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Li ZP, Li H, Ruan YH, Wang P, Zhu MT, Fu WP, Wang RB, Tang XD, Zhang Q, Li SL, Yin H, Li CJ, Tian YG, Han RN, Wang YB, Zhang CJ. Stem cell therapy for intervertebral disc degeneration: Clinical progress with exosomes and gene vectors. World J Stem Cells 2025; 17:102945. [PMID: 40308883 PMCID: PMC12038459 DOI: 10.4252/wjsc.v17.i4.102945] [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: 11/05/2024] [Revised: 01/25/2025] [Accepted: 03/10/2025] [Indexed: 04/23/2025] Open
Abstract
Intervertebral disc degeneration is a leading cause of lower back pain and is characterized by pathological processes such as nucleus pulposus cell apoptosis, extracellular matrix imbalance, and annulus fibrosus rupture. These pathological changes result in disc height loss and functional decline, potentially leading to disc herniation. This comprehensive review aimed to address the current challenges in intervertebral disc degeneration treatment by evaluating the regenerative potential of stem cell-based therapies, with a particular focus on emerging technologies such as exosomes and gene vector systems. Through mechanisms such as differentiation, paracrine effects, and immunomodulation, stem cells facilitate extracellular matrix repair and reduce nucleus pulposus cell apoptosis. Despite recent advancements, clinical applications are hindered by challenges such as hypoxic disc environments and immune rejection. By analyzing recent preclinical and clinical findings, this review provided insights into optimizing stem cell therapy to overcome these obstacles and highlighted future directions in the field.
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Affiliation(s)
- Zhi-Peng Li
- Second Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Tianjian Advanced Biomedical Laboratory, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Han Li
- Department of Orthopedics, Affiliated Dongyang Hospital of Wenzhou Medical University, Jinhua 322100, Zhejiang Province, China
| | - Yu-Hua Ruan
- Second Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Peng Wang
- Second Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Meng-Ting Zhu
- Department of Neurology, Union Medical College Hospital of Fujian Medical University, Fuzhou 350001, Fujian Province, China
| | - Wei-Ping Fu
- Second Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Rui-Bo Wang
- Second Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Xiao-Dong Tang
- Second Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Qi Zhang
- Second Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Sen-Li Li
- Second Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - He Yin
- Second Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Cheng-Jin Li
- Second Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yi-Gong Tian
- Third Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Rui-Ning Han
- Third Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yao-Bin Wang
- Second Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Henan Key Laboratory for Helicobacter pylori and Digestive Tract Microecology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Chang-Jiang Zhang
- Second Department of Orthopedics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
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Li C, Sun Y, Xu W, Chang F, Wang Y, Ding J. Mesenchymal Stem Cells-Involved Strategies for Rheumatoid Arthritis Therapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2305116. [PMID: 38477559 PMCID: PMC11200100 DOI: 10.1002/advs.202305116] [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] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 12/13/2023] [Indexed: 03/14/2024]
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the joints and bone destruction. Because of systemic administration and poor targeting, traditional anti-rheumatic drugs have unsatisfactory treatment efficacy and strong side effects, including myelosuppression, liver or kidney function damage, and malignant tumors. Consequently, mesenchymal stem cells (MSCs)-involved therapy is proposed for RA therapy as a benefit of their immunosuppressive and tissue-repairing effects. This review summarizes the progress of MSCs-involved RA therapy through suppressing inflammation and promoting tissue regeneration and predicts their potential clinical application.
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Affiliation(s)
- Chaoyang Li
- Department of OrthopedicsThe Second Hospital of Jilin University4026 Yatai StreetChangchun130041P. R. China
- Key Laboratory of Polymer EcomaterialsChangchun Institute of Applied ChemistryChinese Academy of Sciences5625 Renmin StreetChangchun130022P. R. China
| | - Yifu Sun
- Department of OrthopedicsThe Second Hospital of Jilin University4026 Yatai StreetChangchun130041P. R. China
| | - Weiguo Xu
- Key Laboratory of Polymer EcomaterialsChangchun Institute of Applied ChemistryChinese Academy of Sciences5625 Renmin StreetChangchun130022P. R. China
| | - Fei Chang
- Department of OrthopedicsThe Second Hospital of Jilin University4026 Yatai StreetChangchun130041P. R. China
| | - Yinan Wang
- Department of BiobankDivision of Clinical ResearchThe First Hospital of Jilin University1 Xinmin StreetChangchun130061P. R. China
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of EducationThe First Hospital of Jilin University1 Xinmin StreetChangchun130061P. R. China
