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Rahnama M, Ghasemzadeh N, Latifi Z, Kheradmand F, Koukia FA, Khan S, Golchin A. Menstrual blood and endometrial mesenchymal stem/stromal cells: A frontier in regenerative medicine and cancer therapy. Eur J Pharmacol 2025; 1000:177726. [PMID: 40350020 DOI: 10.1016/j.ejphar.2025.177726] [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: 12/24/2024] [Revised: 05/08/2025] [Accepted: 05/09/2025] [Indexed: 05/14/2025]
Abstract
The acquisition of suitable stem cell sources is a significant issue in regenerative medicine. There has been considerable interest in utilizing mesenchymal stem cells (MSCs) derived from endometrial and menstrual blood as a promising resource of MSCs, owing to their unique biochemical properties and prospective use in clinical therapies. This population of stem cells has distinct characteristics in terms of immunophenotype, proliferation rate, and differentiation capacity. A notable characteristic of these stem cells is their capacity to develop into mesodermal lineages, highlighting their regenerative capability. Moreover, the presence of certain surface markers facilitates the augmentation of clonogenic endometrial MSCs. Their distinctive characteristics, along with their swift multiplication ability, underscore their significant promise for therapeutic applicability in regenerative medicine and cell-based treatments. Current investigations are examining possible usage of diverse stem cell resources in the treatment of inflammatory diseases and perhaps intractable illnesses like Parkinson's disease, utilizing their immunomodulatory properties. This review aims to analyze stem cell-related research that has utilized endometrial and menstrual blood-derived MSCs (enMSCs and MenSCs) with a special focus on their clinical application. We will explore the existing evidence about the therapeutic potential for these stem cells across many medical diseases and address the obstacles and prospective trajectories in this domain. Additionally, we will study the unique properties of enMSCs and MenSCs that make them promising candidates for regenerative medicine.
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Affiliation(s)
- Maryam Rahnama
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran; Department of Applied Cell Sciences, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Navid Ghasemzadeh
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran; Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Zeinab Latifi
- Department of Biochemistry, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Kheradmand
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Fariba Abbasi Koukia
- Department of Pathology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Sharun Khan
- Graduate Institute of Medicine, Yuan Ze University, Taoyuan 32003, Taiwan
| | - Ali Golchin
- Department of Applied Cell Sciences, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran; Independent Researcher, Urmia, Iran.
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Fang Y, Chen L, Yuan Y, Zhou S, Fu J, Zhang Q, Zhang N, Huang Y, Li Y, Yuan L, Chen L, Xiang C. Human menstrual blood-derived stem cells secreted ECM1 directly interacts with LRP1α to ameliorate hepatic fibrosis through FoxO1 and mTOR signaling pathway. Stem Cell Res Ther 2025; 16:230. [PMID: 40336034 PMCID: PMC12060366 DOI: 10.1186/s13287-025-04351-0] [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: 12/12/2024] [Accepted: 04/17/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND Human menstrual blood-derived stem cells (MenSCs), a major class of mesenchymal stem cells (MSCs), modulate intercellular signals via paracrine factors. Previous studies found that MenSC-derived secretomes exert protective effects against liver fibrosis. However, the underlying mechanisms of these observations remain unclear. METHODS Extracellular Matrix Protein 1 (ECM1), identified in MenSCs culture medium using mass spectrometry, was employed to stably overexpress ECM1-HA or silence in MenSCs using lentiviral vectors. These genetically engineered cells were either intravenously injected into the carbon tetrachloride (CCl4)-induced liver fibrosis mice or co-cultured with hepatic stellate cells (HSCs)-LX-2. The interaction between ECM1 and low-density lipoprotein receptor-related protein 1α (LRP1α) was confirmed using Co-Immunoprecipitation (Co-ip), Duolink Proximity Ligation Assays (PLA) and pull-down. LRP1 deficient mice were generated via intravenous administration of adeno-associated-virus-8. The downstream molecular mechanisms were characterized by non-target metabolomics and multiplex immunohistochemical staining. RNA sequencing was performed to evaluate the genetic alterations in various genes within the MenSCs. RESULTS MenSC-secreted ECM1 exhibits potential to ameliorate liver fibrosis by inactivating HSCs, improving liver functions, and reducing collagen deposition in both cellular and mouse model of the CCl4-induced liver fibrosis. Mechanistically, a novel interaction was identified that ECM1 directly bound to cell surface receptor LRP1α. Notably, the antifibrotic efficacy of MenSC was negated in LRP1-deficient cells and mice. Moreover, the ECM1-LRP1 axis contributed to the alleviation of liver fibrosis by suppressing AKT/mTOR while activating the FoxO1 signaling pathway, thereby facilitating pyrimidine and purine metabolism. Additionally, ECM1-modified MenSCs regulate the transcription of intrinsic cytokine genes, further mitigating liver fibrosis. CONCLUSIONS These findings highlight an extensive network of ECM1-LRP1 interaction, which serve as a link for providing promising insights into the mechanism of MenSC-based drug development for liver fibrosis. Our study also potentially presents novel avenues for clinical antifibrotic therapy.
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Affiliation(s)
- Yangxin Fang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China
| | - Lin Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China
| | - Yin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China
| | - Sining Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China
| | - Jiamin Fu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China
| | - Qi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China
| | - Ning Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China
| | - Yuqi Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China
| | - Yifei Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Li Yuan
- Innovative Precision Medicine (IPM) Group, Hangzhou, Zhejiang, 311215, China
| | - Lijun Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China.
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, 100730, China.
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China.
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, 100730, China.
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, 250117, China.
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Sadiasa A, Werkmeister JA, Gurung S, Gargett CE. Steps towards the clinical application of endometrial and menstrual fluid mesenchymal stem cells for the treatment of gynecological disorders. Expert Opin Biol Ther 2025; 25:285-307. [PMID: 39925343 DOI: 10.1080/14712598.2025.2465826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 01/28/2025] [Accepted: 02/07/2025] [Indexed: 02/11/2025]
Abstract
INTRODUCTION The human endometrium is a highly regenerative tissue that contains mesenchymal stem/stromal cells (MSCs). These MSCs are sourced via office-based biopsies and menstrual fluid, providing a less invasive and readily available option for cell-based therapies. This review provides an update on endometrial-derived MSCs as a treatment option for gynecological diseases. AREAS COVERED This narrative review covers the characterization and therapeutic mechanisms of endometrium biopsy-derived MSCs (eMSCs) and menstrual fluid-derived mesenchymal stromal cells (MenSCs), highlighting similarities and differences. It also covers studies of their application in preclinical animal models and in clinical trials as potential cell-based therapies for gynecological diseases. EXPERT OPINION eMSCs and MenSCs from a homologous tissue source have the potential to promote regenerative activity as a treatment for gynecological diseases. Both eMSCs and MenSCs demonstrate therapeutic benefits through their paracrine activity in tissue regeneration, immunomodulation, angiogenesis, and mitigating fibrosis. Further research is essential to establish standardized isolation and characterization protocols, particularly for heterogeneous MenSCs, and to fully understand their mechanisms of action. Implementing SUSD2 magnetic bead sorting for purifying eMSCs from endometrial tissues and menstrual fluid is crucial for their use in future cell-based therapies. Optimization of production, storage, and delivery methods will maximize their therapeutic effectiveness.
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Affiliation(s)
- Alexander Sadiasa
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Jerome A Werkmeister
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Shanti Gurung
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Caroline E Gargett
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
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Wan R, Liu Y, Yan J, Lin J. Cell therapy: A beacon of hope in the battle against pulmonary fibrosis. FASEB J 2025; 39:e70356. [PMID: 39873972 DOI: 10.1096/fj.202402790r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 12/28/2024] [Accepted: 01/15/2025] [Indexed: 01/30/2025]
Abstract
Pulmonary fibrosis (PF) is a chronic and progressive interstitial lung disease characterized by abnormal activation of myofibroblasts and pathological remodeling of the extracellular matrix, with a poor prognosis and limited treatment options. Lung transplantation is currently the only approach that can extend the life expectancy of patients; however, its applicability is severely restricted due to donor shortages and patient-specific limitations. Therefore, the search for novel therapeutic strategies is imperative. In recent years, stem cells have shown great promise in the field of regenerative medicine due to their self-renewal capacity and multidirectional differentiation potential, and a growing body of literature supports the efficacy of stem cell therapy in PF treatment. This paper systematically summarizes the research progress of various stem cell types in the treatment of PF. Furthermore, it discusses the primary methods and clinical outcomes of stem cell therapy in PF, based on both preclinical and clinical data. Finally, the current challenges and key factors to consider in stem cell therapy for PF are objectively analyzed, and future directions for improving this therapy are proposed, providing new insights and references for the clinical treatment of PF patients.
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Affiliation(s)
- Ruyan Wan
- Stem Cell and Biotherapy Technology Research Center, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, China
| | - Yanli Liu
- Stem Cell and Biotherapy Technology Research Center, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, China
| | - Jingwen Yan
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Juntang Lin
- Stem Cell and Biotherapy Technology Research Center, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, China
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Biomedical Engineering, Xinxiang Medical University, Xinxiang, China
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Ning G, Guo X, Zhu K, Xu Z, Cai P, Dang Y, Lu C, Xu F, Shen R, Kang N, Zhang R, Chen K. Human decidual mesenchymal stem cells obtained from early pregnancy attenuate bleomycin-induced lung fibrosis by inhibiting inflammation and apoptosis. Int Immunopharmacol 2024; 142:113224. [PMID: 39306886 DOI: 10.1016/j.intimp.2024.113224] [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: 04/14/2024] [Revised: 09/17/2024] [Accepted: 09/18/2024] [Indexed: 10/12/2024]
Abstract
BACKGROUND Decidual mesenchymal stem cells (DMSCs) are easily obtained and exhibit strong anti-inflammatory and anti-apoptotic effects. Compared with bone marrow mesenchymal stem cells (BMSCs), their role in cell transplantation after idiopathic pulmonary fibrosis remains unclear. We investigated whether the transplantation of BMSCs and DMSCs could alleviate pulmonary inflammation and fibrosis in a bleomycin-induced mouse model of pulmonary fibrosis. METHODS BMSCs and DMSCs were derived from healthy donors. The anti-inflammatory and anti-apoptotic effects on both cell types were evaluated in vitro. The function of DMSCs in MLE-12 cells and mouse lung fibroblasts was examined using additional transwell coculture experiments in vitro. Twenty-one days after MSC transplantation, we examined the inflammatory factors in the serum and bronchoalveolar lavage fluid, collagen content, pathology, fibrotic area, lung function, and micro-computed tomography of the lung tissue. RESULTS DMSCs exhibited better anti-inflammatory and anti-apoptotic effects than BMSCs on MLE-12 cells in vitro. In addition, DMSCs inhibited tumor growth factor β-dependent epithelial-mesenchymal transition in MLE-12 cells and attenuated mouse lung fibroblasts fibrosis. Furthermore, transplantation of DMSCs in the mouse idiopathic pulmonary fibrosis model significantly attenuated pulmonary inflammation and lung fibrosis compared with BMSCs transplantation. CONCLUSIONS DMSCs exhibited better efficacy in improving pulmonary inflammation and lung fibrosis than BMSCs. Thus, DMSCs are a potential therapeutic target for pulmonary fibrosis.
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Affiliation(s)
- Guangyao Ning
- Department of Thoracic Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, PR China
| | - Xiaohui Guo
- Department of Pathology, the First Affiliated Hospital of Anhui Medical University, Hefei, PR China
| | - Kechao Zhu
- Department of Thoracic Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, PR China
| | - Ziqiang Xu
- Department of Thoracic Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, PR China
| | - Peian Cai
- Department of Thoracic Surgery, Henan Cancer Hospital, Zhengzhou, PR China
| | - Yan Dang
- Department of Thoracic Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, PR China
| | - Chen Lu
- Department of Thoracic Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, PR China
| | - Feng Xu
- Department of Thoracic Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, PR China
| | - Ruifang Shen
- Laboratory for Space Environment and Physical Sciences, Harbin Institute of Technology, Harbin, PR China
| | - Ningning Kang
- Department of Thoracic Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, PR China.
| | - Renquan Zhang
- Department of Thoracic Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, PR China.
| | - Kegong Chen
- Department of Thoracic Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, PR China; Research and experiment center, the First Affiliated Hospital of Anhui Medical University, Hefei, PR China.
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Hu Z, Zhu L, Zhu Y, Xu Y. Mesenchymal Stem Extracellular Vesicles in Various Respiratory Diseases: A New Opportunity. J Inflamm Res 2024; 17:9041-9058. [PMID: 39583853 PMCID: PMC11586120 DOI: 10.2147/jir.s480345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 10/26/2024] [Indexed: 11/26/2024] Open
Abstract
Lung diseases are associated with high morbidity and mortality rates, thereby jeopardizing human health and imposing a great burden on society. Currently, lung diseases are mainly treated with medications, oxygen therapy and mechanical ventilation, but these approaches are unable to effectively reduce the mortality rate. Therefore, lung transplantation remains the ultimate treatment for various chronic lung diseases, but this treatment is also hindered by the limited availability of lung sources, immature technology and a low survival rate after transplantation. With constant changes in the environment, pathogens, type and amount of harmful substances and the prevalence of respiratory diseases, there is an urgent need to identify alternative treatment methods. Research on stem cell therapy has been very successful in recent years, and mesenchymal stem cells (MSCs), together with their secretory bodies, play a significant therapeutic role. Extracellular vesicles of MSCs (MSC-EVs) are also major components of the paracrine secretion of MSCs, including exosomes, microvesicles, and apoptotic bodies, among which exosomes are the most typical. MSC-EVs are believed to be present in various tissues of the human body where they can carry proteins, DNA, RNA and biologically active factors, just to name a few. They can also transmit various biological signals to participate in different biological activities, including the maintenance of homeostasis within the tissue. Several studies have further demonstrated that MSCs and their generated extracellular vesicles play an important role in the treatment of diseases. In this paper, the origin, properties and roles of MSCs and MSC-EVs are reviewed, the mechanisms of different lung diseases, the limitations of current therapeutic options and the roles of MSC-EVs in Chronic Obstructive Pulmonary Disease, asthma, infectious lung disease, lung cancer, pulmonary fibrosis, pulmonary arterial hypertension, and acute lung injury/ acute respiratory distress syndrome are also discussed (Figure 1). In addition, the current limitations and possible future research directions are also discussed in view of providing new ideas for the role of MSC-EVs in the treatment of lung diseases.
