: 35563809 PMCID: PMC9101276 DOI: 10.3390/cells11091503] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 04/14/2022] [Accepted: 04/21/2022] [Indexed: 02/01/2023] Open
Abstract
Mesenchymal stem cells (MSC) have emerged as a promising tool to treat inflammatory diseases, such as inflammatory bowel disease (IBD), due to their immunoregulatory properties. Frequently, IBD is modeled in mice by using dextran sulfate sodium (DSS)-induced colitis. Recently, the modulation of autophagy in MSC has been suggested as a novel strategy to improve MSC-based immunotherapy. Hence, we investigated a possible role of Pacer, a novel autophagy enhancer, in regulating the immunosuppressive function of MSC in the context of DSS-induced colitis. We found that Pacer is upregulated upon stimulation with the pro-inflammatory cytokine TNFα, the main cytokine released in the inflammatory environment of IBD. By modulating Pacer expression in MSC, we found that Pacer plays an important role in regulating the autophagy pathway in this cell type in response to TNFα stimulation, as well as in regulating the immunosuppressive ability of MSC toward T-cell proliferation. Furthermore, increased expression of Pacer in MSC enhanced their ability to ameliorate the symptoms of DSS-induced colitis in mice. Our results support previous findings that autophagy regulates the therapeutic potential of MSC and suggest that the augmentation of autophagic capacity in MSC by increasing Pacer levels may have therapeutic implications for IBD.
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Affiliation(s)
- Cristian A. Bergmann
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
| | - Sebastian Beltran
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
- Escuela de Tecnología Médica, Universidad Mayor, Santiago 7500000, Chile
| | - Ana Maria Vega-Letter
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago 7620001, Chile;
- Centro de Investigación e Innovación Biomédica, Universidad de los Andes, Santiago 7620157, Chile
| | - Paola Murgas
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
- Escuela de Tecnología Médica, Universidad Mayor, Santiago 7500000, Chile
- Escuela de Biotecnología, Facultad de Ciencias, Universidad Mayor, Santiago 7500000, Chile
| | - Maria Fernanda Hernandez
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
| | - Laura Gomez
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
| | - Luis Labrador
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
| | - Bastián I. Cortés
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
| | - Cristian Poblete
- Laboratorio de Morfofisiopatología y Citodiagnóstico, Escuela de Tecnología Médica, Facultad de Ciencias, Universidad Mayor, Santiago 7500000, Chile;
| | - Cristobal Quijada
- Servicio de Anatomía Patológica, Hospital Clínico de la Universidad de Chile, Santiago 8380456, Chile;
| | - Flavio Carrion
- Programa de Inmunología Translacional, Facultad de Medicina, Universidad del Desarrollo Clínica Alemana, Santiago 7590943, Chile;
- Departamento de Investigación, Postgrado y Educación Contínua (DIPEC), Facultad de Ciencias de la Salud, Universidad del Alba, Santiago 8320000, Chile
| | - Ute Woehlbier
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
- Escuela de Biotecnología, Facultad de Ciencias, Universidad Mayor, Santiago 7500000, Chile
- Correspondence: (U.W.); (P.A.M.)
| | - Patricio A. Manque
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
- Center for Genomics and Bioinformatics (CGB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile
- Centro de Oncologia de Precision (COP), Escuela de Medicina, Universidad Mayor, Santiago 7500000, Chile
- Correspondence: (U.W.); (P.A.M.)
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Bekić M, Radanović M, Đokić J, Tomić S, Eraković M, Radojević D, Duka M, Marković D, Marković M, Ismaili B, Bokonjić D, Čolić M. Mesenchymal Stromal Cells from Healthy and Inflamed Human Gingiva Respond Differently to Porphyromonas gingivalis. Int J Mol Sci 2022; 23:ijms23073510. [PMID: 35408871 PMCID: PMC8998418 DOI: 10.3390/ijms23073510] [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: 01/14/2022] [Revised: 03/02/2022] [Accepted: 03/08/2022] [Indexed: 01/09/2023] Open
Abstract
Gingiva-Derived Mesenchymal Stromal Cells (GMSCs) have been shown to play an important role in periodontitis. However, how P. gingivalis, one of the key etiological agents of the disease, affects healthy (H)- and periodontitis (P)-GMSCs is unknown. To address this problem, we established 10 H-GMSC and 12 P-GMSC lines. No significant differences in morphology, differentiation into chondroblasts and adipocytes, expression of characteristic MSCS markers, including pericyte antigens NG2 and PDGFR, were observed between H- and P-GMSC lines. However, proliferation, cell size and osteogenic potential were higher in P-GMSCs, in contrast to their lower ability to suppress mononuclear cell proliferation. P. gingivalis up-regulated the mRNA expression of IL-6, IL-8, MCP-1, GRO-α, RANTES, TLR-2, HIF-1α, OPG, MMP-3, SDF-1, HGF and IP-10 in P-GMSCs, whereas only IL-6, MCP-1 and GRO-α were up-regulated in H-GMSCs. The expression of MCP-1, RANTES, IP-10 and HGF was significantly higher in P-GMSCs compared to H-GMSCs, but IDO1 was lower. No significant changes in the expression of TLR-3, TLR-4, TGF-β, LAP, IGFBP4 and TIMP-1 were observed in both types of GMSCs. In conclusion, our results suggest that P-GMSCs retain their pro-inflammatory properties in culture, exhibit lower immunosuppressive potential than their healthy counterparts, and impaired regeneration-associated gene induction in culture. All these functions are potentiated significantly by P. gingivalis treatment.