| | - Jianxun Ding
- Key Laboratory of Polymer EcomaterialsChangchun Institute of Applied ChemistryChinese Academy of Sciences5625 Renmin StreetChangchun130022P. R. China
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Rajput SN, Naeem BK, Ali A, Salim A, Khan I. Expansion of human umbilical cord derived mesenchymal stem cells in regenerative medicine. World J Stem Cells 2024; 16:410-433. [PMID: 38690517 PMCID: PMC11056638 DOI: 10.4252/wjsc.v16.i4.410] [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: 11/30/2023] [Revised: 02/01/2024] [Accepted: 03/18/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND Stem cells are undifferentiated cells that possess the potential for self-renewal with the capacity to differentiate into multiple lineages. In humans, their limited numbers pose a challenge in fulfilling the necessary demands for the regeneration and repair of damaged tissues or organs. Studies suggested that mesenchymal stem cells (MSCs), necessary for repair and regeneration via transplantation, require doses ranging from 10 to 400 million cells. Furthermore, the limited expansion of MSCs restricts their therapeutic application. AIM To optimize a novel protocol to achieve qualitative and quantitative expansion of MSCs to reach the targeted number of cells for cellular transplantation and minimize the limitations in stem cell therapy protocols. METHODS Human umbilical cord (hUC) tissue derived MSCs were obtained and re-cultured. These cultured cells were subjected to the following evaluation procedures: Immunophenotyping, immunocytochemical staining, trilineage differentiation, population doubling time and number, gene expression markers for proliferation, cell cycle progression, senescence-associated β-galactosidase assay, human telomerase reverse transcriptase (hTERT) expression, mycoplasma, cytomegalovirus and endotoxin detection. RESULTS Analysis of pluripotent gene markers Oct4, Sox2, and Nanog in recultured hUC-MSC revealed no significant differences. The immunophenotypic markers CD90, CD73, CD105, CD44, vimentin, CD29, Stro-1, and Lin28 were positively expressed by these recultured expanded MSCs, and were found negative for CD34, CD11b, CD19, CD45, and HLA-DR. The recultured hUC-MSC population continued to expand through passage 15. Proliferative gene expression of Pax6, BMP2, and TGFb1 showed no significant variation between recultured hUC-MSC groups. Nevertheless, a significant increase (P < 0.001) in the mitotic phase of the cell cycle was observed in recultured hUC-MSCs. Cellular senescence markers (hTERT expression and β-galactosidase activity) did not show any negative effect on recultured hUC-MSCs. Additionally, quality control assessments consistently confirmed the absence of mycoplasma, cytomegalovirus, and endotoxin contamination. CONCLUSION This study proposes the development of a novel protocol for efficiently expanding stem cell population. This would address the growing demand for larger stem cell doses needed for cellular transplantation and will significantly improve the feasibility of stem cell based therapies.
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Affiliation(s)
- Shafiqa Naeem Rajput
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Bushra Kiran Naeem
- Surgical Unit 4, Dr. Ruth KM Pfau Civil Hospital, Karachi 74400, Pakistan
| | - Anwar Ali
- Department of Physiology, University of Karachi, Karachi 75270, Pakistan
| | - Asmat Salim
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Irfan Khan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
- Center for Regenerative Medicine and Stem Cells Research, and Department of Ophthalmology and Visual Sciences, The Aga Khan University, Karachi 74800, Sindh, Pakistan.
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Fan S, Sun X, Su C, Xue Y, Song X, Deng R. Macrophages-bone marrow mesenchymal stem cells crosstalk in bone healing. Front Cell Dev Biol 2023; 11:1193765. [PMID: 37427382 PMCID: PMC10327485 DOI: 10.3389/fcell.2023.1193765] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 06/14/2023] [Indexed: 07/11/2023] Open
Abstract
Bone healing is associated with many orthopedic conditions, including fractures and osteonecrosis, arthritis, metabolic bone disease, tumors and periprosthetic particle-associated osteolysis. How to effectively promote bone healing has become a keen topic for researchers. The role of macrophages and bone marrow mesenchymal stem cells (BMSCs) in bone healing has gradually come to light with the development of the concept of osteoimmunity. Their interaction regulates the balance between inflammation and regeneration, and when the inflammatory response is over-excited, attenuated, or disturbed, it results in the failure of bone healing. Therefore, an in-depth understanding of the function of macrophages and bone marrow mesenchymal stem cells in bone regeneration and the relationship between the two could provide new directions to promote bone healing. This paper reviews the role of macrophages and bone marrow mesenchymal stem cells in bone healing and the mechanism and significance of their interaction. Several new therapeutic ideas for regulating the inflammatory response in bone healing by targeting macrophages and bone marrow mesenchymal stem cells crosstalk are also discussed.
