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Qiao Y, Tang X, Liu Z, Ocansey DKW, Zhou M, Shang A, Mao F. Therapeutic Prospects of Mesenchymal Stem Cell and Their Derived Exosomes in the Regulation of the Gut Microbiota in Inflammatory Bowel Disease. Pharmaceuticals (Basel) 2024; 17:607. [PMID: 38794176 PMCID: PMC11124012 DOI: 10.3390/ph17050607] [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: 04/04/2024] [Revised: 05/05/2024] [Accepted: 05/06/2024] [Indexed: 05/26/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have shown great potential in the treatment of several inflammatory diseases due to their immunomodulatory ability, which is mediated by exosomes secreted by MSCs (MSC-Exs). The incidence of inflammatory bowel disease (IBD) is increasing globally, but there is currently no long-term effective treatment. As an emerging therapy, MSC-Exs have proven to be effective in alleviating IBD experimentally, and the specific mechanism continues to be explored. The gut microbiota plays an important role in the occurrence and development of IBD, and MSCs and MSC-Exs can effectively regulate gut microbiota in animal models of IBD, but the mechanism involved and whether the outcome can relieve the characteristic dysbiosis necessary to alleviate IBD still needs to be studied. This review provides current evidence on the effective modulation of the gut microbiota by MSC-Exs, offering a basis for further research on the pathogenic mechanism of IBD and MSC-Ex treatments through the improvement of gut microbiota.
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Affiliation(s)
- Yaru Qiao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang 212013, China; (Y.Q.); (Z.L.); (D.K.W.O.); (M.Z.)
- Department of Laboratory Medicine, Lianyungang Clinical College, Jiangsu University, Lianyungang 222006, China;
| | - Xiaohua Tang
- The People’s Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Zhenjiang 212300, China;
| | - Ziyue Liu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang 212013, China; (Y.Q.); (Z.L.); (D.K.W.O.); (M.Z.)
| | - Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang 212013, China; (Y.Q.); (Z.L.); (D.K.W.O.); (M.Z.)
- Department of Medical Laboratory Science, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast CC0959347, Ghana
| | - Mengjiao Zhou
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang 212013, China; (Y.Q.); (Z.L.); (D.K.W.O.); (M.Z.)
| | - Anquan Shang
- Department of Laboratory Medicine, Lianyungang Clinical College, Jiangsu University, Lianyungang 222006, China;
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang 212013, China; (Y.Q.); (Z.L.); (D.K.W.O.); (M.Z.)
- Department of Laboratory Medicine, Lianyungang Clinical College, Jiangsu University, Lianyungang 222006, China;
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Chen QQ, Wang C, Wang WH, Gong Y, Chen HX. Histopathological and Immunohistochemical Mechanisms of Bone Marrow-Derived Mesenchymal Stem Cells in Reversion of Gastric Precancerous Lesions. FRONT BIOSCI-LANDMRK 2024; 29:127. [PMID: 38538255 DOI: 10.31083/j.fbl2903127] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 11/24/2023] [Accepted: 12/13/2023] [Indexed: 01/02/2025]
Abstract
BACKGROUND Gastric cancer (GC) stands as one of the most prevalent cancer types worldwide, holding the position of the second leading cause of cancer-related deaths. Gastric lesions represent pathological alterations to the gastric mucosa, with an elevated propensity to advance to gastric cancer. Limited research has explored the potential of stem cells in the treatment of gastric lesions. METHODS This study aimed to explore the potential of intravenous transplantation of labeled bone marrow-derived mesenchymal stem cells (BMMSCs) to inhibit the progression of precancerous gastric lesions. RESULTS In the gastric lesion disease model group, the rat tissue exhibited noteworthy mucosal atrophy, intestinal metaplasia, dysplasia, and inflammatory cell infiltration. Following the infusion of BMMSCs, a notable decrease in gastric lesions was found, with atrophic gastritis being the sole remaining lesion, which was confirmed by morphological and histological examinations. BMMSCs that were colonized at gastric lesions could differentiate into epithelial and stromal cells, as determined by the expression of pan-keratin or vimentin. The expression of vascular endothelial growth factor was significantly elevated following BMMSC transplantation. BMMSCs could also upregulate the production of humoral immune response cytokines, including interleukin (IL)-4 and IL-10, and downregulate the production of IL-17 and interferon-gamma, which could be highly associated with the cellular immune response and inflammation severity of the lesions. CONCLUSIONS BMMSC transplantation significantly reduced inflammation and reversed gastric lesion progression.