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Affiliation(s)
- Zijun Hu
- School of Medicine, Shaoxing University, Shaoxing, Zhejiang, People’s Republic of China
| | - Lujian Zhu
- Department of Infectious Disease, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, People’s Republic of China
| | - Yanglin Zhu
- Department of Hepatobiliary Pancreatic Gastrointestinal Surgery 2, Affiliated Jinhua Hospital of Wenzhou Medical University, Jinhua, Zhejiang, People’s Republic of China
| | - Yejin Xu
- Department of Infectious Disease, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, People’s Republic of China
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Chen Q, Shao B, Xu YN, Li X, Ren SH, Wang HD, Zhang JY, Sun CL, Liu T, Xiao YY, Zhao PY, Yang GM, Liu X, Wang H. IGF2 contributes to the immunomodulatory effects of exosomes from endometrial regenerative cells on experimental colitis. Int Immunopharmacol 2024; 140:112825. [PMID: 39079347 DOI: 10.1016/j.intimp.2024.112825] [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: 05/13/2024] [Revised: 07/19/2024] [Accepted: 07/25/2024] [Indexed: 09/01/2024]
Abstract
BACKGROUND Exosomes derived from endometrial regenerative cells (ERC-Exos) can inherit the immunomodulatory function from ERCs, however, whether ERC-Exos exhibit such effect on inflammatory bowel diseases with mucosal immune dysregulation has not been explored. Insulin-like growth factor-Ⅱ (IGF2) is considered to possess the potential to induce an anti-inflammatory phenotype in immune cells. In this study, the contribution of IGF2 in mediating the protective efficacy of ERC-Exos on colitis was investigated. METHODS Lentiviral transfection was employed to obtain IGF2-specific knockout ERC-Exos (IGF2-/--ERC-Exos). Experimental colitis mice induced by dextran sulfate sodium (DSS) were divided into the phosphate-buffered saline (untreated), ERC-Exos-treated and IGF2-/--ERC-Exos-treated groups. Colonic histopathological analysis and intestinal barrier function were explored. The infiltration of CD4+ T cells and dendritic cells (DCs) were analyzed by immunofluorescence staining and flow cytometry. The maturation and function of bone marrow-derived dendritic cells (BMDCs) in different exosome administrations were evaluated by flow cytometry, ELISA and the coculture system, respectively. RESULTS Compared with the untreated group, ERC-Exos treatment significantly attenuated DSS-induced weight loss, bloody stools, shortened colon length, pathological damage, as well as repaired the weakened intestinal mucosal barrier, including promoting the goblet cells retention, restoring the intestinal barrier integrity and enhancing the expression of tight junction proteins, while the protective effect of exosomes was impaired with the knockout of IGF2 in ERC-Exos. Additionally, IGF2-expressing ERC-Exos decreased the proportions of Th1 and Th17, increased the proportions of Treg, as well as attenuated DC infiltration and maturation in mesenteric lymph nodes and lamina propria of the colitis mice. ERC-Exos were also observed to be phagocytosed by BMDCs and IGF2 is responsible for the modulating effect of ERC-Exos on BMDCs in vitro. CONCLUSIONS Exosomes derived from ERCs can exert a therapeutic effect on experimental colitis with remarkable alleviation of the intestinal barrier damage and the abnormal mucosal immune responses. We emphasized that IGF2 plays a critical role for ERC-Exos mediated immunomodulatory function and protection against colitis.
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Affiliation(s)
- Qiang Chen
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Bo Shao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Yi-Ni Xu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Xiang Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Shao-Hua Ren
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China; Department of General Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China.
| | - Hong-da Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Jing-Yi Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Cheng-Lu Sun
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Tong Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Yi-Yi Xiao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Peng-Yu Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Guang-Mei Yang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Xu Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China; Tianjin Key Laboratory of Precise Vascular Reconstruction and Organ Function Repair, Tianjin, China.
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Attia SH, Saadawy SF, El-Mahroky SM, Nageeb MM. Alleviation of pulmonary fibrosis by the dual PPAR agonist saroglitazar and breast milk mesenchymal stem cells via modulating TGFß/SMAD pathway. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:5953-5974. [PMID: 38376539 PMCID: PMC11329427 DOI: 10.1007/s00210-024-03004-y] [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: 12/16/2023] [Accepted: 02/09/2024] [Indexed: 02/21/2024]
Abstract
Pulmonary fibrosis (PF) is a complex disorder with high morbidity and mortality. Limited efficacies of the available drugs drive researchers to seek for new therapies. Saroglitazar (Saro), a full (PPAR α/γ) agonist, is devoid of known PPAR-mediated adverse effects. Breast milk mesenchymal stem cells (BrMSCs) are contemplated to be the ideal cell type harboring differentiation/anti-inflammatory/immunosuppressive properties. Accordingly, our aims were to investigate the potential roles of Saro and/or BrMSCs in PF and to spot their underlying protective mechanisms. In this study, PF was induced by bleomycin (BLM) via intratracheal instillation. Treatment started 14 days later. Animals were treated with oral saroglitazar (3 mg/kg daily) or intraperitoneal single BrMSCs injection (0.5 ml phosphate buffer saline (PBS) containing 2 × 107 cells) or their combination with same previous doses. At the work end, 24 h following the 6 weeks of treatment period, the levels of oxidative (MDA, SOD), inflammatory (IL-1ß, IL-10), and profibrotic markers (TGF-ß, αSMA) were assessed. The autophagy-related genes (LC3, Beclin) and the expression of PPAR-α/γ and SMAD-3/7 were evaluated. Furthermore, immunohistochemical and histological work were evaluated. Our study revealed marked lung injury influenced by BLM with severe oxidative/inflammatory/fibrotic damage, autophagy inhibition, and deteriorated lung histology. Saro and BrMSCs repaired the lung structure worsened by BLM. Treatments greatly declined the oxidative/inflammatory markers. The pro-fibrotic TGF-ß, αSMA, and SMAD-3 were decreased. Contrarily, autophagy markers were increased. SMAD-7 and PPAR α/γ were activated denoting their pivotal antifibrotic roles. Co-administration of Saro and BrMSCs revealed the top results. Our findings support the study hypothesis that Saro and BrMSCs can be proposed as potential treatments for IPF.
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Affiliation(s)
- Seba Hassan Attia
- Clinical Pharmacology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
| | - Sara F Saadawy
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Samaa M El-Mahroky
- Medical Histology and Cell Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Mahitab M Nageeb
- Clinical Pharmacology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Chen L, Huang Y, Zhang N, Qu J, Fang Y, Fu J, Yuan Y, Zhang Q, Li H, Wen Z, Yuan L, Chen L, Xu Z, Li Y, Yan H, Izawa H, Li L, Xiang C. Single-cell RNA sequencing reveals reduced intercellular adhesion molecule crosstalk between activated hepatic stellate cells and neutrophils alleviating liver fibrosis in hepatitis B virus transgenic mice post menstrual blood-derived mesenchymal stem cell transplantation. MedComm (Beijing) 2024; 5:e654. [PMID: 39040848 PMCID: PMC11261812 DOI: 10.1002/mco2.654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 06/03/2024] [Accepted: 06/10/2024] [Indexed: 07/24/2024] Open
Abstract
Liver fibrosis can cause hepatitis B virus (HBV)-associated hepatocellular carcinoma. Menstrual blood-derived mesenchymal stem cells (MenSCs) can ameliorate liver fibrosis through paracrine. Single-cell RNA sequencing (scRNA-seq) may be used to explore the roadmap of activated hepatic stellate cell (aHSC) inactivation to target liver fibrosis. This study established HBV transgenic (HBV-Tg) mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis and demonstrated that MenSCs migrated to the injured liver to improve serological indices and reduce fibrotic accumulation. RNA-bulk analysis revealed that MenSCs mediated extracellular matrix accumulation and cell adhesion. Liver parenchymal cells and nonparenchymal cells were identified by scRNA-seq in the control, CCl4, and MenSC groups, revealing the heterogeneity of fibroblasts/HSCs. A CellChat analysis revealed that diminished intercellular adhesion molecule (ICAM) signaling is vital for MenSC therapy. Specifically, Icam1 in aHSCs acted on Itgal/Itgb2 and Itgam/Itgb2 in neutrophils, causing decreased adhesion. The expression of Itgal, Itgam, and Itgb2 was higher in CCl4 group than in the control group and decreased after MenSC therapy in neutrophil clusters. The Lcn2, Pglyrp1, Wfdc21, and Mmp8 had high expression and may be potential targets in neutrophils. This study highlights interacting cells, corresponding molecules, and underlying targets for MenSCs in treating HBV-associated liver fibrosis.
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Affiliation(s)
- Lijun Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Research Units of Infectious Disease and MicroecologyChinese Academy of Medical SciencesBeijingChina
| | - Yuqi Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Ning Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jingjing Qu
- Department of Respiratory DiseaseThoracic Disease CentreThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Yangxin Fang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jiamin Fu
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Yin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Qi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Hang Li
- Innovative Precision Medicine (IPM) GroupHangzhouChina
| | - Zuoshi Wen
- Department of CardiologyThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Li Yuan
- Innovative Precision Medicine (IPM) GroupHangzhouChina
| | - Lu Chen
- Innovative Precision Medicine (IPM) GroupHangzhouChina
| | - Zhenyu Xu
- Innovative Precision Medicine (IPM) GroupHangzhouChina
| | - Yifei Li
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Research Units of Infectious Disease and MicroecologyChinese Academy of Medical SciencesBeijingChina
| | - Huadong Yan
- Infectious Disease DepartmentShulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical CollegeHangzhouChina
| | | | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Research Units of Infectious Disease and MicroecologyChinese Academy of Medical SciencesBeijingChina
- Jinan Microecological Biomedicine Shandong LaboratoryJinanChina
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Research Units of Infectious Disease and MicroecologyChinese Academy of Medical SciencesBeijingChina
- Jinan Microecological Biomedicine Shandong LaboratoryJinanChina
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Yuan Y, Chen L, Yang J, Zhou S, Fang Y, Zhang Q, Zhang N, Li Y, Yuan L, Jia F, Ni S, Xiang C. Enhanced homing of mesenchymal stem cells for in situ niche remodeling and bone regeneration. NANO RESEARCH 2024; 17:7449-7460. [DOI: 10.1007/s12274-024-6715-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 04/20/2024] [Accepted: 04/22/2024] [Indexed: 09/09/2024]
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Zhang B, Gao S, Liu S, Gong X, Wu J, Zhang Y, Ma L, Sheng L. Regenerative mechanisms of stem cells and their clinical applications for degenerative eye diseases. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2024; 29:42. [PMID: 40224196 PMCID: PMC11992415 DOI: 10.4103/jrms.jrms_358_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 01/14/2024] [Accepted: 03/18/2024] [Indexed: 04/15/2025]
Abstract
There are different types of treatment for eye diseases. Although the majority of eye diseases are curable with primary treatments and surgery, some of degenerative eye damages need regeneration that is not gained by conventional procedures. Stem cells, such as mesenchymal stem cells, human embryonic stem cell-derived retinal pigmented epithelium, and inducible pluripotent stem cells, are now considered one of the most important and safe methods for regeneration of various damaged tissues or organs. However, how will stem cell therapy contribute to regeneration and overcome degenerative eye diseases? This review discusses the regenerative mechanisms, clinical applications, and advantages of different types of stem cells for restoring degenerative eye diseases.
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Affiliation(s)
- Baodong Zhang
- Department of Ophthalmology, Hulun Buir Aier Eye Hospital, Hulunbuir, Inner Mongolia, China
| | - Shusong Gao
- Department of Ophthalmology, Ezhou Central Hospital, Ezhou, Hubei, China
| | - Shibo Liu
- Department of Ophthalmology, Hulun Buir Aier Eye Hospital, Hulunbuir, Inner Mongolia, China
| | - Xuewu Gong
- Department of Ophthalmologic, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang, China
| | - Jing Wu
- Department of Ophthalmologic, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang, China
| | - Yu Zhang
- Department of Ophthalmologic, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang, China
| | - Li Ma
- Department of Ophthalmologic, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang, China
| | - Lijie Sheng
- Department of Ophthalmologic, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang, China
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Fu J, Zhang Q, Zhang N, Zhou S, Fang Y, Li Y, Yuan L, Chen L, Xiang C. Human Menstrual Blood-Derived Stem Cells Protect against Tacrolimus-Induced Islet Dysfunction via Cystathionine β-Synthase Mediated IL-6/STAT3 Inactivation. Biomolecules 2024; 14:671. [PMID: 38927074 PMCID: PMC11201965 DOI: 10.3390/biom14060671] [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: 04/19/2024] [Revised: 06/02/2024] [Accepted: 06/06/2024] [Indexed: 06/28/2024] Open
Abstract
Diabetes imposes a huge burden worldwide. Islet transplantation is an alternative therapy for diabetes. However, tacrolimus, a kind of immunosuppressant after organ transplantation, is closely related to post-transplant diabetes mellitus. Mesenchymal stem cells (MSCs) have attracted interest for their potential to alleviate diabetes. In vivo experiments revealed that human menstrual blood-derived stem cells (MenSCs) treatment improved tacrolimus-induced blood glucose, body weight, and glucose tolerance disorders in mice. RNA sequencing was used to analyze the potential therapeutic targets of MenSCs. In this study, we illustrated that cystathionine β-synthase (CBS) contributed to tacrolimus -induced islet dysfunction. Using β-cell lines (MIN6, β-TC-6), we demonstrated that MenSCs ameliorated tacrolimus-induced islet dysfunction in vitro. Moreover, MenSC reduced the tacrolimus-induced elevation of CBS levels and significantly enhanced the viability, anti-apoptotic ability, glucose-stimulated insulin secretion (GSIS), and glycolytic flux of β-cells. We further revealed that MenSCs exerted their therapeutic effects by inhibiting CBS expression to activate the IL6/JAK2/STAT3 pathway. In conclusion, we showed that MenSCs may be a potential strategy to improve tacrolimus-induced islet dysfunction.