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Affiliation(s)
- Siyu Fan
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Xin Sun
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Chuanchao Su
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Yiwen Xue
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Xiao Song
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Runzhi Deng
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
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Slovinska L, Harvanova D. The Role of Mesenchymal Stromal Cells and Their Products in the Treatment of Injured Spinal Cords. Curr Issues Mol Biol 2023; 45:5180-5197. [PMID: 37367078 DOI: 10.3390/cimb45060329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/09/2023] [Accepted: 06/14/2023] [Indexed: 06/28/2023] Open
Abstract
Spinal cord injury (SCI) is a destructive condition that results in lasting neurological damage resulting in disruption of the connection between the central nervous system and the rest of the body. Currently, there are several approaches in the treatment of a damaged spinal cord; however, none of the methods allow the patient to return to the original full-featured state of life before the injury. Cell transplantation therapies show great potential in the treatment of damaged spinal cords. The most examined type of cells used in SCI research are mesenchymal stromal cells (MSCs). These cells are at the center of interest of scientists because of their unique properties. MSCs regenerate the injured tissue in two ways: (i) they are able to differentiate into some types of cells and so can replace the cells of injured tissue and (ii) they regenerate tissue through their powerful known paracrine effect. This review presents information about SCI and the treatments usually used, aiming at cell therapy using MSCs and their products, among which active biomolecules and extracellular vesicles predominate.
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Affiliation(s)
- Lucia Slovinska
- Associated Tissue Bank, P.J. Šafárik University and L. Pasteur University Hospital, 040 01 Košice, Slovakia
- Department of Regenerative Medicine and Cell Therapy, Institute of Neurobiology Biomedical Research Center, Slovak Academy of Sciences, 040 01 Košice, Slovakia
| | - Denisa Harvanova
- Associated Tissue Bank, P.J. Šafárik University and L. Pasteur University Hospital, 040 01 Košice, Slovakia
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Han X, He X, Zhan X, Yao L, Sun Z, Gao X, Wang S, Wang Z. Disturbed microbiota-metabolites-immune interaction network is associated with olfactory dysfunction in patients with chronic rhinosinusitis. Front Immunol 2023; 14:1159112. [PMID: 37292198 PMCID: PMC10245275 DOI: 10.3389/fimmu.2023.1159112] [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: 02/05/2023] [Accepted: 05/05/2023] [Indexed: 06/10/2023] Open
Abstract
Purpose Olfactory dysfunction (OD) is a debilitating symptom frequently reported by patients with chronic rhinosinusitis (CRS) and it is associated with a dysregulated sinonasal inflammation. However, little information is available about the effect of the inflammation-related nasal microbiota and related metabolites on the olfactory function in these patients. Therefore, the current study aimed to investigate the nasal microbiota-metabolites-immune interactions and their role in the pathogenesis of OD in CRS patients. Methods 23 and 19 CRS patients with and without OD, respectively, were enrolled in the present study. The "Sniffin' Sticks" was used to measure the olfactory function, while the metagenomic shotgun sequencing and the untargeted metabolite profiling were performed to assess the differences in terms of the nasal microbiome and metabolome between the two groups. The levels of nasal mucus inflammatory mediators were investigated by a multiplex flow Cytometric Bead Array (CBA). Results A decreased diversity in the nasal microbiome from the OD group compared to the NOD group was evidenced. The metagenomic analysis revealed a significant enrichment of Acinetobacter johnsonii in the OD group, while Mycoplasma arginini, Aeromonas dhakensis, and Salmonella enterica were significantly less represented (LDA value > 3, p < 0.05). The nasal metabolome profiles were significantly different between the OD and NOD groups (P < 0.05). The purine metabolism was the most significantly enriched metabolic subpathway in OD patients compared with NOD patients (P < 0.001). The expressions of IL-5, IL-8, MIP-1α, MCP-1, and TNF were statistically and significantly increased in the OD group (P < 0.05). All these data, including the dysregulation of the nasal microbiota, differential metabolites, and elevated inflammatory mediators in OD patients demonstrated a clear interaction relationship. Conclusion The disturbed nasal microbiota-metabolite-immune interaction networks may be implicated in the pathogenesis of OD in CRS patients and the underlying pathophysiological mechanisms need to be further investigated in future studies.