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Affiliation(s)
- Qian-Qian Chen
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, 100853 Beijing, China
| | - Cong Wang
- Department of Gastroenterology and Hepatology, The Second Medical Center, Chinese PLA General Hospital, 100853 Beijing, China
- Medical School of Chinese PLA, 100853 Beijing, China
| | - Wei-Hua Wang
- Department of Gastroenterology and Hepatology, The Second Medical Center, Chinese PLA General Hospital, 100853 Beijing, China
| | - Yuan Gong
- Department of Gastroenterology and Hepatology, The Second Medical Center, Chinese PLA General Hospital, 100853 Beijing, China
| | - Hai-Xu Chen
- Department of Gastroenterology and Hepatology, The Second Medical Center, Chinese PLA General Hospital, 100853 Beijing, China
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Chen Z, Yao MW, Shen ZL, Li SD, Xing W, Guo W, Li Z, Wu XF, Ao LQ, Lu WY, Lian QZ, Xu X, Ao X. Interferon-gamma and tumor necrosis factor-alpha synergistically enhance the immunosuppressive capacity of human umbilical-cord-derived mesenchymal stem cells by increasing PD-L1 expression. World J Stem Cells 2023; 15:787-806. [PMID: 37700823 PMCID: PMC10494569 DOI: 10.4252/wjsc.v15.i8.787] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 06/20/2023] [Accepted: 07/24/2023] [Indexed: 08/25/2023] Open
Abstract
BACKGROUND The immunosuppressive capacity of mesenchymal stem cells (MSCs) is dependent on the "license" of several proinflammatory factors to express immunosuppressive factors such as programmed cell death 1 ligand 1 (PD-L1), which determines the clinical therapeutic efficacy of MSCs for inflammatory or immune diseases. In MSCs, interferon-gamma (IFN-γ) is a key inducer of PD-L1 expression, which is synergistically enhanced by tumor necrosis factor-alpha (TNF-α); however, the underlying mechanism is unclear. AIM To reveal the mechanism of pretreated MSCs express high PD-L1 and explore the application of pretreated MSCs in ulcerative colitis. METHODS We assessed PD-L1 expression in human umbilical-cord-derived MSCs (hUC-MSCs) induced by IFN-γ and TNF-α, alone or in combination. Additionally, we performed signal pathway inhibitor experiments as well as RNA interference experiments to elucidate the molecular mechanism by which IFN-γ alone or in combination with TNF-α induces PD-L1 expression. Moreover, we used luciferase reporter gene experiments to verify the binding sites of the transcription factors of each signal transduction pathway to the targeted gene promoters. Finally, we evaluated the immunosuppressive capacity of hUC-MSCs treated with IFN-γ and TNF-α in both an in vitro mixed lymphocyte culture assay, and in vivo in mice with dextran sulfate sodium-induced acute colitis. RESULTS Our results suggest that IFN-γ induction alone upregulates PD-L1 expression in hUC-MSCs while TNF-α alone does not, and that the co-induction of IFN-γ and TNF-α promotes higher expression of PD-L1. IFN-γ induces hUC-MSCs to express PD-L1, in which IFN-γ activates the JAK/STAT1 signaling pathway, up-regulates the expression of the interferon regulatory factor 1 (IRF1) transcription factor, promotes the binding of IRF1 and the PD-L1 gene promoter, and finally promotes PD-L1 mRNA. Although TNF-α alone did not induce PD-L1 expression in hUC-MSCs, the addition of TNF-α significantly enhanced IFN-γ-induced JAK/STAT1/IRF1 activation. TNF-α up-regulated IFN-γ receptor expression through activation of the nuclear factor kappa-B signaling pathway, which significantly enhanced IFN-γ signaling. Finally, co-induced hUC-MSCs have a stronger inhibitory effect on lymphocyte proliferation, and significantly ameliorate weight loss, mucosal damage, inflammatory cell infiltration, and up-regulation of inflammatory factors in colitis mice. CONCLUSION Overall, our results suggest that IFN-γ and TNF-α enhance both the immunosuppressive ability of hUC-MSCs and their efficacy in ulcerative colitis by synergistically inducing high expression of PD-L1.
