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Luby AO, Nelson JM, Sacks GN, Daniel M, Buchman L, Lynn JV, Nelson NS, Buchman SR. Intraoperative Optimization of Stromal Vascular Fraction for Remediation of Radiated Fracture Repair: Closing the Gap on Clinical Translation of Cell-Based Therapies. Ann Plast Surg 2025:00000637-990000000-00819. [PMID: 40401910 DOI: 10.1097/sap.0000000000004407] [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: 05/23/2025]
Abstract
BACKGROUND Mechanical processing techniques to isolate the stromal vascular fraction (SVF) may optimize clinical translation of cell-based therapeutics. Therefore, the purpose of this study was to develop a technique for intraoperative isolation of SVF for immediate therapeutic use with the primary aim of enhancing bone healing at irradiated fracture sites. METHODS Male Lewis rats (n = 29) were divided into groups: fracture, radiation with fracture, and radiation with fracture and SVF implantation. Experimental groups received 35 Gy of targeted radiation. All groups underwent mandibular osteotomy and external fixation. SVF was isolated from inguinal fat pads using Tulip Sizing Transfers, serial filtration, and centrifugation. The resultant cell pellet was implanted at the osteotomy site. After 40 days, bone union and mineralization were evaluated based on gross pathology and micro-computed tomography, respectively, and biomechanical strength testing was performed. RESULTS SVF treatment increased union rates after radiation (79% vs 20%). Additionally, SVF improved both bone mineral density (666.2 ± 32.0 vs 312.2 ± 51.7; P = 0.000) and bone volume fraction (0.744 ± 0.072 vs 0.350 ± 0.041; P = 0.000) compared with the irradiated control. In fact, SVF treatment into irradiated fracture sites resulted in bone mineral density and bone volume fraction similar to the bone formed at nonirradiated fracture sites, as there was no significant difference between groups. SVF treatment did not significantly improve biomechanical strength compared with the irradiated control. CONCLUSIONS In this study, we developed a novel approach utilizing mechanical methods to enable intraoperative SVF isolation for immediate implantation. SVF demonstrates therapeutic potential for applications in irradiated fracture healing. The results of this study are promising for the long-awaited translation of cell-based therapeutics into the clinical arena.
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Affiliation(s)
- Alexandra O Luby
- From the Craniofacial Research Laboratory, Section of Plastic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI
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Yarahmadi A, Dorri Giv M, Hosseininejad R, Rezaie A, Mohammadi N, Afkhami H, Farokhi A. Mesenchymal stem cells and their extracellular vesicle therapy for neurological disorders: traumatic brain injury and beyond. Front Neurol 2025; 16:1472679. [PMID: 39974358 PMCID: PMC11835705 DOI: 10.3389/fneur.2025.1472679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 01/08/2025] [Indexed: 02/21/2025] Open
Abstract
Traumatic brain injury (TBI) is a complex condition involving mechanisms that lead to brain dysfunction and nerve damage, resulting in significant morbidity and mortality globally. Affecting ~50 million people annually, TBI's impact includes a high death rate, exceeding that of heart disease and cancer. Complications arising from TBI encompass concussion, cerebral hemorrhage, tumors, encephalitis, delayed apoptosis, and necrosis. Current treatment methods, such as pharmacotherapy with dihydropyridines, high-pressure oxygen therapy, behavioral therapy, and non-invasive brain stimulation, have shown limited efficacy. A comprehensive understanding of vascular components is essential for developing new treatments to improve blood vessel-related brain damage. Recently, mesenchymal stem cells (MSCs) have shown promising results in repairing and mitigating brain damage. Studies indicate that MSCs can promote neurogenesis and angiogenesis through various mechanisms, including releasing bioactive molecules and extracellular vesicles (EVs), which help reduce neuroinflammation. In research, the distinctive characteristics of MSCs have positioned them as highly desirable cell sources. Extensive investigations have been conducted on the regulatory properties of MSCs and their manipulation, tagging, and transportation techniques for brain-related applications. This review explores the progress and prospects of MSC therapy in TBI, focusing on mechanisms of action, therapeutic benefits, and the challenges and potential limitations of using MSCs in treating neurological disorders.