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Affiliation(s)
- Jiamin Fu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (J.F.); (Q.Z.); (N.Z.); (S.Z.); (Y.F.); (Y.L.)
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, China
| | - Qi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (J.F.); (Q.Z.); (N.Z.); (S.Z.); (Y.F.); (Y.L.)
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, China
| | - Ning Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (J.F.); (Q.Z.); (N.Z.); (S.Z.); (Y.F.); (Y.L.)
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, China
| | - Sining Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (J.F.); (Q.Z.); (N.Z.); (S.Z.); (Y.F.); (Y.L.)
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, China
| | - Yangxin Fang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (J.F.); (Q.Z.); (N.Z.); (S.Z.); (Y.F.); (Y.L.)
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, China
| | - Yifei Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (J.F.); (Q.Z.); (N.Z.); (S.Z.); (Y.F.); (Y.L.)
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, China
| | - Li Yuan
- Innovative Precision Medicine (IPM) Group, Hangzhou 311215, China;
| | - Lijun Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (J.F.); (Q.Z.); (N.Z.); (S.Z.); (Y.F.); (Y.L.)
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, China
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (J.F.); (Q.Z.); (N.Z.); (S.Z.); (Y.F.); (Y.L.)
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250117, China
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Chen Y, Zhong J, Cai Z, Xia Z, Qing B, Yuan Y, Zhang J. Meta-analysis of the association between sex hormones and pulmonary fibrosis. Postgrad Med 2024; 136:567-576. [PMID: 39109519 DOI: 10.1080/00325481.2024.2373683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 06/17/2024] [Indexed: 08/15/2024]
Abstract
BACKGROUND This study aimed to investigate the association between sex hormones and the risk of pulmonary fibrosis by conducting a meta-analysis of previously published studies. METHODS We executed a comprehensive search of the PubMed, Embase, Cochrane Library, and Web of Science databases to locate pertinent studies published up to April 2024. We included studies that reported the association between sex hormones and the risk of pulmonary fibrosis. Standardized mean difference (SMD) with 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS A total of 10 articles, encompassing 1371 patients, were finally incorporated in this meta-analysis. Based on the evaluation of the included studies, it was observed that the levels of dehydroepiandrosterone sulfate (DHEA-S) (pooled SMD: -0.72, 95% CI: -1.21 to -0.24, p < 0.001), testosterone (pooled SMD: -1.25, CI: -2.39 and -0.11, p < 0.001) and estrogen (pooled SMD: -0.56, 95% CI: -0.96 to -0.15, p < 0.001) were significantly lower in patients with pulmonary fibrosis, whereas the levels of luteinizing hormone (LH) remained unaffected. Publication bias was ruled out through funnel plots. CONCLUSION This meta-analysis indicates that reduced levels of DHEA-S, testosterone, estrogen may serve as potential risk factors for pulmonary fibrosis. There is a pressing need for additional studies to confirm this association and explore the underlying biological mechanisms. Clinicians should recognize the potential influence of sex hormones in the etiology of pulmonary fibrosis and consider this aspect during the patient management process.
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Affiliation(s)
- Ying Chen
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Jiaxin Zhong
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zixin Cai
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhenkun Xia
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Bei Qing
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yunchang Yuan
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Jingjing Zhang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
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14
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Akbaribazm M. Exploring the Regenerative Potential of Stem Cells for Treating Eye Diseases: A Review of the New Findings. OBM GENETICS 2024; 08:1-14. [DOI: 10.21926/obm.genet.2401212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The escalating prevalence of vision loss due to eye diseases has instigated a quest for innovative therapies, given that conventional approaches often fall short in repairing and regenerating damaged eye tissues, particularly the retina. Stem cell-based interventions have emerged as a promising avenue, with numerous studies in animal models and human trials exploring their potential to enhance visual acuity. Beyond addressing conditions like age-related macular degeneration (AMD) and diabetic retinopathy (DR), stem cell therapies demonstrate efficacy in treating genetic disorders such as retinitis pigmentosa (RP). In severe eye damage necessitating regeneration, stem cells play a pivotal role, leveraging their regenerative capabilities. Noteworthy is the transplantation of retinal pigment epithelial (RPE) cells derived from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), showcasing promising results in preclinical models and clinical studies, leading to improved retinal function without severe side effects. Mesenchymal stem cells (MSCs) have successfully treated optic neuropathy, RP, DR, and glaucoma, yielding positive clinical outcomes. The safety of adult stem cells, particularly MSCs derived from adipose tissue or bone marrow, has been firmly established. This review highlights significant advancements in utilizing human ESC-derived retinal pigmented epithelium and iPSCs for treating eye injuries. While cell-based therapy is relatively nascent, with numerous clinical trials pending review, stem cells' regenerative potential and clinical applications in addressing eye diseases offer substantial promise. This study aims to comprehensively examine the applications of stem cells in the context of eye diseases and their potential role in regenerative medicine.
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Diwan R, Bhatt HN, Beaven E, Nurunnabi M. Emerging delivery approaches for targeted pulmonary fibrosis treatment. Adv Drug Deliv Rev 2024; 204:115147. [PMID: 38065244 PMCID: PMC10787600 DOI: 10.1016/j.addr.2023.115147] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 11/02/2023] [Accepted: 11/29/2023] [Indexed: 01/01/2024]
Abstract
Pulmonary fibrosis (PF) is a progressive, and life-threatening interstitial lung disease which causes scarring in the lung parenchyma and thereby affects architecture and functioning of lung. It is an irreversible damage to lung functioning which is related to epithelial cell injury, immense accumulation of immune cells and inflammatory cytokines, and irregular recruitment of extracellular matrix. The inflammatory cytokines trigger the differentiation of fibroblasts into activated fibroblasts, also known as myofibroblasts, which further increase the production and deposition of collagen at the injury sites in the lung. Despite the significant morbidity and mortality associated with PF, there is no available treatment that efficiently and effectively treats the disease by reversing their underlying pathologies. In recent years, many therapeutic regimens, for instance, rho kinase inhibitors, Smad signaling pathway inhibitors, p38, BCL-xL/ BCL-2 and JNK pathway inhibitors, have been found to be potent and effective in treating PF, in preclinical stages. However, due to non-selectivity and non-specificity, the therapeutic molecules also result in toxicity mediated severe side effects. Hence, this review demonstrates recent advances on PF pathology, mechanism and targets related to PF, development of various drug delivery systems based on small molecules, RNAs, oligonucleotides, peptides, antibodies, exosomes, and stem cells for the treatment of PF and the progress of various therapeutic treatments in clinical trials to advance PF treatment.
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Affiliation(s)
- Rimpy Diwan
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX 79902, United States; Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX 79968, United States
| | - Himanshu N Bhatt
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX 79902, United States; Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX 79968, United States
| | - Elfa Beaven
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX 79902, United States; Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX 79968, United States
| | - Md Nurunnabi
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX 79902, United States; Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX 79968, United States; The Border Biomedical Research Center, The University of Texas El Paso, El Paso, TX 79968, United States.
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Lee H, Jeong OY, Park HJ, Lee SL, Bok EY, Kim M, Suh YS, Cheon YH, Kim HO, Kim S, Chun SH, Park JM, Lee YJ, Lee SI. Promising Therapeutic Effects of Embryonic Stem Cells-Origin Mesenchymal Stem Cells in Experimental Pulmonary Fibrosis Models: Immunomodulatory and Anti-Apoptotic Mechanisms. Immune Netw 2023; 23:e45. [PMID: 38188598 PMCID: PMC10767550 DOI: 10.4110/in.2023.23.e45] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/04/2023] [Accepted: 12/05/2023] [Indexed: 01/09/2024] Open
Abstract
Interstitial lung disease (ILD) involves persistent inflammation and fibrosis, leading to respiratory failure and even death. Adult tissue-derived mesenchymal stem cells (MSCs) show potential in ILD therapeutics but obtaining an adequate quantity of cells for drug application is difficult. Daewoong Pharmaceutical's MSCs (DW-MSCs) derived from embryonic stem cells sustain a high proliferative capacity following long-term culture and expansion. The aim of this study was to investigate the therapeutic potential of DW-MSCs in experimental mouse models of ILD. DW-MSCs were expanded up to 12 passages for in vivo application in bleomycin-induced pulmonary fibrosis and collagen-induced connective tissue disease-ILD mouse models. We assessed lung inflammation and fibrosis, lung tissue immune cells, fibrosis-related gene/protein expression, apoptosis and mitochondrial function of alveolar epithelial cells, and mitochondrial transfer ability. Intravenous administration of DW-MSCs consistently improved lung fibrosis and reduced inflammatory and fibrotic markers expression in both models across various disease stages. The therapeutic effect of DW-MSCs was comparable to that following daily oral administration of nintedanib or pirfenidone. Mechanistically, DW-MSCs exhibited immunomodulatory effects by reducing the number of B cells during the early phase and increasing the ratio of Tregs to Th17 cells during the late phase of bleomycin-induced pulmonary fibrosis. Furthermore, DW-MSCs exhibited anti-apoptotic effects, increased cell viability, and improved mitochondrial respiration in alveolar epithelial cells by transferring their mitochondria to alveolar epithelial cells. Our findings indicate the strong potential of DW-MSCs in the treatment of ILD owing to their high efficacy and immunomodulatory and anti-apoptotic effects.
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Affiliation(s)
- Hanna Lee
- Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon 51427, Korea
- Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Hospital, Jinju 52727, Korea
| | - Ok-Yi Jeong
- Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Hospital, Jinju 52727, Korea
| | - Hee Jin Park
- Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Hospital, Jinju 52727, Korea
| | - Sung-Lim Lee
- College of Veterinary Medicine and Research Institute of Life Sciences, Gyeongsang National University, Jinju 52828, Korea
| | - Eun-yeong Bok
- College of Veterinary Medicine and Research Institute of Life Sciences, Gyeongsang National University, Jinju 52828, Korea
| | - Mingyo Kim
- Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Hospital, Jinju 52727, Korea
| | - Young Sun Suh
- Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon 51427, Korea
- Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Hospital, Jinju 52727, Korea
| | - Yun-Hong Cheon
- Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Hospital, Jinju 52727, Korea
| | - Hyun-Ok Kim
- Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon 51427, Korea
- Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Hospital, Jinju 52727, Korea
| | - Suhee Kim
- Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Hospital, Jinju 52727, Korea
| | - Sung Hak Chun
- Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Hospital, Jinju 52727, Korea
| | - Jung Min Park
- Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Hospital, Jinju 52727, Korea
| | - Young Jin Lee
- Cell Therapy Center, Daewoong Pharmaceutical, Co., Ltd., Yongin 17028, Korea
| | - Sang-Il Lee
- Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Hospital, Jinju 52727, Korea
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Huang RL, Li Q, Ma JX, Atala A, Zhang Y. Body fluid-derived stem cells - an untapped stem cell source in genitourinary regeneration. Nat Rev Urol 2023; 20:739-761. [PMID: 37414959 PMCID: PMC11639537 DOI: 10.1038/s41585-023-00787-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/30/2023] [Indexed: 07/08/2023]
Abstract
Somatic stem cells have been obtained from solid organs and tissues, including the bone marrow, placenta, corneal stroma, periosteum, adipose tissue, dental pulp and skeletal muscle. These solid tissue-derived stem cells are often used for tissue repair, disease modelling and new drug development. In the past two decades, stem cells have also been identified in various body fluids, including urine, peripheral blood, umbilical cord blood, amniotic fluid, synovial fluid, breastmilk and menstrual blood. These body fluid-derived stem cells (BFSCs) have stemness properties comparable to those of other adult stem cells and, similarly to tissue-derived stem cells, show cell surface markers, multi-differentiation potential and immunomodulatory effects. However, BFSCs are more easily accessible through non-invasive or minimally invasive approaches than solid tissue-derived stem cells and can be isolated without enzymatic tissue digestion. Additionally, BFSCs have shown good versatility in repairing genitourinary abnormalities in preclinical models through direct differentiation or paracrine mechanisms such as pro-angiogenic, anti-apoptotic, antifibrotic, anti-oxidant and anti-inflammatory effects. However, optimization of protocols is needed to improve the efficacy and safety of BFSC therapy before therapeutic translation.