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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
| | - Zhi-Lin Shen
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Shi-Dan Li
- Department of Orthopedics, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Wei Xing
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Wei Guo
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Zhan Li
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Xiao-Feng Wu
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Luo-Quan Ao
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Wen-Yong Lu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, The South of Shangcai Village, Wenzhou 325005, Zhejiang Province, China
| | - Qi-Zhou Lian
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, 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
| | - Xiang Ao
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
- Department of Orthopedics, 953 Hospital of PLA Army, Shigatse Branch of Xinqiao Hospital, Army Medical University, Shigatse 857000, Tibet Autonomous Region, China.
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Serafini MA, Sirena DH, da Silveira ABT, Franco-da-Silva M, Aubin MR, Garcez TNA, Araújo A, dos Santos Pereira F, Hoogduijn MJ, da Costa Gonçalves F, Paz AH. Mesenchymal stromal cell-derived membrane particles: A novel cell-free therapy for inflammatory bowel diseases. Int Immunopharmacol 2023; 118:110076. [PMID: 37030123 DOI: 10.1016/j.intimp.2023.110076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/02/2023] [Accepted: 03/21/2023] [Indexed: 04/08/2023]
Abstract
Inflammatory bowel diseases (IBD), including ulcerative colitis, are chronic and idiopathic inflammations of the gastrointestinal tract. A disruption of the epithelial barrier and an imbalance between Th1 and Th2 subsets are associated with the onset and progression of these diseases. Mesenchymal stromal cells (MSC) are a promising therapy for IBD. However, cell-tracking studies have shown that intravenously infused MSC localize to the lungs and present short-term survival. To reduce practical complexities arising from living cells, we generated membrane particles (MP) from MSC membranes, which possess some of the immunomodulatory properties of MSC. This study investigated the effect of MSC-derived MP and conditioned media (CM) as cell-free therapies in the dextran sulfate sodium (DSS)-induced colitis model. Acute colitis was induced in C57BL/6 mice by oral administration of 2% DSS in drinking water ad libitum from days 0 to 7. Mice were treated with MP, CM, or living MSC on days 2 and 5. Our findings revealed that MP, CM, and living MSC ameliorated DSS-induced colitis by reducing colonic inflammation, the loss of colonic goblet cells, and intestinal mucosa permeability, preventing apoptosis of damaged colonic cells and balancing Th1 and Th2 activity. Therefore, MSC-derived MP have high therapeutic potential for treating IBD, overcoming the deficiencies of living MSC therapy, and opening novel frontiers in inflammatory diseases medicine.
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Qi LL, Fan ZY, Mao HG, Wang JB. The Therapeutic Efficacy of Adipose Tissue-Derived Mesenchymal Stem Cell Conditioned Medium on Experimental Colitis Was Improved by the Serum From Colitis Rats. Front Bioeng Biotechnol 2021; 9:694908. [PMID: 34604183 PMCID: PMC8484792 DOI: 10.3389/fbioe.2021.694908] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 09/06/2021] [Indexed: 01/07/2023] Open
Abstract
Adipose derived mesenchymal stem cells (AD-MSCs) have shown therapeutic potential in treatments of inflammatory bowel disease (IBD). Due to the harsh host environment and poor survival of the cells, controversy concerning the homing, proliferation and differentiation of MSCs in lesion tissue still remains. It has been reported that conditioned media from MSCs could improve the colitis, whereas the therapeutic efficiency could be significantly elevated by the stimulation of pro-cytokines. In this study, we pre-treated the adipose derived MSCs with the serum from colitis rats and then the activated conditioned media (CM-AcMSC) were collected. To compare the therapeutic effects of CM-MSC and CM-AcMSC on IBD, we constructed dextran sodium sulphate (DSS)-induced colitis rat models. The colitis was induced in rats by administrating 5% DSS in drinking water for 10 days, and the disease symptoms were recorded daily. The colon histopathological changes were observed by different staining methods (H&E and PAS). The expression levels of MUC2 and tight junctions (TJs) were determined by RT-qPCR. The levels of inflammatory cytokines were analyzed by ELISA and western blot analysis. Our findings suggested that CM-AcMSC was more effective in ameliorating the clinical features and histological damage scores. Treatment with CM-AcMSC significantly increased the expression of MUC2 and TJs and suppressed the production of pro-inflammatory cytokines in colonic tissues of colitis rats. The inhibitory effects of CM-AcMSC on inflammatory responses of colitis rats were mediated by NF-κB signaling pathway. These results suggested that pre-activation of MSCs with serum from colitis rats could promote the production of paracrine factors and improve the therapeutic effects of conditioned medium on colitis rats.