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Affiliation(s)
- Aref Yarahmadi
- Department of Biology, Khorramabad Branch, Islamic Azad University, Khorramabad, Iran
| | - Masoumeh Dorri Giv
- Nuclear Medicine Research Center, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Hosseininejad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Azin Rezaie
- Department of Microbiology, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Narges Mohammadi
- Department of Molecular Cell Biology and Microbiology, Faculty of Biological Sciences and Technologies, University of Isfahan, Isfahan, Iran
| | - Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Arastoo Farokhi
- Department of Anesthesiology, Kermanshah University of Medical Sciences, Imam Reza Hospital, Kermanshah, Iran
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Roseti L, Cavallo C, Desando G, D’Alessandro M, Grigolo B. Forty Years of the Use of Cells for Cartilage Regeneration: The Research Side. Pharmaceutics 2024; 16:1622. [PMID: 39771600 PMCID: PMC11677864 DOI: 10.3390/pharmaceutics16121622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/13/2024] [Accepted: 12/20/2024] [Indexed: 01/11/2025] Open
Abstract
Background: The treatment of articular cartilage damage has always represented a problem of considerable practical interest for orthopedics. Over the years, many surgical techniques have been proposed to induce the growth of repairing tissue and limit degeneration. In 1994, the turning point occurred: implanted autologous cells paved the way for a new treatment option based more on regeneration than repair. Objectives: This review aims to outline biological and clinical advances, from the use of mature adult chondrocytes to cell-derived products, going through progenitor cells derived from bone marrow or adipose tissue and their concentrates for articular cartilage repair. Moreover, it highlights the relevance of gene therapy as a valuable tool for successfully implementing current regenerative treatments, and overcoming the limitations of the local delivery of growth factors. Conclusions: Finally, this review concludes with an outlook on the importance of understanding the role and mechanisms of action of the different cell compounds with a view to implementing personalized treatments.
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Affiliation(s)
| | - Carola Cavallo
- Laboratorio RAMSES, IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano, 1/10, 40136 Bologna, Italy; (L.R.); (G.D.); (M.D.); (B.G.)
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Erol Bozkurt A, Sel FA, Suleymanoğlu M, Demirayak G, Kuruca DS, Oğuz FS. The Cytokine Levels of Cord Blood- and Wharton's Jelly-Derived Mesenchymal Stem Cells from Early to Late Passages. Cell Biochem Biophys 2024; 82:3345-3350. [PMID: 39018006 DOI: 10.1007/s12013-024-01416-4] [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] [Accepted: 07/07/2024] [Indexed: 07/18/2024]
Abstract
Mesenchymal stem cells (MSCs) are promising for clinical studies owing to their self-renewal, multipotency, trophic, and immunomodulatory properties. This study aimed to investigate the cytokine levels of human umbilical cord blood (CB) and Wharton's Jelly-(WJ) derived MSCs relevant to immune modulation on different passage levels in vitro. Umbilical CB MSCs were isolated using the ficoll-paque gradient method, and WJ-MSCs were isolated by the explant method. After isolation, the MSCs were characterized using flow cytometry. The supernatant cytokine levels (interferon-gamma (IFN-γ), interleukin 4 (IL-4), interleukin 17 (IL-17)) of MSCs at each passage were evaluated using the ELISA assay. MSCs exhibited different cytokine levels with each passage number. In WJ-MSC culture supernatants, IL-17 levels significantly increased at P4 and P5 compared to the first passage (p < 0.005), while the other passages showed a decrease. IFN-γ levels increased at passage P1 and P4 and decreased at other passages (p < 0.005). IL-4 levels significantly increased only at passage P3 (p < 0.005). In CB-MSC culture supernatants, IL-17 and IL-4 cytokines decreased compared to P0, while IFN-γ cytokine increased from P0 (p < 0.005). The changing ratio of cytokine levelsfor both CB-MSCs and WJ-MSCs were similarly maintained from early to late passages. More research is needed to understand the immunomodulatory functions of MSCs.
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Affiliation(s)
- Ayşe Erol Bozkurt
- Istanbul University, Istanbul Faculty of Medicine, Department of Medical Biology, Istanbul, Türkiye.