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Affiliation(s)
- Ru-Lin Huang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qingfeng Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jian-Xing Ma
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Anthony Atala
- Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Yuanyuan Zhang
- Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
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Zhang S, Zhang R, Yin X, Lu Y, Cheng H, Pan Y, Liu Y, Lin J. MenSCs Transplantation Improve the Viability of Injured Endometrial Cells Through Activating PI3K/Akt Pathway. Reprod Sci 2023; 30:3325-3338. [PMID: 37308799 DOI: 10.1007/s43032-023-01282-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 06/01/2023] [Indexed: 06/14/2023]
Abstract
Endometrial injury is one of the leading causes of female infertility and is caused by intrauterine surgery, endometrial infection, repeated abortion, or genital tuberculosis. Currently, there is little effective treatment to restore the fertility of patients with severe intrauterine adhesions and thin endometrium. Recent studies have confirmed the promising therapeutic effects of mesenchymal stem cell transplantation on various diseases with definite tissue injury. The aim of this study is to investigate the improvements of menstrual blood-derived endometrial stem cells (MenSCs) transplantation on functional restoration in the endometrium of mouse model. Therefore, ethanol-induced endometrial injury mouse models were randomly divided into two groups: the PBS-treated group, and the MenSCs-treated group. As expected, the endometrial thickness and gland number in the endometrium of MenSCs-treated mice were significantly improved compared to those of PBS-treated mice (P < 0.05), and fibrosis levels were significantly reduced (P < 0.05). Subsequent results revealed that MenSCs treatment significantly promoted angiogenesis in the injured endometrium. Simultaneously, MenSCs enhance the proliferation and antiapoptotic capacity of endometrial cells, which is likely contributed by activating the PI3K/Akt signaling pathway. Further tests also confirmed the chemotaxis of GFP-labeled MenSCs towards the injured uterus. Consequently, MenSCs treatment significantly improved the pregnant mice and the number of embryos in pregnant mice. This study confirmed the superior improvements of MenSCs transplantation on the injured endometrium and uncovered the potential therapeutic mechanism, which provides a promising alternative for patients with serious endometrial injury.
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Affiliation(s)
- Shenghui Zhang
- Stem Cell and Biotherapy Technology Research Center, College of Life Science and Technology, Xinxiang Medical University, NO 601, East of JinSui Road, Xinxiang, 453003, Henan Province, China
- Department of Biomedical Sciences, Advanced Medical and Dental Institute (IPPT), Universiti Sains Malaysia, Gelugor, Penang, Malaysia
| | - Ruiyun Zhang
- Stem Cell and Biotherapy Technology Research Center, College of Life Science and Technology, Xinxiang Medical University, NO 601, East of JinSui Road, Xinxiang, 453003, Henan Province, China
| | - Xiyao Yin
- The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453000, China
| | - Yuyu Lu
- The Third Affiliated Hospital of Xinxiang Medical University, Hualan Road, XinxiangHenan Province, 453100, China
| | - Hongbin Cheng
- College of Biomedical Engineering, Xinxiang Medical University, Xinxiang, 453003, China
- The Third Medical Center of Chinese, PLA General Hospital, Beijing, 100039, China
| | - Ying Pan
- Stem Cell and Biotherapy Technology Research Center, College of Life Science and Technology, Xinxiang Medical University, NO 601, East of JinSui Road, Xinxiang, 453003, Henan Province, China.
- The Third Affiliated Hospital of Xinxiang Medical University, Hualan Road, XinxiangHenan Province, 453100, China.
| | - Yanli Liu
- Stem Cell and Biotherapy Technology Research Center, College of Life Science and Technology, Xinxiang Medical University, NO 601, East of JinSui Road, Xinxiang, 453003, Henan Province, China.
| | - Juntang Lin
- Stem Cell and Biotherapy Technology Research Center, College of Life Science and Technology, Xinxiang Medical University, NO 601, East of JinSui Road, Xinxiang, 453003, Henan Province, China
- College of Biomedical Engineering, Xinxiang Medical University, Xinxiang, 453003, China
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Hosoya S, Yokomizo R, Kishigami H, Fujiki Y, Kaneko E, Amita M, Saito T, Kishi H, Sago H, Okamoto A, Umezawa A. Novel therapeutic strategies for injured endometrium: intrauterine transplantation of menstrual blood‑derived cells from infertile patients. Stem Cell Res Ther 2023; 14:297. [PMID: 37840125 PMCID: PMC10577920 DOI: 10.1186/s13287-023-03524-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Accepted: 09/27/2023] [Indexed: 10/17/2023] Open
Abstract
BACKGROUND Menstrual blood-derived cells show regenerative potential as a mesenchymal stem cell and may therefore be a novel stem cell source of treatment for refractory infertility with injured endometrium. However, there have been few pre-clinical studies using cells from infertile patients, which need to be addressed before establishing an autologous transplantation. Herein, we aimed to investigate the therapeutic capacity of menstrual blood-derived cells from infertile patients on endometrial infertility. METHODS We collected menstrual blood-derived cells from volunteers and infertile patients and confirmed their mesenchymal stem cell phenotype by flow cytometry and induction of tri-lineage differentiation. We compared the proliferative and paracrine capacities of these cells. Furthermore, we also investigated the regenerative potential and safety concerns of the intrauterine transplantation of infertile patient-derived cells using a mouse model with mechanically injured endometrium. RESULTS Menstrual blood-derived cells from both infertile patients and volunteers showed phenotypic characteristics of mesenchymal stem cells. In vitro proliferative and paracrine capacities for wound healing and angiogenesis were equal for both samples. Furthermore, the transplantation of infertile patient-derived cells into uterine horns of the mouse model ameliorated endometrial thickness, prevented fibrosis, and improved fertility outcomes without any apparent complications. CONCLUSIONS In our pre-clinical study, intrauterine transplantation of menstrual blood-derived cells may be a novel and attractive stem cell source for the curative and prophylactic therapy for injured endometrium. Further studies will be warranted for future clinical application.
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Affiliation(s)
- Satoshi Hosoya
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato, Tokyo, 105-8461, Japan
- Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
| | - Ryo Yokomizo
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato, Tokyo, 105-8461, Japan
- Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
| | - Harue Kishigami
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
| | - Yukiko Fujiki
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
| | - Erika Kaneko
- Division of Reproductive Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
| | - Mitsuyoshi Amita
- Division of Reproductive Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
| | - Takakazu Saito
- Division of Reproductive Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
| | - Hiroshi Kishi
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato, Tokyo, 105-8461, Japan
| | - Haruhiko Sago
- Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
| | - Aikou Okamoto
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato, Tokyo, 105-8461, Japan
| | - Akihiro Umezawa
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan.
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Zhang Q, Zhou SN, Fu JM, Chen LJ, Fang YX, Xu ZY, Xu HK, Yuan Y, Huang YQ, Zhang N, Li YF, Xiang C. Interferon-γ priming enhances the therapeutic effects of menstrual blood-derived stromal cells in a mouse liver ischemia-reperfusion model. World J Stem Cells 2023; 15:876-896. [PMID: 37900937 PMCID: PMC10600742 DOI: 10.4252/wjsc.v15.i9.876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/21/2023] [Accepted: 07/18/2023] [Indexed: 09/25/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have been used in liver transplantation and have certain effects in alleviating liver ischemia-reperfusion injury (IRI) and regulating immune rejection. However, some studies have indicated that the effects of MSCs are not very significant. Therefore, approaches that enable MSCs to exert significant and stable therapeutic effects are worth further study. AIM To enhance the therapeutic potential of human menstrual blood-derived stromal cells (MenSCs) in the mouse liver ischemia-reperfusion (I/R) model via interferon-γ (IFN-γ) priming. METHODS Apoptosis was analyzed by flow cytometry to evaluate the safety of IFN-γ priming, and indoleamine 2,3-dioxygenase (IDO) levels were measured by quantitative real-time reverse transcription polymerase chain reaction, western blotting, and ELISA to evaluate the efficacy of IFN-γ priming. In vivo, the liver I/R model was established in male C57/BL mice, hematoxylin and eosin and TUNEL staining was performed and serum liver enzyme levels were measured to assess the degree of liver injury, and regulatory T cell (Treg) numbers in spleens were determined by flow cytometry to assess immune tolerance potential. Metabolomics analysis was conducted to elucidate the potential mechanism underlying the regulatory effects of primed MenSCs. In vitro, we established a hypoxia/reoxygenation (H/R) model and analyzed apoptosis by flow cytometry to investigate the mechanism through which primed MenSCs inhibit apoptosis. Transmission electron microscopy, western blotting, and immunofluorescence were used to analyze autophagy levels. RESULTS IFN-γ-primed MenSCs secreted higher levels of IDO, attenuated liver injury, and increased Treg numbers in the mouse spleens to greater degrees than untreated MenSCs. Metabolomics and autophagy analyses proved that primed MenSCs more strongly induced autophagy in the mouse livers. In the H/R model, autophagy inhibitors increased the level of H/R-induced apoptosis, indicating that autophagy exerted protective effects. In addition, primed MenSCs decreased the level of H/R-induced apoptosis via IDO and autophagy. Further rescue experiments proved that IDO enhanced the protective autophagy by inhibiting the mammalian target of rapamycin (mTOR) pathway and activating the AMPK pathway. CONCLUSION IFN-γ-primed MenSCs exerted better therapeutic effects in the liver I/R model by secreting higher IDO levels. MenSCs and IDO activated the AMPK-mTOR-autophagy axis to reduce IRI, and IDO increased Treg numbers in the spleen and enhanced the MenSC-mediated induction of immune tolerance. Our study suggests that IFN-γ-primed MenSCs may be a novel and superior MSC product for liver transplantation in the future.
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Affiliation(s)
- Qi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, Zhejiang Province, China
| | - Si-Ning Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, Zhejiang Province, China
| | - Jia-Min Fu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, Zhejiang Province, China
| | - Li-Jun Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, Zhejiang Province, China
| | - Yang-Xin Fang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, Zhejiang Province, China
| | - Zhen-Yu Xu
- Innovative Precision Medicine Group, Shulan Hospital, Hangzhou 311215, Zhejiang Province, China
| | - Hui-Kang Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, Zhejiang Province, China
| | - Yin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, Zhejiang Province, China
| | - Yu-Qi Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, Zhejiang Province, China
| | - Ning Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, Zhejiang Province, China
| | - Yi-Fei Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, Zhejiang Province, China
| | - Charlie Xiang
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China.
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Steele H, Cheng J, Willicut A, Dell G, Breckenridge J, Culberson E, Ghastine A, Tardif V, Herro R. TNF superfamily control of tissue remodeling and fibrosis. Front Immunol 2023; 14:1219907. [PMID: 37465675 PMCID: PMC10351606 DOI: 10.3389/fimmu.2023.1219907] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 06/13/2023] [Indexed: 07/20/2023] Open
Abstract
Fibrosis is the result of extracellular matrix protein deposition and remains a leading cause of death in USA. Despite major advances in recent years, there remains an unmet need to develop therapeutic options that can effectively degrade or reverse fibrosis. The tumor necrosis super family (TNFSF) members, previously studied for their roles in inflammation and cell death, now represent attractive therapeutic targets for fibrotic diseases. In this review, we will summarize select TNFSF and their involvement in fibrosis of the lungs, the heart, the skin, the gastrointestinal tract, the kidney, and the liver. We will emphasize their direct activity on epithelial cells, fibroblasts, and smooth muscle cells. We will further report on major clinical trials targeting these ligands. Whether in isolation or in combination with other anti-TNFSF member or treatment, targeting this superfamily remains key to improve efficacy and selectivity of currently available therapies for fibrosis.
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Affiliation(s)
- Hope Steele
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- University of Cincinnati, Cincinnati, OH, United States
| | - Jason Cheng
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Ashley Willicut
- University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Garrison Dell
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- University of Cincinnati, Cincinnati, OH, United States
| | - Joey Breckenridge
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- University of Cincinnati, Cincinnati, OH, United States
| | - Erica Culberson
- University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Andrew Ghastine
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Virginie Tardif
- Normandy University, UniRouen, Institut National de la Santé et de la Recherche Médicale (INSERM), UMR1096 (EnVI Laboratory), Rouen, France
| | - Rana Herro
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- Department of Pediatrics, University of Cincinnati, Cincinnati, OH, United States
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22
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Li H, Wei J, Zhang Z, Li J, Ma Y, Zhang P, Lin J. Menstrual blood-derived endometrial stem cells alleviate neuroinflammation by modulating M1/M2 polarization in cell and rat Parkinson's disease models. Stem Cell Res Ther 2023; 14:85. [PMID: 37055866 PMCID: PMC10099022 DOI: 10.1186/s13287-023-03330-7] [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: 07/28/2022] [Accepted: 04/05/2023] [Indexed: 04/15/2023] Open
Abstract
BACKGROUND Neuroinflammation is closely related to the development of Parkinson's disease (PD). Because of the extensive sources, non-invasive and periodical collection method, human menstrual blood-derived endometrial stem cells (MenSCs) have been explored as a promising tool for treatment of PD. This study aimed to investigate if MenSCs could inhibit neuroinflammation in PD rats by regulating M1/M2 polarization and to excavate the underlying mechanisms. METHODS MenSCs were co-cultured with 6-OHDA-exposed microglia cell lines. Then the morphology of microglia cells and the level of inflammatory factors were assessed by immunofluorescence and qRT-PCR. After MenSCs were transplanted into the brain of PD rats, animal motor function, the expression of tyrosine hydroxylase, and the level of inflammatory factors in the cerebrospinal fluid (CSF) and serum were detected to evaluate the therapeutic potential of MenSCs. Meanwhile, the expression of M1/M2 phenotype related genes was detected by qRT-PCR. One protein array kit containing 1000 kinds of factors was used to detect the protein components in the conditioned medium of MenSCs. Finally, bioinformatic analysis was performed to analyze the function of factors secreted by MenSCs and the signal pathways involved in. RESULTS MenSCs could suppress 6-OHDA-induced microglia cell activation and significantly decrease inflammation in vitro. After transplantation into the brain of PD rats, MenSCs improved animal motor function, which was indicated by the increased movement distance, ambulatory episodes, exercise time on the rotarod, and less contralateral rotation. Additionally, MenSCs reduced the loss of dopaminergic neurons and down-regulated the level of pro-inflammatory factors in the CSF and serum. Moreover, q-PCR and WB results showed the transplantation of MenSCs significantly down-regulated the expression of M1 phenotype cell markers and meanwhile up-regulated the expression of M2 phenotype cell markers in the brain of PD rats. 176 biological processes including inflammatory response, negative regulation of apoptotic process, and microglial cell activation were enriched by GO-BP analysis. 58 signal pathways including PI3K/Akt and MAPK were enriched by KEGG analysis. CONCLUSIONS In conclusion, our results provide preliminary evidence for the anti-inflammation capacity of MenSCs by regulating M1/M2 polarization. We firstly demonstrated the biological process of factors secreted by MenSCs and the signal pathways involved in using protein array and bioinformatic analysis.