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Affiliation(s)
- Xingyu Han
- Department of Otolaryngology-Head and Neck Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Department of Otolaryngology-Head and Neck Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- Department of Otorhinolaryngology-Head and Neck Surgery, Capital Institute of Pediatrics, Beijing, China
| | - Xuejia He
- Capital Institute of Pediatrics, Peking University Teaching Hospital, Beijing, China
| | - Xiaojun Zhan
- Department of Otorhinolaryngology-Head and Neck Surgery, Capital Institute of Pediatrics, Beijing, China
| | - Linyin Yao
- Department of Otolaryngology-Head and Neck Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Zhifu Sun
- Department of Otolaryngology-Head and Neck Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Xing Gao
- Department of Otorhinolaryngology-Head and Neck Surgery, Capital Institute of Pediatrics, Beijing, China
| | - Shan Wang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China
| | - Zhenlin Wang
- Department of Otolaryngology-Head and Neck Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
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Mesenchymal stem cell therapy attenuates complement C3 deposition and improves the delicate equilibrium between angiogenic and anti-angiogenic factors in abortion-prone mice. Mol Immunol 2021; 141:246-256. [PMID: 34875452 DOI: 10.1016/j.molimm.2021.11.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 10/15/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022]
Abstract
Immunological disorders are one of the main causes of recurrent spontaneous abortions (RSA). A rapidly expanding body of evidence indicates that excessive activation of the complement system is critically involved in the development of miscarriages. In the CBA/J × DBA/2 murine model of recurrent miscarriage, exaggerated and unrestrained complement activation is reported to be the underlying cause of angiogenic factor imbalance and persistent inflammation. We have previously shown that mesenchymal stem cell (MSC) therapy can significantly reduce the abortion rate in abortion-prone mice through regulating the feto-maternal immune response. In the present study, we hypothesized that MSCs might improve the balance of angiogenic factors at the feto-maternal unit of CBA/J × DBA/2 mice by restraining complement activation and deposition. To explore this hypothesis, autologous adipose tissue-derived mesenchymal stem cells (AD-MSCs) were administered intra-peritoneally to abortion-prone mice on the 4.5th day of gestation. Control mice received PBS as vehicle. On day 13.5 of pregnancy, deposition of the complement component C3 and expression levels of Crry, CFD (adipsin), VEGF, PlGF and FLT-1 were measured at the feto-maternal interface by immunohistochemistry and real-time PCR, respectively. Decidual cells were also cultured in RPMI 1640 medium for 48 h and VEGF and sFLT-1 protein levels were quantified in supernatants using enzyme-linked immunosorbent assay (ELISA). Our results indicated that MSC therapy significantly reduced C3 deposition and adipsin transcription in the fetal-maternal interface of abortion-prone mice. Furthermore, administration of MSCs robustly upregulated the mRNA expression levels of Crry, VEGF, PlGF and FLT-1 in the placenta and decidua of CBA/J × DBA/2 mice. Consistently, the in vitro results demonstrated that decidual cells obtained from MSC-treated dams produced increased concentrations of VEGF in culture supernatants, with concomitant decreased levels of sFLT-1 protein. Here, we show for the first time that adoptive transfer of MSCs rectifies the disturbed balance of angiogenic factors observed at the feto-maternal unit of CBA/J × DBA/2 mice, in part at least, through inhibiting excessive complement activation and promoting the production of angiogenic factors. Collectively, these alterations seem to play a pivotal role in reducing the abortion rate and improving the intrauterine condition for the benefit of the fetus.
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Lu D, Xu Y, Liu Q, Zhang Q. Mesenchymal Stem Cell-Macrophage Crosstalk and Maintenance of Inflammatory Microenvironment Homeostasis. Front Cell Dev Biol 2021; 9:681171. [PMID: 34249933 PMCID: PMC8267370 DOI: 10.3389/fcell.2021.681171] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/28/2021] [Indexed: 12/13/2022] Open
Abstract
Macrophages are involved in almost every aspect of biological systems and include development, homeostasis and repair. Mesenchymal stem cells (MSCs) have good clinical application prospects due to their ability to regulate adaptive and innate immune cells, particularly macrophages, and they have been used successfully for many immune disorders, including inflammatory bowel disease (IBD), acute lung injury, and wound healing, which have been reported as macrophage-mediated disorders. In the present review, we focus on the interaction between MSCs and macrophages and summarize their methods of interaction and communication, such as cell-to-cell contact, soluble factor secretion, and organelle transfer. In addition, we discuss the roles of MSC-macrophage crosstalk in the development of disease and maintenance of homeostasis of inflammatory microenvironments. Finally, we provide optimal strategies for applications in immune-related disease treatments.
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Affiliation(s)
- Di Lu
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yan Xu
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qiuli Liu
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qi Zhang
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Fu X, Xu B, Jiang J, Du X, Yu X, Yan Y, Li S, Inglis BM, Ma H, Wang H, Pei X, Si W. Effects of cryopreservation and long-term culture on biological characteristics and proteomic profiles of human umbilical cord-derived mesenchymal stem cells. Clin Proteomics 2020; 17:15. [PMID: 32489333 PMCID: PMC7247169 DOI: 10.1186/s12014-020-09279-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 05/15/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Human umbilical cord-derived MSCs (hUC-MSCs) have been identified as promising seeding cells in tissue engineering and clinical applications of regenerative medicine due to their advantages of simple acquisition procedure and the capability to come from a young tissue donor over the other MSCs sources. In clinical applications, large scale production is required and optimal cryopreservation and culture conditions are essential to autologous and allogeneic transplantation in the future. However, the influence of cryopreserved post-thaw and long-term culture on hUC-MSCs remains unknown, especially in terms of specific protein expression. Therefore, biological characteristics and proteomic profiles of hUC-MSCs after cryopreserving and long-term culturing were investigated. METHODS Firstly, hUC-MSCs were isolated from human umbilical cord tissues and identified through morphology, surface markers and tri-lineage differentiation potential at passage 3, and then the biological characteristics and proteomic profiles were detected and compared after cryopreserving and long-term culturing at passage 4 and continuously cultured to passage 10 with detection occurring here as well. The proteomic profiles were tested by using the isobaric tags for relative and absolute quantification (iTRAQ) labeling technique and differential protein were confirmed by mass spectrometry. RESULTS The results showed no significant differences in phenotypes including morphology, surface marker and tri-lineage differentiation potential but have obvious changes in translation level, which is involved in metabolism, cell cycle and other pathways. CONCLUSION This suggests that protein expression may be used as an indicator of hUC-MSCs security testing before applying in clinical settings, and it is also expected to provide the foundation or standardization guide of hUC-MSCs applications in regenerative medicine.