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Affiliation(s)
- Marina Bekić
- Institute for the Application of Nuclear Energy, University of Belgrade, 11060 Belgrade, Serbia; (M.B.); (S.T.); (M.M.)
| | - Marina Radanović
- Medical Faculty Foča, University of East Sarajevo, 73300 Foča, Bosnia and Herzegovina; (M.R.); (D.B.)
| | - Jelena Đokić
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11042 Belgrade, Serbia; (J.Đ.); (D.R.)
| | - Sergej Tomić
- Institute for the Application of Nuclear Energy, University of Belgrade, 11060 Belgrade, Serbia; (M.B.); (S.T.); (M.M.)
| | - Mile Eraković
- Clinic for Stomatology, Medical Faculty of the Military Medical Academy, University of Defense, 11154 Belgrade, Serbia; (M.E.); (M.D.)
| | - Dušan Radojević
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11042 Belgrade, Serbia; (J.Đ.); (D.R.)
| | - Miloš Duka
- Clinic for Stomatology, Medical Faculty of the Military Medical Academy, University of Defense, 11154 Belgrade, Serbia; (M.E.); (M.D.)
| | - Dejan Marković
- Faculty of Dental Medicine, University of Belgrade, 11118 Belgrade, Serbia;
| | - Milan Marković
- Institute for the Application of Nuclear Energy, University of Belgrade, 11060 Belgrade, Serbia; (M.B.); (S.T.); (M.M.)
| | - Bashkim Ismaili
- Faculty of Dental Medicine, International Balkan University, 1000 Skopje, North Macedonia;
| | - Dejan Bokonjić
- Medical Faculty Foča, University of East Sarajevo, 73300 Foča, Bosnia and Herzegovina; (M.R.); (D.B.)
| | - Miodrag Čolić
- Institute for the Application of Nuclear Energy, University of Belgrade, 11060 Belgrade, Serbia; (M.B.); (S.T.); (M.M.)
- Medical Faculty Foča, University of East Sarajevo, 73300 Foča, Bosnia and Herzegovina; (M.R.); (D.B.)
- Correspondence: ; Tel.: +381-11-2619525
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Wu R, Fan X, Wang Y, Shen M, Zheng Y, Zhao S, Yang L. Mesenchymal Stem Cell-Derived Extracellular Vesicles in Liver Immunity and Therapy. Front Immunol 2022; 13:833878. [PMID: 35309311 PMCID: PMC8930843 DOI: 10.3389/fimmu.2022.833878] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 02/15/2022] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs), as the most common cell source for stem cell therapy, play an important role in the modulation of innate and adaptive immune responses and have been widely used in clinical trials to treat autoimmune and inflammatory diseases. Recent experimental and clinical studies have shown that MSC-derived extracellular vesicles (MSC-EVs) can inhibit the activation and proliferation of a variety of proinflammatory cells, such as Th1, Th17 and M1 macrophages, reducing the secretion of proinflammatory cytokines, while promoting the proliferation of anti-inflammatory cells, such as M2 macrophages and Tregs, and increasing the secretion of anti-inflammatory cytokines, thus playing a role in immune regulation and exhibiting immunomodulatory functions. Besides MSC-EVs are more convenient and less immunogenic than MSCs. There is growing interest in the role of MSC-EVs in liver diseases owing to the intrinsic liver tropism of MSC-EVs. In this review, we focus on the immunomodulatory effects of MSC-EVs and summarize the pivotal roles of MSC-EVs as a cell-free therapy in liver diseases, including NAFLD, AIH, acute liver failure, liver fibrosis and hepatic ischemia–reperfusion injury. Moreover, we provide a concise overview of the potential use and limits of MSC-EVs in clinical application.