| | - Figen Abatay Sel
- Istanbul University, Istanbul Faculty of Medicine, Department of Medical Biology, Istanbul, Türkiye
| | - Mediha Suleymanoğlu
- Istanbul University, Istanbul Faculty of Medicine, Department of Medical Biology, Istanbul, Türkiye
| | - Gökhan Demirayak
- University of Health Sciences, Bakırköy Sadi Konuk Education and Research Hospital, Department of Gynecologic Oncology, Istanbul, Türkiye
| | - Dürdane Serap Kuruca
- Istanbul University, Istanbul Faculty of Medicine, Department of Physiology, Istanbul, Türkiye
| | - Fatma Savran Oğuz
- Istanbul University, Istanbul Faculty of Medicine, Department of Medical Biology, Istanbul, Türkiye
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Ju R, Gao X, Zhang C, Tang W, Tian W, He M. Exogenous MSC based tissue regeneration: a review of immuno-protection strategies from biomaterial scaffolds. J Mater Chem B 2024; 12:8868-8882. [PMID: 39171946 DOI: 10.1039/d4tb00778f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Abstract
Mesenchymal stem cell (MSC)-based tissue engineering holds great potential for regenerative medicine as a means of replacing damaged or lost tissues to restore their structure and function. However, the efficacy of MSC-based regeneration is frequently limited by the low survival rate and limited survival time of transplanted MSCs. Despite the inherent immune privileges of MSCs, such as low expression of major histocompatibility complex antigens, tolerogenic properties, local immunosuppressive microenvironment creation, and induction of immune tolerance, immune rejection remains a major obstacle to their survival and regenerative potential. Evidence suggests that immune protection strategies can enhance MSC therapeutic efficacy by prolonging their survival and maintaining their biological functions. Among various immune protection strategies, biomaterial-based scaffolds or cell encapsulation systems that mediate the interaction between transplanted MSCs and the host immune system or spatially isolate MSCs from the immune system for a specific time period have shown great promise. In this review, we provide a comprehensive overview of these biomaterial-based immune protection strategies employed for exogenous MSCs, highlighting the crucial role of modulating the immune microenvironment. Each strategy is critically examined, discussing its strengths, limitations, and potential applications in MSC-based tissue engineering. By elucidating the mechanisms behind immune rejection and exploring immune protection strategies, we aim to address the challenges faced by MSC-based tissue engineering and pave the way for enhancing the therapeutic outcomes of MSC therapies. The insights gained from this review will contribute to the development of more effective strategies to protect transplanted MSCs from immune rejection and enable their successful application in regenerative medicine.
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Affiliation(s)
- Rongbai Ju
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xinhui Gao
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Chi Zhang
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Wei Tang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Weidong Tian
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Min He
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, 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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Valim Parca A, Godoy Pieri NC, Fantinato Neto P, Fernandes Bressan F, Ambrósio CE, Santos Martins DD. Comparative Analysis of Fluorescent Labeling Techniques for Tracking Canine Amniotic Stem Cells. Tissue Eng Part C Methods 2024; 30:183-192. [PMID: 38411508 DOI: 10.1089/ten.tec.2023.0286] [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] [Indexed: 02/28/2024] Open
Abstract
The utmost aim of regenerative medicine is to promote the regeneration of injured tissues using stem cells. Amniotic mesenchymal stem cells (AmMSCs) have been used in several studies mainly because of their easy isolation from amniotic tissue postpartum and immunomodulatory and angiogenic properties and the low level of rejection. These cells share characteristics of both embryonic/fetal and adult stem cells and are particularly advantageous because they do not trigger tumorigenic activity when injected into immunocompromised animals. The large-scale use of AmMSCs for cellular therapies would greatly benefit from fluorescence labeling studies to validate their tracking in future therapies. This study evaluated the fluorophore positivity, fluorescence intensity, and longevity of canine AmMSCs. For this purpose, canine AmMSCs from the GDTI/USP biobank were submitted to three labeling conditions, two commercial fluorophores [CellTrace CFSE Cell Proliferation kit - CTrace, and CellTracker Green CMFDA - CTracker (CellTracker Green CMFDA, CT, #C2925, Molecular Probes®; Life Technologies)] and green fluorescent protein (GFP) expression after lentiviral transduction, to select the most suitable tracer in terms of adequate persistence and easy handling and analysis that could be used in studies of domestic animals. Fluorescence was detected in all groups; however, the patterns were different. Specifically, CTrace and CTracker fluorescence was detected 6 h after labeling, while GFP was visualized no earlier than 48 h after transduction. Flow cytometry analysis revealed more than 70% of positive cells on day 7 in the CTrace and CTracker groups, while fluorescence decreased significantly to 10% or less on day 20. Variations between repetitions were observed in the GFP group under the present conditions. Our results showed earlier fluorescence detection and more uniform results across repetitions for the commercial fluorophores. In contrast, fluorescence persisted for more extended periods in the GFP group. These results indicate a promising direction for assessing the roles of canine AmMSCs in regenerative medicine without genomic integration.