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Affiliation(s)
- Xufeng Fu
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan, 750004 China
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500 China
| | - Bo Xu
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan, 750004 China
| | - Jiang Jiang
- Department of Obstetrics, The First People’s Hospital of Yunnan Province, Kunming, 650032 China
| | - Xing Du
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan, 750004 China
| | - Xiaoli Yu
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan, 750004 China
| | - Yaping Yan
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500 China
| | - Shanshan Li
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500 China
| | - Briauna Marie Inglis
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500 China
| | - Huiming Ma
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan, 750004 China
| | - Hongyan Wang
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan, 750004 China
| | - Xiuying Pei
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan, 750004 China
| | - Wei Si
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500 China
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Joel MDM, Yuan J, Wang J, Yan Y, Qian H, Zhang X, Xu W, Mao F. MSC: immunoregulatory effects, roles on neutrophils and evolving clinical potentials. Am J Transl Res 2019; 11:3890-3904. [PMID: 31312397 PMCID: PMC6614638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 05/07/2019] [Indexed: 06/10/2023]
Abstract
Mesenchymal stem cells (MSCs) are multipotent, non-hematopoietic stem cells capable of differentiating into varieties of mature cell types such as osteoblasts, chondrocytes, adipocytes, and myoblasts. MSCs can be isolated from different kinds of tissues and cultivated in vitro for amplification and passage easily. These cells have drawn researcher's attention lately due to their ability of tissue repair, properties of hematopoiesis support and function of immunoregulation through the secretion of a variety of cytokines and growth factors that have both paracrine and autocrine activities. MSCs can regulate the proliferation of T cells, the antibodies secretion of B cells, maturation of DC, polarization of macrophages and also have many effects on neutrophils such as the suppression of NO secretion, inhibition of apoptosis, reduction of their infiltration, decreasing of N-Formy l-L-Methionine-L-leucy l-L-phenylalanine, induction of respiratory bursts and promotion of survivals. In some conditions, MSCs exert their function of treatment through immunoregulation. We reviewed the multifaceted roles of MSCs in communicating with immune cells mainly neutrophils in both in vivo and in vitro experiments. MSCs may provide promising trends for cell therapy in future.
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Affiliation(s)
- Mbobda Defo Marius Joel
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu UniversityZhenjiang 212013, Jiangsu, P. R. China
| | - Jintao Yuan
- The People’s Hospital of Danyang, Affiliated Danyang Hospital of Nantong UniversityZhenjiang 212300, Jiangsu, P. R. China
| | - Jingyan Wang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu UniversityZhenjiang 212013, Jiangsu, P. R. China
| | - Yongmin Yan
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu UniversityZhenjiang 212013, Jiangsu, P. R. China
| | - Hui Qian
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu UniversityZhenjiang 212013, Jiangsu, P. R. China
| | - Xu Zhang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu UniversityZhenjiang 212013, Jiangsu, P. R. China
| | - Wenrong Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu UniversityZhenjiang 212013, Jiangsu, P. R. China
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu UniversityZhenjiang 212013, Jiangsu, P. R. China
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11
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Makabe K, Sugita S, Hono A, Kamao H, Takahashi M. Mycoplasma Ocular Infection in Subretinal Graft Transplantation of iPS Cells-Derived Retinal Pigment Epithelial Cells. ACTA ACUST UNITED AC 2019; 60:1298-1308. [DOI: 10.1167/iovs.18-26222] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Affiliation(s)
- Kenichi Makabe
- Laboratory for Retinal Regeneration, Center for Biosystems Dynamics Research, RIKEN, Kobe, Japan
- Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Sunao Sugita
- Laboratory for Retinal Regeneration, Center for Biosystems Dynamics Research, RIKEN, Kobe, Japan
| | - Ayumi Hono
- Laboratory for Retinal Regeneration, Center for Biosystems Dynamics Research, RIKEN, Kobe, Japan
| | - Hiroyuki Kamao
- Department of Ophthalmology, Kawasaki Medical School, Okayama, Japan
| | - Masayo Takahashi
- Laboratory for Retinal Regeneration, Center for Biosystems Dynamics Research, RIKEN, Kobe, Japan
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12
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O'Rourke F, Kempf VAJ. Interaction of bacteria and stem cells in health and disease. FEMS Microbiol Rev 2019; 43:162-180. [DOI: 10.1093/femsre/fuz003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 01/11/2019] [Indexed: 12/11/2022] Open