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Affiliation(s)
- Li-Li Qi
- School of Biological and Chemical Engineering, Ningbo Tech University, Ningbo, China
| | - Zhe-Yu Fan
- School of Biological and Chemical Engineering, Ningbo Tech University, Ningbo, China
| | - Hai-Guang Mao
- School of Biological and Chemical Engineering, Ningbo Tech University, Ningbo, China
| | - Jin-Bo Wang
- School of Biological and Chemical Engineering, Ningbo Tech University, Ningbo, China
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Cai X, Zhang ZY, Yuan JT, Ocansey DKW, Tu Q, Zhang X, Qian H, Xu WR, Qiu W, Mao F. hucMSC-derived exosomes attenuate colitis by regulating macrophage pyroptosis via the miR-378a-5p/NLRP3 axis. Stem Cell Res Ther 2021; 12:416. [PMID: 34294138 PMCID: PMC8296541 DOI: 10.1186/s13287-021-02492-6] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 06/29/2021] [Indexed: 12/15/2022] Open
Abstract
Background Human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes are recognized as novel cell-free therapeutic agents for inflammatory bowel disease (IBD), a condition caused by dysregulated intestinal mucosal immunity. In this event, macrophage pyroptosis, a process of cell death following the activation of NLRP3 (NOD-like receptor family, pyrin domain-containing 3) inflammasomes, is believed to partially account for inflammatory reactions. However, the role of macrophage pyroptosis in the process of hucMSC-derived exosomes alleviating colitis remains unknown. This study aimed at exploring the therapeutic effect and mechanism of hucMSC-derived exosomes on colitis repair. Methods In vivo, we used BALB/c mice to establish a dextran sulfate sodium (DSS)-induced colitis model and administrated hucMSC-derived exosomes intravenously to estimate its curative effect. Human myeloid leukemia mononuclear (THP-1) cells and mouse peritoneal macrophages (MPMs) were stimulated with lipopolysaccharides (LPS) and Nigericin to activate NLRP3 inflammasomes, which simulated an inflammation environment in vitro. A microRNA mimic was used to verify the role of miR-378a-5p/NLRP3 axis in the colitis repair. Results hucMSC-derived exosomes inhibited the activation of NLRP3 inflammasomes in the mouse colon. The secretion of interleukin (IL)-18, IL-1β, and Caspase-1 cleavage was suppressed, resulting in reduced cell pyroptosis. The same outcome was observed in the in vitro cell experiments, where the co-culture of THP-1 cells and MPMs with hucMSC-derived exosomes caused decreased expression of NLRP3 inflammasomes and increased cell survival. Furthermore, miR-378a-5p was highly expressed in hucMSC-derived exosomes and played a vital function in colitis repair. Conclusion hucMSC-derived exosomes carrying miR-378a-5p inhibited NLRP3 inflammasomes and abrogated cell pyroptosis to protect against DSS-induced colitis.
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Affiliation(s)
- Xiu Cai
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
| | - Zhi-Yu Zhang
- The People's Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Zhenjiang, Jiangsu, 212300, People's Republic of China
| | - Jin-Tao Yuan
- The People's Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Zhenjiang, Jiangsu, 212300, People's Republic of China
| | - Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.,Directorate of University Health Services, University of Cape Coast, Cape Coast, Ghana
| | - Qiang Tu
- Nanjing Jiangning Hospital, Nanjing, Jiangsu, 211100, People's Republic of China
| | - Xu Zhang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
| | - Hui Qian
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
| | - Wen-Rong Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
| | - Wei Qiu
- Nanjing Jiangning Hospital, Nanjing, Jiangsu, 211100, People's Republic of China.
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.