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Affiliation(s)
- Andressa Valim Parca
- Department of Veterinary Medicine, Faculty of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
| | - Naira Caroline Godoy Pieri
- Department of Veterinary Medicine, Faculty of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
| | - Paulo Fantinato Neto
- Department of Veterinary Medicine, Faculty of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
| | - Fabiana Fernandes Bressan
- Department of Veterinary Medicine, Faculty of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
| | - Carlos Eduardo Ambrósio
- Department of Veterinary Medicine, Faculty of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
| | - Daniele Dos Santos Martins
- Department of Veterinary Medicine, Faculty of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga, Brazil
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Montenegro Raudales JL, Okuwa Y, Honda M. Dental Pulp Cell Transplantation Combined with Regenerative Endodontic Procedures Promotes Dentin Matrix Formation in Mature Mouse Molars. Cells 2024; 13:348. [PMID: 38391961 PMCID: PMC10886544 DOI: 10.3390/cells13040348] [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: 01/16/2024] [Revised: 02/06/2024] [Accepted: 02/11/2024] [Indexed: 02/24/2024] Open
Abstract
Regenerative endodontic procedures (REPs) are promising for dental pulp tissue regeneration; however, their application in permanent teeth remains challenging. We assessed the potential combination of an REP and local dental pulp cell (DPC) transplantation in the mature molars of C57BL/6 mice with (REP + DPC group) or without (REP group) transplantation of DPCs from green fluorescent protein (GFP) transgenic mice. After 4 weeks, the regenerated tissue was evaluated by micro-computed tomography and histological analyses to detect odontoblasts, vasculogenesis, and neurogenesis. DPCs were assessed for mesenchymal and pluripotency markers. Four weeks after the REP, the molars showed no signs of periapical lesions, and both the REP and REP + DPC groups exhibited a pulp-like tissue composed of a cellular matrix with vessels surrounded by an eosin-stained acellular matrix that resembled hard tissue. However, the REP + DPC group had a broader cellular matrix and uniquely contained odontoblast-like cells co-expressing GFP. Vasculogenesis and neurogenesis were detected in both groups, with the former being more prominent in the REP + DPC group. Overall, the REP was achieved in mature mouse molars and DPC transplantation improved the outcomes by inducing the formation of odontoblast-like cells and greater vasculogenesis.
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Affiliation(s)
- Jorge Luis Montenegro Raudales
- Department of Oral Anatomy, School of Dentistry, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Aichi, Japan; (Y.O.); (M.H.)
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Cui E, Lv L, Wang B, Li L, Lu H, Hua F, Chen W, Chen N, Yang L, Pan R. Umbilical cord MSC-derived exosomes improve alveolar macrophage function and reduce LPS-induced acute lung injury. J Cell Biochem 2024; 125:e30519. [PMID: 38224137 DOI: 10.1002/jcb.30519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 11/20/2023] [Accepted: 12/22/2023] [Indexed: 01/16/2024]
Abstract
Acute lung injury (ALI) is a severe condition that can progress to acute respiratory distress syndrome (ARDS), with a high mortality rate. Currently, no specific and compelling drug treatment plan exists. Mesenchymal stem cells (MSCs) have shown promising results in preclinical and clinical studies as a potential treatment for ALI and other lung-related conditions due to their immunomodulatory properties and ability to regenerate various cell types. The present study focuses on analyzing the role of umbilical cord MSC (UC-MSC))-derived exosomes in reducing lipopolysaccharide-induced ALI and investigating the mechanism involved. The study demonstrates that UC-MSC-derived exosomes effectively improved the metabolic function of alveolar macrophages and promoted their shift to an anti-inflammatory phenotype, leading to a reduction in ALI. The findings also suggest that creating three-dimensional microspheres from the MSCs first can enhance the effectiveness of the exosomes. Further research is needed to fully understand the mechanism of action and optimize the therapeutic potential of MSCs and their secretome in ALI and other lung-related conditions.