Affiliation(s)
- Fiona O'Rourke
- Institut für Medizinische Mikrobiologie und Krankenhaushygiene, University Hospital, Goethe University, Paul-Ehrlich-Str. 40, D-60596 Frankfurt am Main, Germany
| | - Volkhard A J Kempf
- Institut für Medizinische Mikrobiologie und Krankenhaushygiene, University Hospital, Goethe University, Paul-Ehrlich-Str. 40, D-60596 Frankfurt am Main, Germany
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13
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Krajewska-Włodarczyk M, Owczarczyk-Saczonek A, Placek W, Osowski A, Engelgardt P, Wojtkiewicz J. Role of Stem Cells in Pathophysiology and Therapy of Spondyloarthropathies-New Therapeutic Possibilities? Int J Mol Sci 2017; 19:ijms19010080. [PMID: 29283375 PMCID: PMC5796030 DOI: 10.3390/ijms19010080] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Revised: 12/23/2017] [Accepted: 12/25/2017] [Indexed: 12/14/2022] Open
Abstract
Considerable progress has been made recently in understanding the complex pathogenesis and treatment of spondyloarthropathies (SpA). Currently, along with traditional disease modifying anti-rheumatic drugs (DMARDs), TNF-α, IL-12/23 and IL-17 are available for treatment of such diseases as ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Although they adequately control inflammatory symptoms, they do not affect the abnormal bone formation processes associated with SpA. However, the traditional therapeutic approach does not cover the regenerative treatment of damaged tissues. In this regards, stem cells may offer a promising, safe and effective therapeutic option. The aim of this paper is to present the role of mesenchymal stromal cells (MSC) in pathogenesis of SpA and to highlight the opportunities for using stem cells in regenerative processes and in the treatment of inflammatory changes in articular structures.
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Affiliation(s)
- Magdalena Krajewska-Włodarczyk
- Department of Rheumatology, Municipal Hospital in Olsztyn, 10-900 Olsztyn, Poland.
- Department of Pathophysiology, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
| | - Agnieszka Owczarczyk-Saczonek
- Department of Dermatology, Sexually Transmitted Diseases and Clinical Immunology, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
| | - Waldemar Placek
- Department of Dermatology, Sexually Transmitted Diseases and Clinical Immunology, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
| | - Adam Osowski
- Department of Pathophysiology, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
| | - Piotr Engelgardt
- Department of Forensic Medicine, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
| | - Joanna Wojtkiewicz
- Department of Pathophysiology, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
- Laboratory for Regenerative Medicine, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
- Foundation for Nerve Cell Regeneration, University of Warmia and Mazury in Olsztyn, 10-900 Olsztyn, Poland.
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14
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Talas L, Banfalvi G, Fidrus E, Szigeti ZM, Nagy G. Mycoplasma infection followed by time-lapse microscopy. Med Hypotheses 2017; 108:154-158. [PMID: 29055390 DOI: 10.1016/j.mehy.2017.09.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Accepted: 09/06/2017] [Indexed: 11/29/2022]
Abstract
Early detection of mycoplasma infection is crucial for saving precious often irreplaceable data from the tissues of patients. Mycoplasma infections cause diseases in the upper and lower respiratory tracts, urethritis in men resulting in painful dysuria, urgency and urethral discharge. Cough, fever, headache, urethritis may persist for several weeks and convalescence is slow. The symptoms of these diseases are aggravated by the detection of mycoplasma infections, that takes either a long time, besides being expensive or is specific and restricted to only a limited number of contaminant strains. Mycoplasmas are hard to detect visually but could be seen and followed by time-lapse microscopy. Our hypothesis is that one can detect mycoplasma infection irrespective of its origin and type of mycoplasma. Main lines of supporting evidence are provided by the time-lapse microscopy showing dynamic morphological alterations caused by mycoplasmas before changes in human cell cultures become visible. Morphometric measurements of mycoplasma infections revealed four subphases: i) detachment of infected cells, ii) aggregation, iii) biofilm formation and iv) shrinkage of infected cells. The applicability of time-lapse microscopy for the detection of mycoplasma infection was validated by a mycoplasma test Kit. Most important implications related to morphometric parameters include the observation of mycoplasma infected cultures for an extended period of time instead of applying static snap-shot microscopy. A reliable method is offered to estimate the time of mycoplasma exposure that elapsed during the cell growth. This microphotometric approach served a more economical detection of mycoplasma contamination at its early stage of cell growth and spread, irrespective of the origin of contaminated serum, without defining the type of mycoplasma.