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Mirfakhraie R, Ardakani MT, Hajifathali A, Karami S, Moshari MR, Hassani M, Firouz SM, Roshandel E. Highlighting the interaction between immunomodulatory properties of mesenchymal stem cells and signaling pathways contribute to Graft Versus Host Disease management. Transpl Immunol 2022; 71:101524. [PMID: 34990789 DOI: 10.1016/j.trim.2021.101524] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 12/29/2021] [Accepted: 12/29/2021] [Indexed: 12/11/2022]
Abstract
Background Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) has been increasingly used as a therapeutic approach for hematological malignancies. Several potential strategies have been developed for treating or preventing allo-HSCT complications, specifically graft-versus-host disease (GVHD). GVHD could significantly affect the morbidity and mortality of patients after allo-HSCT. Curative treatment and prophylaxis regimens for GVHD could reduce GVHD incidence and improve survival rate. Among these therapeutic strategies, mesenchymal stem cell (MSCs) mediated immunomodulation has been explored widely in clinical trials. MSCs immunomodulation ability in GVHD correlates with the interactions of MSCs with innate and adaptive immune cells. However, signaling pathways responsible for MSCs' impact on GVHD regulation, like JAK/STAT, NOTCH, MAPK/ERK, and NFκβ signaling pathways, have not been clearly described yet. This review aims to illuminate the effect of MSCs-mediated immunomodulation in GVHD management after allo-HSCT representing the role of MSCs therapy on signaling pathways in GVHD. Conclusion MSCs could potentially modulate immune responses, prevent GVHD, and improve survival after allo-HSCT. Previous studies have investigated different signaling pathways' contributions to MSCs immunoregulatory ability. Accordingly, targeting signaling pathways components involved in MSCs related GVHD regulation is proven to be beneficial.
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Affiliation(s)
- Reza Mirfakhraie
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maria Tavakoli Ardakani
- Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Hajifathali
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samira Karami
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohammad Reza Moshari
- Department of Anesthesiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hassani
- Department of General Surgery, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sahar Mashayekhi Firouz
- Department of Immunology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Elham Roshandel
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Abusarah J, Khodayarian F, El-Hachem N, Salame N, Olivier M, Balood M, Roversi K, Talbot S, Bikorimana JP, Chen J, Jolicoeur M, Trudeau LE, Kamyabiazar S, Annabi B, Robert F, Pelletier J, El-Kadiry AEH, Shammaa R, Rafei M. Engineering immunoproteasome-expressing mesenchymal stromal cells: A potent cellular vaccine for lymphoma and melanoma in mice. Cell Rep Med 2021; 2:100455. [PMID: 35028603 PMCID: PMC8714858 DOI: 10.1016/j.xcrm.2021.100455] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 08/30/2021] [Accepted: 10/22/2021] [Indexed: 11/29/2022]
Abstract
Dendritic cells (DCs) excel at cross-presenting antigens, but their effectiveness as cancer vaccine is limited. Here, we describe a vaccination approach using mesenchymal stromal cells (MSCs) engineered to express the immunoproteasome complex (MSC-IPr). Such modification instills efficient antigen cross-presentation abilities associated with enhanced major histocompatibility complex class I and CD80 expression, de novo production of interleukin-12, and higher chemokine secretion. This cross-presentation capacity of MSC-IPr is highly dependent on their metabolic activity. Compared with DCs, MSC-IPr hold the ability to cross-present a vastly different epitope repertoire, which translates into potent re-activation of T cell immunity against EL4 and A20 lymphomas and B16 melanoma tumors. Moreover, therapeutic vaccination of mice with pre-established tumors efficiently controls cancer growth, an effect further enhanced when combined with antibodies targeting PD-1, CTLA4, LAG3, or 4-1BB under both autologous and allogeneic settings. Therefore, MSC-IPr constitute a promising subset of non-hematopoietic antigen-presenting cells suitable for designing universal cell-based cancer vaccines.