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Pethe P, Kale V. Placenta: A gold mine for translational research and regenerative medicine. Reprod Biol 2021; 21:100508. [PMID: 33930790 DOI: 10.1016/j.repbio.2021.100508] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 04/15/2021] [Accepted: 04/17/2021] [Indexed: 02/06/2023]
Abstract
Stem cell therapy has gained much impetus in regenerative medicine due to some of the encouraging results obtained in the laboratory as well as in translational/clinical studies. Although stem cells are of various types and their therapeutic potential has been documented in several studies, mesenchymal stromal/stem cells (MSCs) have an edge, as in addition to being multipotent, these cells are easy to obtain and expand, pose fewer ethical issues, and possess immense regenerative potential when used in a scientifically correct manner. Currently, MSCs are being sourced from various tissues such as bone marrow, cord, cord blood, adipose tissue, dental tissue, etc., and, quite often, the choice depends on the availability of the source. One such rich source of tissue suitable for obtaining good quality MSCs in large numbers is the placenta obtained in a full-term delivery leading to a healthy child's birth. Several studies have demonstrated the regenerative potential of human placenta-derived MSCs (hPMSC), and most show that these MSCs possess comparable, in some instances, even better, therapeutic potential as that shown by human bone marrow-derived (hBMSC) or human umbilical cord-derived (hUC-MSC) MSCs. The placenta can be easily sourced from the OB/GYN department of any hospital, and if its derivatives such as hPMSC or their EVs are produced under GMP conditions, it could serve as a gold mine for translational/clinical research. Here, we have reviewed recent studies revealing the therapeutic potential of hPMSC and their extracellular vesicles (EVs) published over the past three years.
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Affiliation(s)
- Prasad Pethe
- Symbiosis Centre for Stem Cell Research, Symbiosis International University, Pune, 412115, India
| | - Vaijayanti Kale
- Symbiosis Centre for Stem Cell Research, Symbiosis International University, Pune, 412115, India.
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da Costa Gonçalves F, Korevaar SS, Ortiz Virumbrales M, Baan CC, Reinders MEJ, Merino A, Lombardo E, Hoogduijn MJ. Mesenchymal Stromal Cell Derived Membrane Particles Are Internalized by Macrophages and Endothelial Cells Through Receptor-Mediated Endocytosis and Phagocytosis. Front Immunol 2021; 12:651109. [PMID: 33790914 PMCID: PMC8005704 DOI: 10.3389/fimmu.2021.651109] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 02/15/2021] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stromal cells (MSC) are a promising therapy for inflammatory diseases. However, MSC are large and become trapped in the lungs after intravenous infusion, where they have a short survival time. To steer MSC immunoregulatory therapy beyond the lungs, we generated nm-sized particles from MSC membranes (membrane particles, MP), which have immunomodulatory properties, and investigated their internalization and mode of interaction in macrophages subtypes and human umbilical vein endothelial cells (HUVEC) under control and inflammatory conditions. We found that macrophages and HUVEC take up MP in a dose, time, and temperature-dependent manner. Specific inhibitors for endocytotic pathways revealed that MP internalization depends on heparan sulfate proteoglycan-, dynamin-, and clathrin-mediated endocytosis but does not involve caveolin-mediated endocytosis. MP uptake also involved the actin cytoskeleton and phosphoinositide 3-kinase, which are implicated in macropinocytosis and phagocytosis. Anti-inflammatory M2 macrophages take up more MP than pro-inflammatory M1 macrophages. In contrast, inflammatory conditions did not affect the MP uptake by HUVEC. Moreover, MP induced both anti- and pro-inflammatory responses in macrophages and HUVEC by affecting gene expression and cell surface proteins. Our findings on the mechanisms of uptake of MP under different conditions help the development of target-cell specific MP therapy to modulate immune responses.