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Affiliation(s)
- Enhai Cui
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang, China
| | - Lu Lv
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang, China
| | - Bin Wang
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang, China
| | - Liqin Li
- TCM Key Laboratory Cultivation Base of Zhejiang Province for the Development and Clinical Transformation of Immunomodulatory Drugs, Huzhou, Zhejiang, China
| | - Huadong Lu
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang, China
| | - Feng Hua
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang, China
| | - Wenyan Chen
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang, China
| | - Na Chen
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang, China
| | - Liwei Yang
- Department of Obstetrics, Center for Reproductive Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Ruolang Pan
- Key Laboratory of Cell-Based Drug and Applied Technology Development in Zhejiang Province, Institute for Cell-Based Drug Development of Zhejiang Province, S-Evans Biosciences, Hangzhou, Zhejiang, China
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Wu M, Mi J, Qu GX, Zhang S, Jian Y, Gao C, Cai Q, Liu J, Jiang J, Huang H. Role of Hedgehog Signaling Pathways in Multipotent Mesenchymal Stem Cells Differentiation. Cell Transplant 2024; 33:9636897241244943. [PMID: 38695366 PMCID: PMC11067683 DOI: 10.1177/09636897241244943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 03/09/2024] [Accepted: 03/14/2024] [Indexed: 05/05/2024] Open
Abstract
Multipotent mesenchymal stem cells (MSCs) have high self-renewal and multi-lineage differentiation potentials and low immunogenicity, so they have attracted much attention in the field of regenerative medicine and have a promising clinical application. MSCs originate from the mesoderm and can differentiate not only into osteoblasts, cartilage, adipocytes, and muscle cells but also into ectodermal and endodermal cell lineages across embryonic layers. To design cell therapy for replacement of damaged tissues, it is essential to understand the signaling pathways, which have a major impact on MSC differentiation, as this will help to integrate the signaling inputs to initiate a specific lineage. Hedgehog (Hh) signaling plays a vital role in the development of various tissues and organs in the embryo. As a morphogen, Hh not only regulates the survival and proliferation of tissue progenitor and stem populations but also is a critical moderator of MSC differentiation, involving tri-lineage and across embryonic layer differentiation of MSCs. This review summarizes the role of Hh signaling pathway in the differentiation of MSCs to mesodermal, endodermal, and ectodermal cells.
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Affiliation(s)
- Mengyu Wu
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
- College of Bioengineering, Chongqing University, Chongqing, China
| | - Junwei Mi
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Guo-xin Qu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Shu Zhang
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Yi Jian
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
- College of Bioengineering, Chongqing University, Chongqing, China
| | - Chu Gao
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Qingli Cai
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Jing Liu
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Jianxin Jiang
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
- College of Bioengineering, Chongqing University, Chongqing, China
| | - Hong Huang
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
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Morita Y, Sakata N, Nishimura M, Kawakami R, Shimizu M, Yoshimatsu G, Sawamoto O, Matsumoto S, Wada H, Kodama S. Efficacy of Neonatal Porcine Bone Marrow-Derived Mesenchymal Stem Cell Xenotransplantation for the Therapy of Hind Limb Lymphedema in Mice. Cell Transplant 2024; 33:9636897241260195. [PMID: 38867486 PMCID: PMC11179447 DOI: 10.1177/09636897241260195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 04/22/2024] [Accepted: 05/22/2024] [Indexed: 06/14/2024] Open
Abstract
Lymphedema is an intractable disease with few effective therapeutic options. Autologous mesenchymal stem cell (MSC) transplantation is a promising therapy for this disease. However, its use is limited by the cost and time for preparation. Recently, xenotransplantation of porcine MSCs has emerged as an alternative to autologous MSC transplantation. In this study, we aimed to clarify the usefulness of neonatal porcine bone marrow-derived MSC (NpBM-MSC) xenotransplantation for the treatment of lymphedema. One million NpBM-MSCs were xenotransplanted into the hind limbs of mice with severe lymphedema (MSC transplantation group). The therapeutic effects were assessed by measuring the femoral circumference, the volume of the hind limb, the number and diameter of lymphatic vessels in the hind limb, and lymphatic flow using a near-infrared fluorescence (NIRF) imaging system. We compared the effects using mice with lymphedema that did not undergo NpBM-MSC transplantation (negative control group). The condition of the transplanted NpBM-MSCs was also evaluated histologically. The femoral circumference and volume of the hind limb had been normalized by postoperative day (POD) 14 in the MSC transplantation group, but not in the negative control group (P = 0.041). NIRF imaging revealed that lymphatic flow had recovered in the MSC transplantation group by POD 14, as shown by an increase in luminance in the hind limb. Histological assessment also showed that the xenotransplantation of NpBM-MSC increased the proliferation of lymphatic vessels, but they had been rejected by POD 14. The xenotransplantation of NpBM-MSCs is an effective treatment for lymphedema, and this is mediated through the promotion of lymphangiogenesis.