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Affiliation(s)
- Jamilah Abusarah
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
| | - Fatemeh Khodayarian
- Department of Pharmacology and Physiology, Université de Montréal, Montreal, QC, Canada
| | - Nehme El-Hachem
- Department of Pharmacology and Physiology, Université de Montréal, Montreal, QC, Canada
| | - Natasha Salame
- Department of Biomedical Sciences, Université de Montréal, Montreal, QC, Canada
| | - Martin Olivier
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
| | - Mohammad Balood
- Department of Pharmacology and Physiology, Université de Montréal, Montreal, QC, Canada
| | - Katiane Roversi
- Department of Pharmacology and Physiology, Université de Montréal, Montreal, QC, Canada
| | - Sebastien Talbot
- Department of Pharmacology and Physiology, Université de Montréal, Montreal, QC, Canada
| | - Jean-Pierre Bikorimana
- Department of Microbiology, Infectious Diseases and Immunology, Université de Montréal, Montreal, QC, Canada
| | - Jingkui Chen
- Research Laboratory in Applied Metabolic Engineering, Department of Chemical Engineering, Polytechnique Montréal, Montreal, QC, Canada
| | - Mario Jolicoeur
- Research Laboratory in Applied Metabolic Engineering, Department of Chemical Engineering, Polytechnique Montréal, Montreal, QC, Canada
| | - Louis-Eric Trudeau
- Department of Pharmacology and Physiology, Université de Montréal, Montreal, QC, Canada
| | - Samaneh Kamyabiazar
- Department of Chemistry, Université du Québec à Montréal, Montreal, QC, Canada
| | - Borhane Annabi
- Department of Chemistry, Université du Québec à Montréal, Montreal, QC, Canada
| | - Francis Robert
- Department of Biochemistry, McGill University, Montreal, QC, Canada
| | - Jerry Pelletier
- Department of Biochemistry, McGill University, Montreal, QC, Canada
| | | | - Riam Shammaa
- Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada
- Canadian Centers for Regenerative Therapy, Toronto, ON, Canada
- IntelliStem Technologies Inc., Toronto, ON, Canada
| | - Moutih Rafei
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
- Department of Pharmacology and Physiology, Université de Montréal, Montreal, QC, Canada
- Department of Microbiology, Infectious Diseases and Immunology, Université de Montréal, Montreal, QC, Canada
- Molecular Biology Program, Université de Montréal, Montreal, QC, Canada
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Di Tinco R, Bertani G, Pisciotta A, Bertoni L, Pignatti E, Maccaferri M, Bertacchini J, Sena P, Vallarola A, Tupler R, Croci S, Bonacini M, Salvarani C, Carnevale G. Role of PD-L1 in licensing immunoregulatory function of dental pulp mesenchymal stem cells. Stem Cell Res Ther 2021; 12:598. [PMID: 34863286 PMCID: PMC8643194 DOI: 10.1186/s13287-021-02664-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 11/17/2021] [Indexed: 12/28/2022] Open
Abstract
Background Dental pulp stem cells (DPSCs) are low immunogenic and hold immunomodulatory properties that, along with their well-established multi-potency, might enhance their potential application in autoimmune and inflammatory diseases. The present study focused on the ability of DPSCs to modulate the inflammatory microenvironment through PD1/PD-L1 pathway. Methods Inflammatory microenvironment was created in vitro by the activation of T cells isolated from healthy donors and rheumatoid arthritis (RA) patients with anti-CD3 and anti-CD28 antibodies. Direct and indirect co-cultures between DPSCs and PBMCs were carried out to evaluate the activation of immunomodulatory checkpoints in DPSCs and the inflammatory pattern in PBMCs. Results Our data suggest that the inflammatory stimuli trigger DPSCs immunoregulatory functions that can be exerted by both direct and indirect contact. As demonstrated by using a selective PD-L1 inhibitor, DPSCs were able to activate compensatory pathways targeting to orchestrate the inflammatory process by modulating pro-inflammatory cytokines in pre-activated T lymphocytes. The involvement of PD-L1 mechanism was also observed in autologous inflammatory status (pulpitis) and after direct exposure to pre-activated T cells from RA patients suggesting that immunomodulatory/anti-inflammatory properties are strictly related to their stemness status. Conclusions Our findings point out that the communication with the inflammatory microenvironment is essential in licensing their immunomodulatory properties. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02664-4.
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Affiliation(s)
- Rosanna Di Tinco
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Bertani
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessandra Pisciotta
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, University of Modena and Reggio Emilia, Modena, Italy
| | - Laura Bertoni
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, University of Modena and Reggio Emilia, Modena, Italy
| | - Elisa Pignatti
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, University of Modena and Reggio Emilia, Modena, Italy
| | - Monia Maccaferri
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, University of Modena and Reggio Emilia, Modena, Italy
| | - Jessika Bertacchini
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, University of Modena and Reggio Emilia, Modena, Italy
| | - Paola Sena
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, University of Modena and Reggio Emilia, Modena, Italy
| | - Antonio Vallarola
- Department of Biomedical, Metabolic and Neural Sciences, Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena, Italy
| | - Rossella Tupler
- Department of Biomedical, Metabolic and Neural Sciences, Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena, Italy
| | - Stefania Croci
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Martina Bonacini
- Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Carlo Salvarani
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, University of Modena and Reggio Emilia, Modena, Italy.,Rheumatology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Gianluca Carnevale
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, University of Modena and Reggio Emilia, Modena, Italy.
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