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Affiliation(s)
- Han Li
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, China
| | - Jinghui Wei
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, China
| | - Zhigang Zhang
- Department of Neurology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 45003, China
| | - Junyao Li
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, China
| | - Yaokai Ma
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, China
| | - Ping Zhang
- Department of Neurology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 45003, China
| | - Juntang Lin
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang, 453003, China.
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Zhou S, Liu Y, Zhang Q, Xu H, Fang Y, Chen X, Fu J, Yuan Y, Li Y, Yuan L, Xiang C. Human menstrual blood-derived stem cells reverse sorafenib resistance in hepatocellular carcinoma cells through the hyperactivation of mitophagy. Stem Cell Res Ther 2023; 14:58. [PMID: 37005657 PMCID: PMC10068152 DOI: 10.1186/s13287-023-03278-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 03/13/2023] [Indexed: 04/04/2023] Open
Abstract
BACKGROUND Sorafenib is a first-line drug targeting the RTK-MAPK signalling pathway used to treat advanced hepatocellular carcinoma (HCC). However, tumour cells readily develop sorafenib resistance, limiting long-term therapy with this drug. In our previous study, we found that human menstrual blood-derived stem cells (MenSCs) altered the expression of some sorafenib resistance-associated genes in HCC cells. Therefore, we wanted to further explore the feasibility of MenSC-based combination therapy in treating sorafenib-resistant HCC (HCC-SR) cells. METHODS The therapeutic efficiency of sorafenib was determined using CCK-8 (Cell Counting Kit-8), Annexin V/PI and clone formation assays in vitro and a xenograft mouse model in vivo. DNA methylation was determined using RT‒PCR and methylated DNA immunoprecipitation (MeDIP). Autophagy was detected by measuring LC3-II degradation and autophagosome maturation. Transmission electron microscopy identified autophagosomes and mitochondria. Physiological functions of mitochondria were assessed by measuring the ATP content, reactive oxygen species (ROS) generation, and mitochondrial membrane potential (MMP). RESULTS The tumour suppressor genes BCL2 interacting protein 3 (BNIP3) and BCL2 interacting protein 3 like (BNIP3L) were silenced by promoter methylation and that BNIP3 and BNIP3L levels correlated negatively with sorafenib resistance in HCC-SR cells. Strikingly, MenSCs reversed sorafenib resistance. MenSCs upregulated BNIP3 and BNIP3L expression in HCC-SR cells via tet methylcytosine dioxygenase 2 (TET2)-mediated active demethylation. In HCC-SR cells receiving sorafenib and MenSC combination therapy, pressure from sorafenib and elevated BNIP3 and BNIP3L levels disrupted balanced autophagy. Hyperactivation of mitophagy significantly caused severe mitochondrial dysfunction and eventually led to the autophagic death of HCC-SR cells. CONCLUSIONS Our research suggests that combining sorafenib and MenSCs may be a potentially new strategy to reverse sorafenib resistance in HCC-SR cells.
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Affiliation(s)
- Sining Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yiming Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
- Laboratory of Cancer Biology, Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Qi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Huikang Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yangxin Fang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Xin Chen
- Department of Haematology, Affiliated Hangzhou First People's Hospital, Zhejiang University, School of Medicine, Hangzhou, 310027, China
| | - Jiamin Fu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yifei Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Li Yuan
- Innovative Precision Medicine (IPM) Group, Hangzhou, 311215, China
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, 100730, China.
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Alcayaga-Miranda F, Dutra Silva J, Parada N, Andrade da Silva LH, Ferreira Cruz F, Utreras Y, Hidalgo Y, Cádiz MI, Tapia Limonchi R, Espinoza F, Bruhn A, Khoury M, R. M. Rocco P, Cuenca J. Safety and efficacy of clinical-grade, cryopreserved menstrual blood mesenchymal stromal cells in experimental acute respiratory distress syndrome. Front Cell Dev Biol 2023; 11:1031331. [PMID: 36793446 PMCID: PMC9923023 DOI: 10.3389/fcell.2023.1031331] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 01/16/2023] [Indexed: 01/31/2023] Open
Abstract
Background: Treatment for critical care conditions, such as acute respiratory distress syndrome (ARDS), requires ready-to-administer injectable mesenchymal stromal cells (MSCs). A validated cryopreserved therapy based on MSCs derived from menstrual blood (MenSCs) is an attractive option that offers advantages over freshly cultured cells and allows its use as an off-the-shelf therapy in acute clinical conditions. The main goal of this study is to provide evidence on the impact of cryopreservation on different biological functions of MenSCs and to determine the optimal therapeutic dose, safety, and efficacy profile of clinical-grade, cryopreserved (cryo)-MenSCs in experimental ARDS. Methods: Biological functions of fresh versus cryo-MenSCs were compared in vitro. The effects of cryo-MenSCs therapy were evaluated in vivo in ARDS-induced (Escherichia coli lipopolysaccharide) C57BL/6 mice. After 24 h, the animals were treated with five doses ranging from 0.25×105 to 1.25×106 cells/animal. At 2 and 7 days after induction of ARDS, safety and efficacy were evaluated. Results: Clinical-grade cryo-MenSCs injections improved lung mechanics and reduced alveolar collapse, tissue cellularity, and remodelling, decreasing elastic and collagen fiber content in alveolar septa. In addition, administration of these cells modulated inflammatory mediators and promoted pro-angiogenic and anti-apoptotic effects in lung-injured animals. More beneficial effects were observed with an optimal dose of 4×106 cells/Kg than with higher or lower doses. Conclusion: From a translational perspective, the results showed that clinical-grade cryopreserved MenSCs retain their biological properties and exert a therapeutic effect in mild to moderate experimental ARDS. The optimal therapeutic dose was well-tolerated, safe, and effective, favouring improved lung function. These findings support the potential value of an off-the-shelf MenSCs-based product as a promising therapeutic strategy for treating ARDS.
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Affiliation(s)
- Francisca Alcayaga-Miranda
- Laboratory of Nano-Regenerative Medicine, Centro de Investigación e Innovación Biomédica (CIIB), Faculty of Medicine, Universidad de los Andes, Santiago, Chile,Consorcio Regenero, Chilean Consortium for Regenerative Medicine, Santiago, Chile,Cells for Cells, Santiago, Chile,IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Johnatas Dutra Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Nicol Parada
- Laboratory of Nano-Regenerative Medicine, Centro de Investigación e Innovación Biomédica (CIIB), Faculty of Medicine, Universidad de los Andes, Santiago, Chile
| | - Luisa Helena Andrade da Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fernanda Ferreira Cruz
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Yildy Utreras
- Laboratory of Nano-Regenerative Medicine, Centro de Investigación e Innovación Biomédica (CIIB), Faculty of Medicine, Universidad de los Andes, Santiago, Chile
| | - Yessia Hidalgo
- Laboratory of Nano-Regenerative Medicine, Centro de Investigación e Innovación Biomédica (CIIB), Faculty of Medicine, Universidad de los Andes, Santiago, Chile,Consorcio Regenero, Chilean Consortium for Regenerative Medicine, Santiago, Chile,IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - María Ignacia Cádiz
- Laboratory of Nano-Regenerative Medicine, Centro de Investigación e Innovación Biomédica (CIIB), Faculty of Medicine, Universidad de los Andes, Santiago, Chile,Consorcio Regenero, Chilean Consortium for Regenerative Medicine, Santiago, Chile,Cells for Cells, Santiago, Chile
| | - Rafael Tapia Limonchi
- Consorcio Regenero, Chilean Consortium for Regenerative Medicine, Santiago, Chile,Cells for Cells, Santiago, Chile
| | - Francisco Espinoza
- Cells for Cells, Santiago, Chile,IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Alejandro Bruhn
- Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Maroun Khoury
- Laboratory of Nano-Regenerative Medicine, Centro de Investigación e Innovación Biomédica (CIIB), Faculty of Medicine, Universidad de los Andes, Santiago, Chile,Consorcio Regenero, Chilean Consortium for Regenerative Medicine, Santiago, Chile,Cells for Cells, Santiago, Chile,IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Patricia R. M. Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Jimena Cuenca
- Laboratory of Nano-Regenerative Medicine, Centro de Investigación e Innovación Biomédica (CIIB), Faculty of Medicine, Universidad de los Andes, Santiago, Chile,Consorcio Regenero, Chilean Consortium for Regenerative Medicine, Santiago, Chile,Cells for Cells, Santiago, Chile,IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile,*Correspondence: Jimena Cuenca,
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TNF- α Enhances the Therapeutic Effects of MenSC-Derived Small Extracellular Vesicles on Inflammatory Bowel Disease through Macrophage Polarization by miR-24-3p. Stem Cells Int 2023; 2023:2988907. [PMID: 36895784 PMCID: PMC9991477 DOI: 10.1155/2023/2988907] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/18/2022] [Accepted: 11/24/2022] [Indexed: 03/06/2023] Open
Abstract
Human menstrual blood-derived mesenchymal stem cells (MenSCs) and their secreted small extracellular vesicles (EVs) had been proven to relieve inflammation, tissue damage, and fibrosis in various organs. The microenvironment induced by inflammatory cytokines can promote mesenchymal stem cells (MSCs) to secrete more substances (including EVs) that could regulate inflammation. Inflammatory bowel disease (IBD) is a chronic idiopathic intestinal inflammation, the etiology and mechanism of which are unclear. At present, the existing therapeutic methods are ineffective for many patients and have obvious side effects. Hence, we explored the role of tumor necrosis factor α- (TNF-α-) pretreated MenSC-derived small EV (MenSCs-sEVTNF-α ) in a mouse model of dextran sulfate sodium- (DSS-) induced colitis, expecting to find better therapeutic alterations. In this research, the small EVs of MenSCs were obtained by ultracentrifugation. MicroRNAs of small EVs derived from MenSCs before and after TNF-α treatment were sequenced, and the differential microRNAs were analyzed by bioinformatics. The small EVs secreted by TNF-α-stimulating MenSCs were more effective in colonic mice than those secreted directly by MenSCs, as evidenced by the results of histopathology analysis of colonic tissue, immunohistochemistry for tight junction proteins, and enzyme-linked immunosorbent assay (ELISA) for cytokine expression profiles in vivo. The process of MenSCs-sEVTNF-α relieving colonic inflammation was accompanied by the polarization of M2 macrophages in the colon and miR-24-3p upregulation in small EVs. In vitro, both MenSC-derived sEV (MenSCs-sEV) and MenSCs-sEVTNF-α reduced the expression of proinflammatory cytokines, and MenSCs-sEVTNF-α can increase the portion of M2 macrophages. In conclusion, after TNF-α stimulation, the expression of miR-24-3p in small EVs derived from MenSCs was upregulated. MiR-24-3p was proved to target and downregulate interferon regulatory factor 1 (IRF1) expression in the murine colon and then promoted the polarization of M2 macrophages. The polarization of M2 macrophages in colonic tissues then reduced the damage caused by hyperinflammation.
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Manica DT, Asensi KD, Mazzarelli G, Tura B, Barata G, Goldenberg RCS. Gender bias and menstrual blood in stem cell research: A review of pubmed articles (2008–2020). Front Genet 2022; 13:957164. [DOI: 10.3389/fgene.2022.957164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 11/16/2022] [Indexed: 12/02/2022] Open
Abstract
Despite proven scientific quality of menstrual blood mesenchymal cells, research and science output using those cells is still incipient, which suggests there is a resistance to the study of this type of cell by scientists, and a lack of attention to its potential for cell therapy, regenerative medicine and bioengineering. This study analyzes the literature about the menstrual blood mesenchymal stromal/stem cells (mbMSC) on the PubMed database between 2008–2020 and the social attention it received on Twitter. A comparative analysis showed that mbMSC accounts for a very small portion of mesenchymal cell research (0.25%). Most first authors are women (53.2%), whereas most last authors are men (63.74%), reinforcing an already known, and still significant, gender gap between last and corresponding authors. Menstrual blood tends to be less used in experiments and its scientific value tends to be underestimated, which brings gender bias to a technical and molecular level. Although women are more positive in the mbMSC debate on Twitter, communication efforts toward visibility and public interest in menstrual cells has room to grow.