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Affiliation(s)
- Yuichi Morita
- Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
- Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka, Japan
- Department of Cardiovascular Surgery, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Naoaki Sakata
- Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
- Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka, Japan
- Research Institute for Regenerative Medicine, Fukuoka University, Fukuoka, Japan
| | - Masuhiro Nishimura
- Research and Development Center, Otsuka Pharmaceutical Factory, Inc., Naruto, Japan
| | - Ryo Kawakami
- Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
- Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka, Japan
- Research Institute for Regenerative Medicine, Fukuoka University, Fukuoka, Japan
| | - Masayuki Shimizu
- Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
- Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka, Japan
- Department of Cardiovascular Surgery, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Gumpei Yoshimatsu
- Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
- Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka, Japan
- Research Institute for Regenerative Medicine, Fukuoka University, Fukuoka, Japan
| | - Osamu Sawamoto
- Research and Development Center, Otsuka Pharmaceutical Factory, Inc., Naruto, Japan
| | - Shinichi Matsumoto
- Research and Development Center, Otsuka Pharmaceutical Factory, Inc., Naruto, Japan
| | - Hideichi Wada
- Department of Cardiovascular Surgery, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
- Research Institute for Regenerative Medicine, Fukuoka University, Fukuoka, Japan
| | - Shohta Kodama
- Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
- Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka, Japan
- Research Institute for Regenerative Medicine, Fukuoka University, Fukuoka, Japan
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12
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Lee JH, Chellasamy G, Yun K, Nam MJ. EGF-expressed human mesenchymal stem cells inhibit collagenase1 expression in keratinocytes. Cell Signal 2023; 110:110827. [PMID: 37506859 DOI: 10.1016/j.cellsig.2023.110827] [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: 09/27/2022] [Revised: 07/20/2023] [Accepted: 07/25/2023] [Indexed: 07/30/2023]
Abstract
Mesenchymal stem cells (MSCs) repair tissue injury by upregulating the paracrine secretion of cytokines and growth factors. Human MSC has been recognized as a promising therapeutic material for treatment of various human diseases. Even though the effect of epidermal growth factor (EGF) has been well investigated, the synergetic effect of EGF and MSC has not been studied. Therefore, we expect our basic study to contribute to developing new therapeutic reagents for skin diseases or innovative cosmetics. In this study, we examined the effect of human epidermal growth factor-transfected MSCs (hEGF MSCs) on human keratinocyte HaCaT cell proliferation and the mechanisms that regulate matrix metalloproteinase (MMP)-1 expression in HaCaT cells. To identify the hEGF plasmid and its transfection into MSCs, we performed gel electrophoresis and quantitative PCR. Proliferation and migration of HaCaT cells were examined using water Soluble Tetrazolium (WST-1) and wound-healing assays, respectively. Zymography was performed to investigate the correlation between hEGF MSC-conditioned medium (CM)-treated HaCaT cells and MMP-1 expression. We found that cell proliferation and wound-healing rates were increased in hEGF MSC-CM-treated HaCaT cells compared to those in MSC-CM-treated cells, and conversely collagenase activity was decreased. The mRNA and protein levels of MMP-1 were also decreased in hEGF MSC-CM-treated HaCaT cells. 2-DE analysis showed that the expression of carboxypeptidase, which promotes growth factors and wound healing, was increased in hEGF MSC-CM-treated HaCaT cells. Finally, western blot was used to determine whether MMP-1 expression was reduced via the mitogen-activated protein kinase (MAPK) pathway; the results showed that the levels of MAPK pathway-related proteins (pErk, pJNK, and p-p38) and the levels of transcription factors (pCREB, NFκB, and p-c-Fos) were decreased. In addition, pAkt expression was found to be elevated. The results of our study suggest that hEGF MSCs promote cell proliferation and reduce MMP-1 expression via the MAPK pathway in human keratinocyte HaCaT cells.
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Affiliation(s)
- Jeong Hyun Lee
- Department of Biological Sciences, Gachon University, Seongnam, South Korea
| | - Gayathri Chellasamy
- Department of Bionanotechnology, Gachon University, Gyeonggi-do 13120, Republic of Korea
| | - Kyusik Yun
- Department of Bionanotechnology, Gachon University, Gyeonggi-do 13120, Republic of Korea
| | - Myeong Jin Nam
- Department of Biological Sciences, Gachon University, Seongnam, South Korea.