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Affiliation(s)
- Laszlo Talas
- Department of Biotechnology and Microbiology, University of Debrecen, Hungary
| | - Gaspar Banfalvi
- Department of Biotechnology and Microbiology, University of Debrecen, Hungary.
| | - Eszter Fidrus
- Department of Biotechnology and Microbiology, University of Debrecen, Hungary
| | - Zsuzsa M Szigeti
- Department of Biotechnology and Microbiology, University of Debrecen, Hungary
| | - Gabor Nagy
- Department of Biotechnology and Microbiology, University of Debrecen, Hungary
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15
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Li N, Hua J. Interactions between mesenchymal stem cells and the immune system. Cell Mol Life Sci 2017; 74:2345-2360. [PMID: 28214990 PMCID: PMC11107583 DOI: 10.1007/s00018-017-2473-5] [Citation(s) in RCA: 224] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Revised: 12/24/2016] [Accepted: 01/23/2017] [Indexed: 02/07/2023]
Abstract
In addition to being multi-potent, mesenchymal stem cells (MSCs) possess immunomodulatory functions that have been investigated as potential treatments in various immune disorders. MSCs can robustly interact with cells of the innate and adaptive immune systems, either through direct cell-cell contact or through their secretome. In this review, we discuss current findings regarding the interplay between MSCs and different immune cell subsets. We also draw attention to the mechanisms involved.
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Affiliation(s)
- Na Li
- College of Veterinary Medicine, Shaanxi Center of Stem Cells Engineering and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Jinlian Hua
- College of Veterinary Medicine, Shaanxi Center of Stem Cells Engineering and Technology, Northwest A&F University, Yangling, Shaanxi, China.
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16
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Yao Y, Song W, Deng Q, Zhang H, Wang J, Liu H, Zhou Y. General regulatory effects of hypoxia on human cartilage endplate‑derived stem cells: A genome‑wide analysis of differential gene expression and alternative splicing events. Mol Med Rep 2017; 16:3001-3009. [PMID: 28677762 DOI: 10.3892/mmr.2017.6907] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Accepted: 05/12/2017] [Indexed: 11/06/2022] Open
Abstract
Intervertebral disc (IVD) degeneration of is considered to be initiated by the degeneration of the cartilage endplate (CEP). CEP‑derived stem cells (CESCs) with the capacity for osteochondrogenic differentiation may be responsible for CEP cartilage restoration. As CEP is avascular and hypoxic, and hypoxia can greatly influence biological activities of stem cells, physiological hypoxia may serve important roles in regulating the physiological functions of CESCs. The aim of the present study was to investigate the mechanisms of hypoxia‑regulated CESCs fate by using the Human Transcriptome Array 2.0 system to identify differentially expressed genes (DEGs) and alternatively spliced genes (ASGs) in CESCs cultured under hypoxic and normoxic conditions. The high‑throughput analysis of both DEGs and ASGs were notably enriched in the immune response signal, which so far has not been investigated in IVD cells, due to their avascular nature and low immunogenicity. The present results provided a referential study direction of the mechanisms of hypoxia‑regulated CESC fate at the level of gene expression and alternative splicing, which may aid in our understanding of the processes of CEP degeneration.
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Affiliation(s)
- Yuan Yao
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Weilin Song
- Department of Ophthalmology, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
| | - Qiyue Deng
- Department of Neurobiology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, P.R. China
| | - Huiyu Zhang
- Department of Stomatology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Jian Wang
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Huan Liu
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Yue Zhou
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
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17
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Yao Y, Deng Q, Sun C, Song W, Liu H, Zhou Y. A genome-wide analysis of the gene expression profiles and alternative splicing events during the hypoxia-regulated osteogenic differentiation of human cartilage endplate-derived stem cells. Mol Med Rep 2017; 16:1991-2001. [PMID: 28656244 PMCID: PMC5562021 DOI: 10.3892/mmr.2017.6846] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 04/25/2017] [Indexed: 12/20/2022] Open
Abstract
It has been hypothesized that intervertebral disc degeneration is initiated by degeneration of the cartilage endplate (CEP), which is characterized by cartilage ossification. CEP‑derived stem cells (CESCs), with the potential for chondro‑osteogenic differentiation, may be responsible for the balance between chondrification and ossification in the CEP. The CEP remains in an avascular and hypoxic microenvironment; the present study observed that hypoxia was able to markedly inhibit the osteogenic differentiation of CESCs. This tissue‑specific CESC differentiation in response to a hypoxic microenvironment was physiologically important for the prevention of ossification in the CEP. In order to study the hypoxia‑regulated mechanisms underlying osteogenic differentiation of CESCs, a Human Transcriptome Array 2.0 was used to detect differentially expressed genes (DEGs) and alternatively spliced genes (ASGs) during the osteogenic differentiation of CESCs under hypoxia, compared with those induced under normoxia. High‑throughput analysis of DEGs and ASGs demonstrated that genes in the complement pathway were enriched, which may be a potential mechanism underlying hypoxia inhibition of CESCs osteogenesis. The results of the present study may provide a basis for future mechanistic studies regarding gene expression levels and alternative splicing events during the hypoxia‑regulated inhibition of osteogenesis, which may be helpful in identifying targets for CEP degeneration therapy.