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27
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Hua C, Chen S, Cheng H. Therapeutic potential of mesenchymal stem cells for refractory inflammatory and immune skin diseases. Hum Vaccin Immunother 2022; 18:2144667. [PMID: 36382475 PMCID: PMC9746473 DOI: 10.1080/21645515.2022.2144667] [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: 11/17/2022] Open
Abstract
Inflammatory and immunological skin diseases such as psoriasis, systemic sclerosis, dermatomyositis and atopic dermatitis, whose abnormal skin manifestations not only affected life quality but also caused social discrimination, have been wildly concerned. Complex variables such as hereditary predisposition, racial differences, age and gender can influence the prevalence and therapeutic options. The population of patients with unsatisfactory curative effects under current therapies is growing, it's advisable to seek novel and advanced therapies that are less likely to cause systemic damage. Mesenchymal stem cells (MSCs) have been proven with therapeutic benefits in tissue regeneration, self-renewal and differentiation abilities when treating refractory skin disorders in preclinical and clinical studies. Here we highlighted the immune modulation and inflammation suppression of MSCs in skin diseases, summarized current studies, research progress and related clinical trials, hoping to strengthen the confidence of promising MSCs therapy in future clinical application.
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Affiliation(s)
- Chunting Hua
- Department of Dermatology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Siji Chen
- Department of Dermatology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hao Cheng
- Department of Dermatology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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28
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Abstract
Pulmonary fibrosis (PF) is a chronic and relentlessly progressive interstitial lung disease in which the accumulation of fibroblasts and extracellular matrix (ECM) induces the destruction of normal alveolar structures, ultimately leading to respiratory failure. Patients with advanced PF are unable to perform physical labor and often have concomitant cough and dyspnea, which markedly impair their quality of life. However, there is a paucity of available pharmacological therapies, and to date, lung transplantation remains the only possible treatment for patients suffering from end-stage PF; moreover, the complexity of transplantation surgery and the paucity of donors greatly restrict the application of this treatment. Therefore, there is a pressing need for alternative therapeutic strategies for this complex disease. Due to their capacity for pluripotency and paracrine actions, stem cells are promising therapeutic agents for the treatment of interstitial lung disease, and an extensive body of literature supports the therapeutic efficacy of stem cells in lung fibrosis. Although stem cell transplantation may play an important role in the treatment of PF, some key issues, such as safety and therapeutic efficacy, remain to be resolved. In this review, we summarize recent preclinical and clinical studies on the stem cell-mediated regeneration of fibrotic lungs and present an analysis of concerning issues related to stem cell therapy to guide therapeutic development for this complex disease.
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Zhou W, Li L, Tao J, Ma C, Xie Y, Ding L, Hou S, Zhang Z, Xue D, Luo J, Zhu Y. Autophagy inhibition restores CD200 expression under IL-1β microenvironment in placental mesenchymal stem cells of fetal origin and improves its pulmonary fibrosis therapeutic potential. Mol Immunol 2022; 151:29-40. [PMID: 36075140 DOI: 10.1016/j.molimm.2022.08.014] [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: 04/12/2022] [Revised: 08/02/2022] [Accepted: 08/21/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are promising remedies for various inflammatory disease including pulmonary fibrosis (PF). However, the properties of MSCs in PF pathological microenvironment remain unclear. In this study, the efficacy of autophagy in placental mesenchymal stem cells of fetal origin (fPMSCs) in either IL-1β treatment or BLM induced pulmonary fibrosis mice model was examined. METHODS The characteristic of fPMSCs was identified by morphological observation, flow cytometry and differentiation potential. In vitro experiments, fPMSCs were stimulated with IL-1β, to mimic inflammatory microenvironment of pulmonary fibrosis. The immunosuppressive properties and autophagic function in fPMSCs treated with IL-1β were evaluated by both macrophage cells THP-1 activation and the expression of CD200 situation, autophagy marker and MAPK signaling pathway. The in vivo anti-fibrotic activity of fPMSCs interfering autophagy was evaluated by using BLM induced pulmonary fibrosis mice model. RESULTS fPMSCs belonged to CD73+CD90+CD105+/CD14- CD34-CD45-HLA-DR- cells, and capable differentiation to adipogenic, osteogenic and chondrogenic cells. In addition, immunoinhibitory activity of fPMSCs for macrophage was restrained by IL-1β treatment in CD200 dependent manner. Suppression of autophagy by sh-Atg5 lentivirus increased the expression of CD200 and ratio of CD200 positive fPMSCs, and enhanced fPMSCs immunosuppression for THP-1 activation. Mechanistically, IL-1β induced autophagy regulated by p38 signaling cascade. In vivo, autophagy inhibition induced by Atg5 knockdown in fPMSCs resulted in strengthening antifibrotic effects on PF mice model. CONCLUSIONS Collectively, autophagy derived from inflammatory microenvironment hampered the immunoinhibitory properties of MSCs. Based on this, adjustment of autophagy may be a valid approach to facilitate their immunomodulatory and anti-fibrotic efficacy.
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Affiliation(s)
- Wei Zhou
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Li Li
- The Center of Laboratory Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Jin Tao
- Human Stem Cell Institute, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Cunxiang Ma
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Yawei Xie
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Lu Ding
- Surgical Laboratory, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Shaozhang Hou
- School of Basic Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Zaiqi Zhang
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Di Xue
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, Yinchuan, Ningxia 750004, China
| | - Jia Luo
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, Yinchuan, Ningxia 750004, China.
| | - Yongzhao Zhu
- Surgical Laboratory, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China.
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Yang S, Liu P, Gao T, Song D, Zhao X, Li Y, Wu J, Wang L, Wang Z, Hao J, Wang C, Dai H. Every road leads to Rome: therapeutic effect and mechanism of the extracellular vesicles of human embryonic stem cell-derived immune and matrix regulatory cells administered to mouse models of pulmonary fibrosis through different routes. Stem Cell Res Ther 2022; 13:163. [PMID: 35413874 PMCID: PMC9006546 DOI: 10.1186/s13287-022-02839-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 11/02/2021] [Indexed: 12/27/2022] Open
Abstract
Background Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. Whether extracellular vesicles are effective in treating IPF and what is the optimal administrative route is not clear. Our previous studies have shown that immunity and matrix regulatory cells (IMRCs) derived from human embryonic stem cells can safely treat lung injury and fibrosis in mouse models, and its mechanism of action is related to the paracrine effect. In this study, we investigated the therapeutic effects of IMRC-derived extracellular vesicles (IMRC-EVs) on a bleomycin-induced pulmonary fibrosis mouse model and explored the optimal route of administration. Methods To study the biodistribution of IMRC-EVs after administration via different routes, NIR labeled-IMRC-EVs were delivered by intratracheal (IT) or intravenous (IV) route, and in vivo imaging was acquired at different time points. The therapeutic effects of IMRC-EVs delivered by different routes were analyzed by assessing histology, lung function, cytokines levels, and transcriptome profiling. RNA-seq of lung tissues was performed to investigate the mechanisms of EV treatment through IT or IV administrations. Results IMRC-EVs mainly reserved in the liver and spleen when administrated via IV route; and mainly retained in the lungs via the IT route. IMRC-EVs administrated via both routes demonstrated a therapeutic effect as attenuated pulmonary fibrosis, improved lung function, and histological parameters. Based on our RNA-seq results, different pathways may be affected by IMRC-EVs administrated via IT or IV routes. In addition, in vitro experiments showed that IMRC-EVs inhibited epithelial-to-mesenchymal transition induced by TGF-β. Conclusion IMRC-EVs administrated via IT or IV routes generate different biodistributions, but are both effective for the treatment of bleomycin-induced pulmonary fibrosis. The therapeutic mechanisms of IMRC-EVs administrated via different routes may be different. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02839-7.
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Affiliation(s)
- Shengnan Yang
- Harbin Medical University, Harbin, 150081, Heilongjiang Province, China.,Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, China.,National Center for Respiratory Medicine, Beijing, 100029, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, 100029, China
| | - Peipei Liu
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, China.,National Center for Respiratory Medicine, Beijing, 100029, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, 100029, China.,Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
| | - Tingting Gao
- National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100190, China.,State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
| | - Dingyun Song
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, China.,National Center for Respiratory Medicine, Beijing, 100029, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, 100029, China
| | - Xinyu Zhao
- Harbin Medical University, Harbin, 150081, Heilongjiang Province, China.,Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, China.,National Center for Respiratory Medicine, Beijing, 100029, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, 100029, China
| | - Yupeng Li
- Harbin Medical University, Harbin, 150081, Heilongjiang Province, China.,Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, China.,National Center for Respiratory Medicine, Beijing, 100029, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, 100029, China
| | - Jun Wu
- National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100190, China.,State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Liu Wang
- National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100190, China.,State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zai Wang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, 100029, China.
| | - Jie Hao
- National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100190, China. .,State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. .,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Chen Wang
- Harbin Medical University, Harbin, 150081, Heilongjiang Province, China. .,Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, China. .,National Center for Respiratory Medicine, Beijing, 100029, China. .,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, 100029, China. .,Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China.
| | - Huaping Dai
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, China. .,National Center for Respiratory Medicine, Beijing, 100029, China. .,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, 100029, China.
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Li S, Yang Q, Chen F, Tian L, Huo J, Meng Y, Tang Q, Wang W. The antifibrotic effect of pheretima protein is mediated by the TGF-β1/Smad2/3 pathway and attenuates inflammation in bleomycin-induced idiopathic pulmonary fibrosis. JOURNAL OF ETHNOPHARMACOLOGY 2022; 286:114901. [PMID: 34890730 DOI: 10.1016/j.jep.2021.114901] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 11/27/2021] [Accepted: 12/06/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Pheretima is a traditional Chinese medicine that could treat various lung diseases such as asthma, pneumonia, and lung cancer effectively; however, limited studies on the use of Pheretima protein in the treatment of lung diseases have been conducted to date. AIM OF THE STUDY The aim of this study was to explain the antipulmonary fibrosis mechanism of the Pheretima protein and elucidate its possible cell signaling pathways. MATERIAL AND METHODS Fresh pheretima was freeze-dried to obtain the Pheretima protein. Divide C57BL/6 mice into control and bleomycin (BLM)-induced models, pirfenidone, and Pheretima protein-treatment groups. Three weeks later, they were treated with H&E and Masson's trichrome staining to assess lung injury and fibrosis. Pulmonary fibrosis was assessed using immunohistochemistry (IHC), realtime-PCR (RT-PCR), and western blotting. Inflammation was assessed using the alveolar lavage fluid. RESULTS Pheretima protein inhibited epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) deposition and reduced inflammation. It also reduced the levels of Smad2/3, pSmad2/3, and transforming growth factor-beta 1 (TGF-β1). Thus, our results indicate that Pheretima protein can alleviate BLM-induced pulmonary fibrosis in a mouse model. CONCLUSION Pheretima protein inhibits ECM, EMT, and antiinflammatory markers, which in turn ameliorates BLM-induced pulmonary fibrosis. Preliminary mechanistic studies indicated that Pheretima protein can exert its biological activity by downregulating the TGF-β1/Smad2/3 pathway.
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Affiliation(s)
- Shuyu Li
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, PR China; Guangdong Provincial Key Laboratory of Chinese Medicine, Pharmaceutics, Guangzhou, 510515, PR China; Guangdong Provincial Engineering Laboratory of Chinese Medicine Preparation Technology Institue of Chinese Medicine, Guangzhou, 510515, PR China
| | - Qixin Yang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, PR China; Guangdong Provincial Key Laboratory of Chinese Medicine, Pharmaceutics, Guangzhou, 510515, PR China; Guangdong Provincial Engineering Laboratory of Chinese Medicine Preparation Technology Institue of Chinese Medicine, Guangzhou, 510515, PR China
| | - Feilong Chen
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, PR China; Guangdong Provincial Key Laboratory of Chinese Medicine, Pharmaceutics, Guangzhou, 510515, PR China; Guangdong Provincial Engineering Laboratory of Chinese Medicine Preparation Technology Institue of Chinese Medicine, Guangzhou, 510515, PR China
| | - Linhua Tian
- Heilongjiang Academy of Chinese Medicine Sciences, Harbin, 150036, China
| | - Jinhai Huo
- Heilongjiang Academy of Chinese Medicine Sciences, Harbin, 150036, China
| | - Yanli Meng
- Heilongjiang Academy of Chinese Medicine Sciences, Harbin, 150036, China
| | - Qingfa Tang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, PR China; Guangdong Provincial Key Laboratory of Chinese Medicine, Pharmaceutics, Guangzhou, 510515, PR China; Guangdong Provincial Engineering Laboratory of Chinese Medicine Preparation Technology Institue of Chinese Medicine, Guangzhou, 510515, PR China.
| | - Weiming Wang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, PR China; Guangdong Provincial Key Laboratory of Chinese Medicine, Pharmaceutics, Guangzhou, 510515, PR China; Guangdong Provincial Engineering Laboratory of Chinese Medicine Preparation Technology Institue of Chinese Medicine, Guangzhou, 510515, PR China; Heilongjiang Academy of Chinese Medicine Sciences, Harbin, 150036, China.