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13
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Yang G, Fan X, Liu Y, Jie P, Mazhar M, Liu Y, Dechsupa N, Wang L. Immunomodulatory Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells. Stem Cell Rev Rep 2023; 19:1214-1231. [PMID: 37058201 PMCID: PMC10103048 DOI: 10.1007/s12015-023-10539-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/29/2023] [Indexed: 04/15/2023]
Abstract
Mesenchymal stem cells (MSCs) are regarded as highly promising cells for allogeneic cell therapy, owing to their multipotent nature and ability to display potent and varied functions in different diseases. The functions of MSCs, including native immunomodulation, high self-renewal characteristic, and secretory and trophic properties, can be employed to improve the immune-modulatory functions in diseases. MSCs impact most immune cells by directly contacting and/or secreting positive microenvironmental factors to influence them. Previous studies have reported that the immunomodulatory role of MSCs is basically dependent on their secretion ability from MSCs. This review discusses the immunomodulatory capabilities of MSCs and the promising strategies to successfully improve the potential utilization of MSCs in clinical research.
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Affiliation(s)
- Guoqiang Yang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- Acupuncture and Rehabilitation Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Xuehui Fan
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention of Cardiovascular Diseases, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany
| | - Yingchun Liu
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Pingping Jie
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Maryam Mazhar
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Yong Liu
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China.
| | - Nathupakorn Dechsupa
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.
| | - Li Wang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China.
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China.
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14
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Lee JC, Brien HJ, Walton BL, Eidman ZM, Toda S, Lim WA, Brunger JM. Instructional materials that control cellular activity through synthetic Notch receptors. Biomaterials 2023; 297:122099. [PMID: 37023529 PMCID: PMC10320837 DOI: 10.1016/j.biomaterials.2023.122099] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 03/13/2023] [Accepted: 03/22/2023] [Indexed: 03/31/2023]
Abstract
The field of regenerative engineering relies primarily on the dual technical platforms of cell selection/conditioning and biomaterial fabrication to support directed cell differentiation. As the field has matured, an appreciation for the influence of biomaterials on cell behaviors has resulted in engineered matrices that meet biomechanical and biochemical demands of target pathologies. Yet, despite advances in methods to produce designer matrices, regenerative engineers remain unable to reliably orchestrate behaviors of therapeutic cells in situ. Here, we present a platform named MATRIX whereby cellular responses to biomaterials can be custom defined by combining engineered materials with cells expressing cognate synthetic biology control modules. Such privileged channels of material-to-cell communication can activate synthetic Notch receptors and govern activities as diverse as transcriptome engineering, inflammation attenuation, and pluripotent stem cell differentiation, all in response to materials decorated with otherwise bioinert ligands. Further, we show that engineered cellular behaviors are confined to programmed biomaterial surfaces, highlighting the potential to use this platform to spatially organize cellular responses to bulk, soluble factors. This integrated approach of co-engineering cells and biomaterials for orthogonal interactions opens new avenues for reproducible control of cell-based therapies and tissue replacements.
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Affiliation(s)
- Joanne C Lee
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37212, USA
| | - Hannah J Brien
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37212, USA
| | - Bonnie L Walton
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37212, USA
| | - Zachary M Eidman
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37212, USA
| | - Satoshi Toda
- WPI Nano Life Science Institute (NanoLSI), Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Wendell A Lim
- Cell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, 94158, USA.
| | - Jonathan M Brunger
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37212, USA; Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, 37212, USA.
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15
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Subayyil AA, Basmaeil YS, Kulayb HB, Alrodayyan M, Alhaber LAA, Almanaa TN, Khatlani T. Preconditioned Chorionic Villus Mesenchymal Stem/Stromal Cells (CVMSCs) Minimize the Invasive Phenotypes of Breast Cancer Cell Line MDA231 In Vitro. Int J Mol Sci 2023; 24:ijms24119569. [PMID: 37298519 DOI: 10.3390/ijms24119569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 03/30/2023] [Accepted: 04/03/2023] [Indexed: 06/12/2023] Open
Abstract
Among the newer choices of targeted therapies against cancer, stem cell therapy is gaining importance because of their antitumor properties. Stem cells suppress growth, metastasis, and angiogenesis, and induce apoptosis in cancer cells. In this study, we have examined the impact of the cellular component and the secretome of preconditioned and naïve placenta-derived Chorionic Villus Mesenchymal Stem Cells (CVMSCs) on the functional characteristics of the Human Breast Cancer cell line MDA231. MDA231 cells were treated with preconditioned CVMSCs and their conditioned media (CM), followed by an evaluation of their functional activities and modulation in gene and protein expression. Human Mammary Epithelial Cells (HMECs) were used as a control. CM obtained from the preconditioned CVMSCs significantly altered the proliferation of MDA231 cells, yet no change in other phenotypes, such as adhesion, migration, and invasion, were observed at various concentrations and time points tested. However, the cellular component of preconditioned CVMSCs significantly inhibited several phenotypes of MDA231 cells, including proliferation, migration, and invasion. CVMSCs-treated MDA231 cells exhibited modulation in the expression of various genes involved in apoptosis, oncogenesis, and Epithelial to Mesenchymal Transition (EMT), explaining the changes in the invasive behavior of MDA231 cells. These studies reveal that preconditioned CVMSCs may make useful candidate in a stem cell-based therapy against cancer.