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Affiliation(s)
- Yuan Yao
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Qiyue Deng
- Department of Neurobiology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, P.R. China
| | - Chao Sun
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Weiling Song
- Department of Ophthalmology, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
| | - Huan Liu
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Yue Zhou
- Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
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18
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Fan L, Hu C, Chen J, Cen P, Wang J, Li L. Interaction between Mesenchymal Stem Cells and B-Cells. Int J Mol Sci 2016; 17:E650. [PMID: 27164080 PMCID: PMC4881476 DOI: 10.3390/ijms17050650] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Revised: 04/19/2016] [Accepted: 04/19/2016] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent; non-hematopoietic stem cells. Because of their immunoregulatory abilities; MSCs are widely used for different clinical applications. Compared with that of other immune cells; the investigation of how MSCs specifically regulate B-cells has been superficial and insufficient. In addition; the few experimental studies on this regulation are often contradictory. In this review; we summarize the various interactions between different types or states of MSCs and B-cells; address how different types of MSCs and B-cells affect this interaction and examine how other immune cells influence the regulation of B-cells by MSCs. Finally; we hypothesize why there are conflicting results on the interaction between MSCs and B-cells in the literature.
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Affiliation(s)
- Linxiao Fan
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.
| | - Chenxia Hu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.
| | - Jiajia Chen
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.
| | - Panpan Cen
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.
| | - Jie Wang
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.
| | - Lanjuan Li
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.
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19
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Schraufstatter IU, Khaldoyanidi SK, DiScipio RG. Complement activation in the context of stem cells and tissue repair. World J Stem Cells 2015; 7:1090-1108. [PMID: 26435769 PMCID: PMC4591784 DOI: 10.4252/wjsc.v7.i8.1090] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 07/27/2015] [Indexed: 02/06/2023] Open
Abstract
The complement pathway is best known for its role in immune surveillance and inflammation. However, its ability of opsonizing and removing not only pathogens, but also necrotic and apoptotic cells, is a phylogenetically ancient means of initiating tissue repair. The means and mechanisms of complement-mediated tissue repair are discussed in this review. There is increasing evidence that complement activation contributes to tissue repair at several levels. These range from the chemo-attraction of stem and progenitor cells to areas of complement activation, to increased survival of various cell types in the presence of split products of complement, and to the production of trophic factors by cells activated by the anaphylatoxins C3a and C5a. This repair aspect of complement biology has not found sufficient appreciation until recently. The following will examine this aspect of complement biology with an emphasis on the anaphylatoxins C3a and C5a.
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20
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Mastellos DC, Yancopoulou D, Kokkinos P, Huber-Lang M, Hajishengallis G, Biglarnia AR, Lupu F, Nilsson B, Risitano AM, Ricklin D, Lambris JD. Compstatin: a C3-targeted complement inhibitor reaching its prime for bedside intervention. Eur J Clin Invest 2015; 45:423-40. [PMID: 25678219 PMCID: PMC4380746 DOI: 10.1111/eci.12419] [Citation(s) in RCA: 175] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 02/06/2015] [Indexed: 12/12/2022]
Abstract
There is a growing awareness that complement plays an integral role in human physiology and disease, transcending its traditional perception as an accessory system for pathogen clearance and opsonic cell killing. As the list of pathologies linked to dysregulated complement activation grows longer, it has become clear that targeted modulation of this innate immune system opens new windows of therapeutic opportunity for anti-inflammatory drug design. Indeed, the introduction of the first complement-targeting drugs has reignited a vibrant interest in the clinical translation of complement-based inhibitors. Compstatin was discovered as a cyclic peptide that inhibits complement activation by binding C3 and interfering with convertase formation and C3 cleavage. As the convergence point of all activation pathways and a molecular hub for crosstalk with multiple pathogenic pathways, C3 represents an attractive target for therapeutic modulation of the complement cascade. A multidisciplinary drug optimization effort encompassing rational 'wet' and in silico synthetic approaches and an array of biophysical, structural and analytical tools has culminated in an impressive structure-function refinement of compstatin, yielding a series of analogues that show promise for a wide spectrum of clinical applications. These new derivatives have improved inhibitory potency and pharmacokinetic profiles and show efficacy in clinically relevant primate models of disease. This review provides an up-to-date survey of the drug design effort placed on the compstatin family of C3 inhibitors, highlighting the most promising drug candidates. It also discusses translational challenges in complement drug discovery and peptide drug development and reviews concerns related to systemic C3 interception.
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Affiliation(s)
- Dimitrios C Mastellos
- Division of Biodiagnostic Sciences and Technologies, INRASTES, National Center for Scientific Research 'Demokritos', Aghia Paraskevi Attikis, Greece
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