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Fathi-Kazerooni M, Fattah-Ghazi S, Darzi M, Makarem J, Nasiri R, Salahshour F, Dehghan-Manshadi SA, Kazemnejad S. Safety and efficacy study of allogeneic human menstrual blood stromal cells secretome to treat severe COVID-19 patients: clinical trial phase I & II. Stem Cell Res Ther 2022; 13:96. [PMID: 35255966 PMCID: PMC8899458 DOI: 10.1186/s13287-022-02771-w] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 02/17/2022] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Cell-free Mesenchymal stromal cells (MSCs) have been considered due to their capacity to modulate the immune system and suppress cytokine storms caused by SARS-CoV-2. This prospective randomized double-blind placebo-controlled clinical trial aimed to assess the safety and efficacy of secretome derived from allogeneic menstrual blood stromal cells (MenSCs) as a treatment in patients with severe COVID-19. METHODS Patients with severe COVID-19 were randomized (1:1) to either MenSC-derived secretome treatment or the control group. Subjects received five intravenous infusions of 5 mL secretome or the same volume of placebo for five days and were monitored for safety and efficacy for 28 days after treatment. Adverse events, laboratory parameters, duration of hospitalization, clinical symptom improvement, dynamic of O2 saturation, lymphocyte number, and serial chest imaging were analyzed. RESULTS All safety endpoints were observed without adverse events after 72 h of secretome injection. Within 28 days after enrollment, 7 patients (50%) were intubated in the treated group versus 12 patients (80%) in the control group. Overall, 64% of patients had improved oxygen levels within 5 days of starting treatment (P < 0.0001) and there was a survival rate of 57% in the treatment group compared to 28% in the control group was (P < 0.0001). Laboratory values revealed that significant acute phase reactants declined, with mean C-reactive protein, ferritin, and D-dimer reduction of 77% (P < 0.001), 43% (P < 0.001), and 42% (P < 0.05), respectively. Significant improvement in lymphopenia was associated with an increase in mean CD4+ and CD8+ lymphocyte counts of 20% (P = 0.06) and 15% (P < 0.05), respectively. Following treatment, percentage of pulmonary involvement showed a significant improvement in the secretome group (P < 0.0001). This improvement differed significantly between survivors and those who were dying (P < 0.005). CONCLUSIONS For the first time, this study demonstrated that in hospitalized patients with severe COVID-19, therapy with MenSCs-derived secretome leads to reversal of hypoxia, immune reconstitution, and downregulation of cytokine storm, with no adverse effects attributable to the treatment. Given these outcomes, it may be possible to use this type of treatment for serious inflammatory lung disease with a mechanism similar to COVID-19 in the future. However, it is necessary to evaluate the safety and efficacy of MenSCs-derived secretome therapy in clinical trials on a larger population of patients. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT05019287. Registered 24AGUEST 2021, retrospectively registered, https://clinicaltrials.gov/ct2/show/record/NCT05019287 . IRCT, IRCT20180619040147N6. Registered 04/01/2021.
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Affiliation(s)
- Mina Fathi-Kazerooni
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Samrand Fattah-Ghazi
- Department of Anesthesiology and Intensive Care, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Darzi
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Jalil Makarem
- Department of Anesthesiology and Intensive Care, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Nasiri
- Avicenna Fertility Clinic, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Faeze Salahshour
- Department of Radiology, Advanced Diagnostic and Interventional Radiology Research Center (ADIR), Tehran University of Medical Sciences, Tehran, Iran.,Liver Transplantation Research Center, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Ali Dehghan-Manshadi
- Department of Infectious Diseases and Tropical Medicine, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran.
| | - Somaieh Kazemnejad
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.
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He Y, Han Y, Ye Y. Therapeutic Potential of Menstrual Blood-Derived Stem Cell Transplantation for Intrauterine Adhesions. Front Surg 2022; 9:847213. [PMID: 35274000 PMCID: PMC8901573 DOI: 10.3389/fsurg.2022.847213] [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: 01/01/2022] [Accepted: 01/24/2022] [Indexed: 12/27/2022] Open
Abstract
An increasing number of women experience intrauterine adhesion as a result of intrauterine operations, such as induced abortion, which can cause infertility, recurrent abortion and amenorrhea. Although some strategies have been applied clinically, such as hysteroscopy adhesiolysis of intrauterine adhesions, the results have not been promising. As regenerative medicine develops, research on menstrual blood-derived stem cell transplantation is increasing due to the properties of these cells, including self-renewal, differentiation, angiogenesis, anti-inflammation and immunomodulation. As a result, menstrual blood-derived stem cells may be an ideal cell source for the treatment of intrauterine adhesion. Excitingly, it has been reported that autologous menstrual blood stem cells could recovery injured endometrium and improve infertility in patients with refractory intrauterine adhesion. In this review, we discuss the possible potential of menstrual blood-derived stem cell transplantation for intrauterine adhesion, including the antifibrosis, angiogenesis, anti-inflammation and immunoregulation properties of the cells, which brings hopes for clinical therapy.
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Affiliation(s)
- Yantao He
- Department of Gynecology and Obstetrics, Zhongshan City People's Hospital, Zhongshan, China
| | - Yanhua Han
- Department of Gynecology and Obstetrics, Zhongshan City People's Hospital, Zhongshan, China
| | - Yun Ye
- Centre for Reproductive Medicine, Zhongshan City People's Hospital, Zhongshan, China
- *Correspondence: Yun Ye
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Mesenchymal stem cell-based treatments for COVID-19: status and future perspectives for clinical applications. Cell Mol Life Sci 2022; 79:142. [PMID: 35187617 PMCID: PMC8858603 DOI: 10.1007/s00018-021-04096-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 11/17/2021] [Accepted: 12/13/2021] [Indexed: 01/08/2023]
Abstract
As a result of cross-species transmission in December 2019, the coronavirus disease 2019 (COVID-19) became a serious endangerment to human health and the causal agent of a global pandemic. Although the number of infected people has decreased due to effective management, novel methods to treat critical COVID-19 patients are still urgently required. This review describes the origins, pathogenesis, and clinical features of COVID-19 and the potential uses of mesenchymal stem cells (MSCs) in therapeutic treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients. MSCs have previously been shown to have positive effects in the treatment of lung diseases, such as acute lung injury, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, lung cancer, asthma, and chronic obstructive pulmonary disease. MSC mechanisms of action involve differentiation potentials, immune regulation, secretion of anti-inflammatory factors, migration and homing, anti-apoptotic properties, antiviral effects, and extracellular vesicles. Currently, 74 clinical trials are investigating the use of MSCs (predominately from the umbilical cord, bone marrow, and adipose tissue) to treat COVID-19. Although most of these trials are still in their early stages, the preliminary data are promising. However, long-term safety evaluations are still lacking, and large-scale and controlled trials are required for more conclusive judgments regarding MSC-based therapies. The main challenges and prospective directions for the use of MSCs in clinical applications are discussed herein. In summary, while the clinical use of MSCs to treat COVID-19 is still in the preliminary stages of investigation, promising results indicate that they could potentially be utilized in future treatments.
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Saleh M, Fotook Kiaei SZ, Kavianpour M. Application of Wharton jelly-derived mesenchymal stem cells in patients with pulmonary fibrosis. Stem Cell Res Ther 2022; 13:71. [PMID: 35168663 PMCID: PMC8845364 DOI: 10.1186/s13287-022-02746-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 01/26/2022] [Indexed: 12/12/2022] Open
Abstract
Pulmonary fibrosis is a devastating disease that eventually leads to death and respiratory failure. Despite the wide range of drugs, including corticosteroids, endothelin antagonist, and pirfenidone, there is no effective treatment, and the only main goal of treatment is to alleviate the symptoms as much as possible to slow down the progression of the disease and improve the quality of life. Lung transplantation may be a treatment option for a few people if pulmonary fibrosis develops and there is no established treatment. Pulmonary fibrosis caused by the COVID19 virus is another problem that we face in most patients despite the efforts of the international medical communities. Therefore, achieving alternative treatment for patients is a great success. Today, basic research using stem cells on pulmonary fibrosis has published promising results. New stem cell-based therapies can be helpful in patients with pulmonary fibrosis. Wharton jelly-derived mesenchymal stem cells are easily isolated in large quantities and made available for clinical trials without causing ethical problems. These cells have higher flexibility and proliferation potential than other cells isolated from different sources and differentiated into various cells in laboratory environments. More clinical trials are needed to determine the safety and efficacy of these cells. This study will investigate the cellular and molecular mechanisms and possible effects of Wharton jelly-derived mesenchymal stem cells in pulmonary fibrosis.
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Affiliation(s)
- Mahshid Saleh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Seyedeh Zahra Fotook Kiaei
- Department of Pulmonary and Critical Care, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Maria Kavianpour
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Yang Y, Chen Y, Zhao Y, Ji F, Zhang L, Tang S, Zhang S, Hu Q, Li Z, Zhang F, Li Q, Li L. Human menstrual blood-derived stem cell transplantation suppresses liver injury in DDC-induced chronic cholestasis. Stem Cell Res Ther 2022; 13:57. [PMID: 35123555 PMCID: PMC8817575 DOI: 10.1186/s13287-022-02734-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 11/08/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Cholestatic liver injury can lead to serious symptoms and prognoses in the clinic. Currently, an effective medical treatment is not available for cholestatic liver injury. Human menstrual blood-derived stem cells (MenSCs) are considered as an emerging treatment in various diseases. This study aimed to explore the treatment effect of MenSCs in cholestatic liver injury. METHODS The treatment effect of MenSCs on chronic cholestatic liver injury was verified in 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC)-induced C57/BL6 mice. Pathological, fibrosis area in the liver tissue and serum liver enzymes were tested. Proteomics and western blot were used to explore the related targets and molecular mechanisms. Adeno-associated virus (AAV) 9-infected mice were applied for verification. RESULTS MenSCs markedly improved the survival rate of the DDC-treated mice (60% vs. 100%), and decreased the mouse serum aspartate aminotransferase (AST) (169.4 vs. 108.0 U/L, p < 0.001), alanine aminotransferase (ALT) (279.0 vs. 228.9 U/L, p < 0.01), alkaline phosphatase (ALP) (45.6 vs. 10.6 U/L, p < 0.0001), direct bilirubin (DBIL) (108.3 vs. 14.0 μmol/L, p < 0.0001) and total bilirubin (TBIL) (179.2 vs. 43.3 μmol/L, p < 0.0001) levels as well as intrahepatic cholestasis, bile duct dilation and fibrotic areas (16.12 vs. 6.57%, p < 0.05). The results further indicated that MenSCs repaired the DDC-induced liver tight junction (TJ) pathway and bile transporter (OATP2, BSEP and NTCP1) injury, thereby inhibiting COL1A1, α-SMA and TGF-β1 activation by upregulating liver β-catenin expression. CONCLUSIONS MenSC transplantation could be an effective treatment method for cholestatic liver injury in mice. MenSCs may exhibit therapeutic effects by regulating β-catenin expression.
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Affiliation(s)
- Ya Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, No.79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang Province, China
| | - Yanfei Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, No.79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang Province, China
| | - Yalei Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, No.79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang Province, China
| | - Feiyang Ji
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, No.79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang Province, China
| | - Lingjian Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, No.79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang Province, China
| | - Shima Tang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, No.79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang Province, China
| | - Sainan Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, No.79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang Province, China
| | - Qingqing Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, No.79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang Province, China
| | - Zuhong Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, No.79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang Province, China
| | - Fen Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, No.79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang Province, China
| | - Qian Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, No.79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang Province, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, No.79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang Province, China.
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Zhao Y, Yan Z, Liu Y, Zhang Y, Shi J, Li J, Ji F. Effectivity of mesenchymal stem cells for bleomycin-induced pulmonary fibrosis: a systematic review and implication for clinical application. Stem Cell Res Ther 2021; 12:470. [PMID: 34420515 PMCID: PMC8380478 DOI: 10.1186/s13287-021-02551-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 08/09/2021] [Indexed: 12/24/2022] Open
Abstract
Pulmonary fibrosis (PF) is a chronic, progressive, fibrotic interstitial disease of the lung with poor prognosis and without effective treatment currently. Data from previous coronavirus infections, such as the Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome, as well as current clinical evidence from the Coronavirus disease 2019 (COVID-19), support that SARS-CoV-2 infection may lead to PF, seriously impacting patient prognosis and quality of life. Therefore, effective prevention and treatment of PF will improve patient prognosis and reduce the overall social and economic burdens. Stem cells, especially mesenchymal stem cells (MSCs) have many great advantages, including migration to damaged lung tissue and secretion of various paracrine factors, thereby regulating the permeability of endothelial and epithelial cells, reducing inflammatory response, promoting tissue repair and inhibiting bacterial growth. Clinical trials of MSCs for the treatment of acute lung injury, PF and severe and critically ill COVID-19 are ongoing. The purpose of this study is to systematically review preclinical studies, explored the effectiveness of MSCs in the treatment of bleomycin (BLM)-induced pulmonary fibrosis and analyze the potential mechanism, combined with clinical trials of current MSCs for idiopathic pulmonary fibrosis (IPF) and COVID-19, so as to provide support for clinical research and transformation of MSCs. Searching PubMed and Embase (- 2021.4) identified a total of 36 preclinical studies of MSCs as treatment of BLM-induced acute lung injury and PF in rodent models. Most of the studies showed the MSCs treatment to reduce BLM-induced lung tissue inflammatory response, inflammatory cell infiltration, inflammatory cytokine expression, extracellular matrix production and collagen deposition, and to improve Ashcroft score. The results of present studies indicate that MSCs may serve as a potential therapeutic modality for the treatment of PF, including viral-induced PF and IPF.
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Affiliation(s)
- Yunyu Zhao
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xi Wu Road, Xi'an, 710004, Shaanxi, China
| | - Zhipeng Yan
- Department of Liver Diseases, The Hospital Affiliated to Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Ying Liu
- The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Yue Zhang
- The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Jie Shi
- Department of Respiratory, The Hospital Affiliated to Shaanxi University of Chinese Medicine, Xianyang, China
| | - Jingtao Li
- Department of Liver Diseases, The Hospital Affiliated to Shaanxi University of Chinese Medicine, Xianyang, 712046, China.
| | - Fanpu Ji
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xi Wu Road, Xi'an, 710004, Shaanxi, China.
- National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Key Laboratory of Environment and Genes Related To Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, China.