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Affiliation(s)
- Fabiany da Costa Gonçalves
- Nephrology and Transplantation, Internal Medicine, Erasmus Medical Center Transplantation Institute, Erasmus Medical Center, Rotterdam, Netherlands
| | - Sander S Korevaar
- Nephrology and Transplantation, Internal Medicine, Erasmus Medical Center Transplantation Institute, Erasmus Medical Center, Rotterdam, Netherlands
| | | | - Carla C Baan
- Nephrology and Transplantation, Internal Medicine, Erasmus Medical Center Transplantation Institute, Erasmus Medical Center, Rotterdam, Netherlands
| | - Marlies E J Reinders
- Nephrology and Transplantation, Internal Medicine, Erasmus Medical Center Transplantation Institute, Erasmus Medical Center, Rotterdam, Netherlands
| | - Ana Merino
- Nephrology and Transplantation, Internal Medicine, Erasmus Medical Center Transplantation Institute, Erasmus Medical Center, Rotterdam, Netherlands
| | | | - Martin J Hoogduijn
- Nephrology and Transplantation, Internal Medicine, Erasmus Medical Center Transplantation Institute, Erasmus Medical Center, Rotterdam, Netherlands
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Luo Y, Wang B, Liu J, Ma F, Luo D, Zheng Z, Lu Q, Zhou W, Zheng Y, Zhang C, Wang Q, Sha W, Chen H. Ginsenoside RG1 enhances the paracrine effects of bone marrow-derived mesenchymal stem cells on radiation induced intestinal injury. Aging (Albany NY) 2020; 13:1132-1152. [PMID: 33293477 PMCID: PMC7835034 DOI: 10.18632/aging.202241] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 10/20/2020] [Indexed: 02/07/2023]
Abstract
UNLABELLED Content and aims: Ginsenoside RG1 (RG1) is thought to enhance proliferation and differentiation of stem cell, however, its role on paracrine efficacy of stem cell remains unclear. Here we examined if and how RG1 enhances the paracrine effects of bone marrow-derived mesenchymal stem cells (BM-MSCs) on radiation induced intestinal injury (RIII). METHOD Irradiated rats randomly received intraperitoneal injection of conditioned medium (CM) derived from non-activated BM-MSCs (MSC-CM) or BM-MSCs pre-activated by RG-1 (RG1-MSC-CM). Intestinal samples were collected, followed by the evaluation of histological and functional change, apoptosis, proliferation, inflammation, angiogenesis and stem cell regeneration. The effects of heme oxygenase-1 (HO-1) were investigated using HO-1 inhibitor or siRNA. RESULT RG1 enhanced the paracrine efficacy of BM-MSCs partially through upregulation of HO-1. RG1-MSC-CM rather than MSC-CM significantly improved the survival and intestinal damage of irradiated rats via improvement of intestinal proliferation/apoptosis, inflammation, angiogenesis and stem cell regeneration in a HO-1 dependent mechanism. The mechanism for the superior paracrine efficacy of RG1-MSC-CM is related to a higher release of two pivotal cytokines VEGF and IL-6. CONCLUSION Our study revealed that RG1 enhances paracrine effects of BM-MSCs on RIII, providing a novel method for maximizing the paracrine potential of MSCs.
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Affiliation(s)
- Yujun Luo
- Shantou University Medical College, Shantou 515041, Guangdong, P.R. China
- Department of Gastroenterology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, P.R. China
| | - Beibei Wang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, Guangdong, P.R. China
- Department of Gastroenterology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, P.R. China
| | - Jianhua Liu
- Department of Oncology, Cancer Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, P.R. China
| | - Faxin Ma
- Shantou University Medical College, Shantou 515041, Guangdong, P.R. China
- Department of Gastroenterology, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen University, Shantou 515041, Guangdong, P.R. China
| | - Dongling Luo
- Shantou University Medical College, Shantou 515041, Guangdong, P.R. China
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, P.R. China
| | - Zhongwen Zheng
- Department of Gastroenterology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, P.R. China
| | - Quan Lu
- Shantou University Medical College, Shantou 515041, Guangdong, P.R. China
- Department of Gastroenterology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, P.R. China
| | - Weijie Zhou
- Department of Gastroenterology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, P.R. China
| | - Yue Zheng
- Department of Gastroenterology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, P.R. China
| | - Chen Zhang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, Guangdong, P.R. China
- Department of Gastroenterology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, P.R. China
| | - Qiyi Wang
- Shantou University Medical College, Shantou 515041, Guangdong, P.R. China
- Department of Gastroenterology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, P.R. China
| | - Weihong Sha
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, Guangdong, P.R. China
- Department of Gastroenterology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, P.R. China
| | - Hao Chen
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, Guangdong, P.R. China
- Department of Gastroenterology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, P.R. China
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10
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Zhao G, Ge Y, Zhang C, Zhang L, Xu J, Qi L, Li W. Progress of Mesenchymal Stem Cell-Derived Exosomes in Tissue Repair. Curr Pharm Des 2020; 26:2022-2037. [PMID: 32310043 DOI: 10.2174/1381612826666200420144805] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 03/25/2020] [Indexed: 12/17/2022]
Abstract
Mesenchymal stem cells (MSCs) are a kind of adult stem cells with self-replication and multidirectional differentiation, which can differentiate into tissue-specific cells under physiological conditions, maintaining tissue self-renewal and physiological functions. They play a role in the pathological condition by lateral differentiation into tissue-specific cells, replacing damaged tissue cells by playing the role of a regenerative medicine , or repairing damaged tissues through angiogenesis, thereby, regulating immune responses, inflammatory responses, and inhibiting apoptosis. It has become an important seed cell for tissue repair and organ reconstruction, and cell therapy based on MSCs has been widely used clinically. The study found that the probability of stem cells migrating to the damaged area after transplantation or differentiating into damaged cells is very low, so the researchers believe the leading role of stem cell transplantation for tissue repair is paracrine secretion, secreting growth factors, cytokines or other components. Exosomes are biologically active small vesicles secreted by MSCs. Recent studies have shown that they can transfer functional proteins, RNA, microRNAs, and lncRNAs between cells, and greatly reduce the immune response. Under the premise of promoting proliferation and inhibition of apoptosis, they play a repair role in tissue damage, which is caused by a variety of diseases. In this paper, the biological characteristics of exosomes (MSCs-exosomes) derived from mesenchymal stem cells, intercellular transport mechanisms, and their research progress in the field of stem cell therapy are reviewed.
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Affiliation(s)
- Guifang Zhao
- School of Basic Medical Sciences, Jilin Medical University, Jilin 132013, China.,Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan 511518, Guangzhou Province, China
| | - Yiwen Ge
- School of Basic Medical Sciences, Jilin Medical University, Jilin 132013, China
| | - Chenyingnan Zhang
- School of Basic Medical Sciences, Jilin Medical University, Jilin 132013, China
| | - Leyi Zhang
- School of Pharmacy, Jilin Medical University, Jilin 132013, China
| | - Junjie Xu
- School of Basic Medical Sciences, Jilin Medical University, Jilin 132013, China
| | - Ling Qi
- Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan 511518, Guangzhou Province, China.,School of Basic Medical Sciences, Department of Pathophysiology, Jilin Medical University, Jilin 132013, China
| | - Wenliang Li
- School of Pharmacy, Jilin Medical University, Jilin 132013, China
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11
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da Costa Gonçalves F, Paz AH. Cell membrane and bioactive factors derived from mesenchymal stromal cells: Cell-free based therapy for inflammatory bowel diseases. World J Stem Cells 2019; 11:618-633. [PMID: 31616539 PMCID: PMC6789183 DOI: 10.4252/wjsc.v11.i9.618] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 05/23/2019] [Accepted: 07/16/2019] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract associated with multifactorial conditions such as ulcerative colitis and Crohn’s disease. Although the underlying mechanisms of IBD remain unclear, growing evidence has shown that dysregulated immune system reactions in genetically susceptible individuals contribute to mucosal inflammation. However, conventional treatments have been effective in inducing remission of IBD but not in preventing the relapse of them. In this way, mesenchymal stromal cells (MSC) therapy has been recognized as a promising treatment for IBD due to their immunomodulatory properties, ability to differentiate into several tissues, and homing to inflammatory sites. Even so, literature is conflicted regarding the location and persistence of MSC in the body after transplantation. For this reason, recent studies have focused on the paracrine effect of the biofactors secreted by MSC, especially in relation to the immunomodulatory potential of soluble factors (cytokines, chemokines, and growth factors) and extracellular vehicles that are involved in cell communication and in the transfer of cellular material, such as proteins, lipids, and nucleic acids. Moreover, treatment with interferon-γ, tumor necrosis factor-α, and interleukin-1β causes MSC to express immunomodulatory molecules that mediate the suppression via cell-contact dependent mechanisms. Taken together, we present an overview of the role of bioactive factors and cell membrane proteins derived from MSC as a cell-free therapy that can improve IBD treatment.
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Affiliation(s)
- Fabiany da Costa Gonçalves
- Nephrology and Transplantation, Internal Medicine, Erasmus Medical Center, Rotterdam, GD 3015, Netherlands
| | - Ana Helena Paz
- Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-903, Brazil
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