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Kong Y, Shao Y, Ren C, Yang G. Endometrial stem/progenitor cells and their roles in immunity, clinical application, and endometriosis. Stem Cell Res Ther 2021; 12:474. [PMID: 34425902 PMCID: PMC8383353 DOI: 10.1186/s13287-021-02526-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 07/19/2021] [Indexed: 12/13/2022] Open
Abstract
Endometrial stem/progenitor cells have been proved to exist in periodically regenerated female endometrium and can be divided into three categories: endometrial epithelial stem/progenitor cells, CD140b+CD146+ or SUSD2+ endometrial mesenchymal stem cells (eMSCs), and side population cells (SPs). Endometrial stem/progenitor cells in the menstruation blood are defined as menstrual stem cells (MenSCs). Due to their abundant sources, excellent proliferation, and autotransplantation capabilities, MenSCs are ideal candidates for cell-based therapy in regenerative medicine, inflammation, and immune-related diseases. Endometrial stem/progenitor cells also participate in the occurrence and development of endometriosis by entering the pelvic cavity from retrograde menstruation and becoming overreactive under certain conditions to form new glands and stroma through clonal expansion. Additionally, the limited bone marrow mesenchymal stem cells (BMDSCs) in blood circulation can be recruited and infiltrated into the lesion sites, leading to the establishment of deep invasive endometriosis. On the other hand, cell derived from endometriosis may also enter the blood circulation to form circulating endometrial cells (CECs) with stem cell-like properties, and to migrate and implant into distant tissues. In this manuscript, by reviewing the available literature, we outlined the characteristics of endometrial stem/progenitor cells and summarized their roles in immunoregulation, regenerative medicine, and endometriosis, through which to provide some novel therapeutic strategies for reproductive and cancerous diseases.
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Affiliation(s)
- Yue Kong
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yang Shao
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Chunxia Ren
- Center for Reproductive Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200120, China.
| | - Gong Yang
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Central Laboratory, The Fifth People's Hospital of Shanghai Fudan University, Shanghai, 200240, China.
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Li DY, Li RF, Sun DX, Pu DD, Zhang YH. Mesenchymal stem cell therapy in pulmonary fibrosis: a meta-analysis of preclinical studies. Stem Cell Res Ther 2021; 12:461. [PMID: 34407861 PMCID: PMC8371890 DOI: 10.1186/s13287-021-02496-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 07/05/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Pulmonary fibrosis (PF) is a devastating disease characterized by remodeling of lung architecture and abnormal deposition of fibroblasts in parenchymal tissue and ultimately results in respiratory failure and death. Preclinical studies suggest that mesenchymal stem cell (MSC) administration may be a safe and promising option in treating PF. The objective of our meta-analysis is to assess the efficacy of MSC therapy in preclinical models of PF. METHODS We performed a comprehensive literature search in PubMed, EMBASE, Web of Science, and Cochrane Library databases from inception to March 17, 2021. Studies that assessed the efficacy of MSC therapy to animals with PF were included. The SYRCLE bias risk tool was employed to evaluate the bias of included studies. The primary outcomes included survival rate and pulmonary fibrosis scores. Meta-analysis was conducted via Cochrane Collaboration Review Manager (version 5.4) and Stata 14.0 statistical software. RESULTS A total of 1120 articles were reviewed, of which 24 articles met inclusion criteria. Of these, 12 studies evaluated the survival rate and 20 studies evaluated pulmonary fibrosis scores. Compared to the control group, MSC therapy was associated with an improvement in survival rate (odds ratios (OR) 3.10, 95% confidence interval (CI) 2.06 to 4.67, P < 0.001, I2 = 0%) and a significant reduction in pulmonary fibrosis scores (weighted mean difference (WMD) 2.05, 95% CI -2.58 to -1.51, P < 0.001, I2 = 90%). CONCLUSIONS MSC therapy is a safe and effective method that can significantly improve the survival and pulmonary fibrosis of PF animals. These results provide an important basis for future translational clinical studies.
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Affiliation(s)
- Deng-Yuan Li
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, People's Republic of China.,The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650500, People's Republic of China.,Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province, Kunming, 650022, People's Republic of China
| | - Ru-Fang Li
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650500, People's Republic of China.,Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province, Kunming, 650022, People's Republic of China
| | - Dan-Xiong Sun
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650500, People's Republic of China.,Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province, Kunming, 650022, People's Republic of China
| | - Dan-Dan Pu
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650500, People's Republic of China.,Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province, Kunming, 650022, People's Republic of China
| | - Yun-Hui Zhang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, People's Republic of China. .,The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650500, People's Republic of China. .,Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province, Kunming, 650022, People's Republic of China.
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40
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Zhao Q, Hao C, Wei J, Huang R, Li C, Yao W. Bone marrow-derived mesenchymal stem cells attenuate silica-induced pulmonary fibrosis by inhibiting apoptosis and pyroptosis but not autophagy in rats. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 216:112181. [PMID: 33848736 DOI: 10.1016/j.ecoenv.2021.112181] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 03/17/2021] [Accepted: 03/21/2021] [Indexed: 06/12/2023]
Abstract
This study aimed to investigate the effect of bone marrow-derived mesenchymal stem cells (BMSCs) on silica-induced lung fibrosis in a rat model. Thirty SD rats were randomly divided into three groups: control group, silica group, and BMSC group (n = 10 rats per group). BMSCs were injected successively into rats on the 14th, 28th, and 42nd days after silica exposure. All rats were sacrificed 56 days after silica exposure. We detected the pathological and fibrotic changes, apoptosis, autophagy, and pyroptosis in their lung tissue by histopathological examination, hydroxyproline content assays, real-time quantitative polymerase chain reactions, western blot assays, immunohistochemistry staining, immunofluorescence staining, and enzyme-linked immunosorbent assays. We found that BMSCs significantly relieved lung inflammatory infiltrates, collagen deposition, hydroxyproline content, and the mRNA and protein levels of collagen 1 and fibronectin. Compared to the silica group, in the BMSC group, apoptosis-associated proteins, including cleaved caspase 3 and Bax, were significantly downregulated, and Bcl-2/Bax was significantly upregulated; pyroptosis-related proteins, including Nlrp3, cleaved caspase 1, IL-1β, and IL-18, were significantly reduced. However, the BMSCs had no significant impact on autophagy-related proteins, including Beclin 1, P62, and LC3. In summary, BMSCs protected lung tissue against severe fibrosis by inhibiting apoptosis and pyroptosis but not autophagy.
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Affiliation(s)
- Qiuyan Zhao
- Department of Occupational Health and Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Changfu Hao
- Department of Occupational Health and Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Jingjing Wei
- Department of Occupational Health and Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Ruoxuan Huang
- Department of Occupational Health and Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Chao Li
- Department of Occupational Health and Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Wu Yao
- Department of Occupational Health and Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China.
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Yang S, Liu P, Jiang Y, Wang Z, Dai H, Wang C. Therapeutic Applications of Mesenchymal Stem Cells in Idiopathic Pulmonary Fibrosis. Front Cell Dev Biol 2021; 9:639657. [PMID: 33768094 PMCID: PMC7985078 DOI: 10.3389/fcell.2021.639657] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 02/15/2021] [Indexed: 12/17/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is an interstitial disease of unknown etiology characterized by progressive pulmonary fibrosis. Pirfenidone and nintedanib are the only drugs that can prolong the time to disease progression, slow down the decline in lung function, and prolong survival. However, they do not offer a cure and are associated with tolerability issues. The pluripotency of mesenchymal stem cells (MSCs) and their ability to regulate immunity, inhibit inflammation, and promote epithelial tissue repair highlight the promise of MSC therapy for treating interstitial lung disease. However, optimal protocols are lacking for multi-parameter selection in MSC therapy. This review summarizes preclinical studies on MSC transplantation for the treatment of interstitial lung disease and clinical studies with known results. An analysis of relevant factors for the optimization of treatment plans is presented, including MSCs with different sources, administration routes and timing, dosages, frequencies, and pretreatments with MSCs. This review proposes an optimized plan for guiding the design of future clinical research to identify therapeutic options for this complex disease.
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Affiliation(s)
- Shengnan Yang
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China.,Harbin Medical University, Harbin, China
| | - Peipei Liu
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.,Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yale Jiang
- School of Medicine, Tsinghua University, Beijing, China
| | - Zai Wang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Huaping Dai
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China
| | - Chen Wang
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China.,Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Xu X, Jiang W, Chen L, Xu Z, Zhang Q, Zhu M, Ye P, Li H, Yu L, Zhou X, Zhou C, Chen X, Zheng X, Xu K, Cai H, Zheng S, Jiang W, Wu X, Li D, Chen L, Luo Q, Wang Y, Qu J, Li Y, Zheng W, Jiang Y, Tang L, Xiang C, Li L. Evaluation of the safety and efficacy of using human menstrual blood-derived mesenchymal stromal cells in treating severe and critically ill COVID-19 patients: An exploratory clinical trial. Clin Transl Med 2021; 11:e297. [PMID: 33634996 PMCID: PMC7839959 DOI: 10.1002/ctm2.297] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 01/07/2021] [Accepted: 01/11/2021] [Indexed: 01/08/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in December 2019 and has subsequently spread worldwide. Currently, there is no effective method to cure COVID-19. Mesenchymal stromal cells (MSCs) may be able to effectively treat COVID-19, especially for severe and critical patients. Menstrual blood-derived MSCs have recently received much attention due to their superior proliferation ability and their lack of ethical problems. Forty-four patients were enrolled from January to April 2020 in a multicenter, open-label, nonrandomized, parallel-controlled exploratory trial. Twenty-six patients received allogeneic, menstrual blood-derived MSC therapy, and concomitant medications (experimental group), and 18 patients received only concomitant medications (control group). The experimental group was treated with three infusions totaling 9 × 107 MSCs, one infusion every other day. Primary and secondary endpoints related to safety and efficacy were assessed at various time points during the 1-month period following MSC infusion. Safety was measured using the frequency of treatment-related adverse events (AEs). Patients in the MSC group showed significantly lower mortality (7.69% died in the experimental group vs 33.33% in the control group; P = .048). There was a significant improvement in dyspnea while undergoing MSC infusion on days 1, 3, and 5. Additionally, SpO2 was significantly improved following MSC infusion, and chest imaging results were improved in the experimental group in the first month after MSC infusion. The incidence of most AEs did not differ between the groups. MSC-based therapy may serve as a promising alternative method for treating severe and critical COVID-19.
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Affiliation(s)
- Xiaowei Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Wanli Jiang
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanHebeiP.R. China
| | - Lijun Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Zhenyu Xu
- Innovative Precision Medicine (IPM) GroupHangzhouZhejiangP. R. China
| | - Qiang Zhang
- Innovative Precision Medicine (IPM) GroupHangzhouZhejiangP. R. China
| | - Mengfei Zhu
- Shulan (Hangzhou) Hospital, Zhejiang Shuren University Shulan International Medical CollegeHangzhouZhejiangP. R. China
| | - Peng Ye
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanHebeiP.R. China
| | - Hang Li
- Innovative Precision Medicine (IPM) GroupHangzhouZhejiangP. R. China
| | - Liang Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Xiaoyang Zhou
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanHebeiP.R. China
| | - Chenliang Zhou
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanHebeiP.R. China
| | - Xiaobei Chen
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanHebeiP.R. China
| | - Xiaoqin Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Kaijin Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Hongliu Cai
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Shufa Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Wubian Jiang
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanHebeiP.R. China
| | - Xiaojun Wu
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanHebeiP.R. China
| | - Dong Li
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanHebeiP.R. China
| | - Lu Chen
- Innovative Precision Medicine (IPM) GroupHangzhouZhejiangP. R. China
| | - Qingqing Luo
- Innovative Precision Medicine (IPM) GroupHangzhouZhejiangP. R. China
| | - Yingyan Wang
- Innovative Precision Medicine (IPM) GroupHangzhouZhejiangP. R. China
| | - Jingjing Qu
- Department of Respiratory DiseaseThoracic Disease CentreThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Yifei Li
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Wendi Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Yingan Jiang
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanHebeiP.R. China
| | - Lingling Tang
- Shulan (Hangzhou) Hospital, Zhejiang Shuren University Shulan International Medical CollegeHangzhouZhejiangP. R. China
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiangP. R. China
- Shulan (Hangzhou) Hospital, Zhejiang Shuren University Shulan International Medical CollegeHangzhouZhejiangP. R. China
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Chugh RM, Bhanja P, Norris A, Saha S. Experimental Models to Study COVID-19 Effect in Stem Cells. Cells 2021; 10:E91. [PMID: 33430424 PMCID: PMC7827246 DOI: 10.3390/cells10010091] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 12/30/2020] [Accepted: 01/06/2021] [Indexed: 12/18/2022] Open
Abstract
The new strain of coronavirus (severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)) emerged in 2019 and hence is often referred to as coronavirus disease 2019 (COVID-19). This disease causes hypoxic respiratory failure and acute respiratory distress syndrome (ARDS), and is considered as the cause of a global pandemic. Very limited reports in addition to ex vivo model systems are available to understand the mechanism of action of this virus, which can be used for testing of any drug efficacy against virus infectivity. COVID-19 induces tissue stem cell loss, resulting inhibition of epithelial repair followed by inflammatory fibrotic consequences. Development of clinically relevant models is important to examine the impact of the COVID-19 virus in tissue stem cells among different organs. In this review, we discuss ex vivo experimental models available to study the effect of COVID-19 on tissue stem cells.
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Affiliation(s)
- Rishi Man Chugh
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS 66160, USA; (R.M.C.); (P.B.)
| | - Payel Bhanja
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS 66160, USA; (R.M.C.); (P.B.)
| | - Andrew Norris
- BCN Bio Sciences, Pasadena, CA 91107, USA;
- David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Subhrajit Saha
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS 66160, USA; (R.M.C.); (P.B.)
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
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