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Affiliation(s)
- Abdullah Al Subayyil
- Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia
| | - Yasser S Basmaeil
- Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia
| | - Hayaa Bin Kulayb
- Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia
| | - Maha Alrodayyan
- Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia
| | - Lama Abdulaziz A Alhaber
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Taghreed N Almanaa
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Tanvir Khatlani
- Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia
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16
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Petrova V, Vachkova E. Outlook of Adipose-Derived Stem Cells: Challenges to Their Clinical Application in Horses. Vet Sci 2023; 10:vetsci10050348. [PMID: 37235430 DOI: 10.3390/vetsci10050348] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/05/2023] [Accepted: 05/11/2023] [Indexed: 05/28/2023] Open
Abstract
Adipose tissue is recognized as the major endocrine organ, potentially acting as a source of mesenchymal stem cells for various applications in regenerative medicine. Athletic horses are often exposed to traumatic injuries, resulting in severe financial losses. The development of adipose-derived stem cells' regenerative potential depends on many factors. The extraction of stem cells from subcutaneous adipose tissue is non-invasive, non-traumatic, cheaper, and safer than other sources. Since there is a lack of unique standards for identification, the isolated cells and applied differentiation protocols are often not species-specific; therefore, the cells cannot reveal their multipotent properties, so their stemness features remain questionable. The current review discusses some aspects of the specificity of equine adipose stem cells concerning their features, immunophenotyping, secretome profile, differentiation abilities, culturing conditions, and consequent possibilities for clinical application in concrete disorders. The presented new approaches elucidate the possibility of the transition from cell-based to cell-free therapy with regenerative purposes in horses as an alternative treatment to cellular therapy. In conclusion, their clinical benefits should not be underestimated due to the higher yield and the physiological properties of adipose-derived stem cells that facilitate the healing and tissue regeneration process and the ability to amplify the effects of traditional treatments. More profound studies are necessary to apply these innovative approaches when treating traumatic disorders in racing horses.
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Affiliation(s)
- Valeria Petrova
- Department of Pharmacology, Animal Physiology and Physiological Chemistry, Faculty of Veterinary Medicine, Trakia University, 6000 Stara Zagora, Bulgaria
| | - Ekaterina Vachkova
- Department of Pharmacology, Animal Physiology and Physiological Chemistry, Faculty of Veterinary Medicine, Trakia University, 6000 Stara Zagora, Bulgaria
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17
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Liang TY, Lu LH, Tang SY, Zheng ZH, Shi K, Liu JQ. Current status and prospects of basic research and clinical application of mesenchymal stem cells in acute respiratory distress syndrome. World J Stem Cells 2023; 15:150-164. [PMID: 37180997 PMCID: PMC10173811 DOI: 10.4252/wjsc.v15.i4.150] [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: 12/20/2022] [Revised: 01/20/2023] [Accepted: 03/20/2023] [Indexed: 04/26/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a common and clinically devastating disease that causes respiratory failure. Morbidity and mortality of patients in intensive care units are stubbornly high, and various complications severely affect the quality of life of survivors. The pathophysiology of ARDS includes increased alveolar-capillary membrane permeability, an influx of protein-rich pulmonary edema fluid, and surfactant dysfunction leading to severe hypoxemia. At present, the main treatment for ARDS is mechanical treatment combined with diuretics to reduce pulmonary edema, which primarily improves symptoms, but the prognosis of patients with ARDS is still very poor. Mesenchymal stem cells (MSCs) are stromal cells that possess the capacity to self-renew and also exhibit multilineage differentiation. MSCs can be isolated from a variety of tissues, such as the umbilical cord, endometrial polyps, menstrual blood, bone marrow, and adipose tissues. Studies have confirmed the critical healing and immunomodulatory properties of MSCs in the treatment of a variety of diseases. Recently, the potential of stem cells in treating ARDS has been explored via basic research and clinical trials. The efficacy of MSCs has been shown in a variety of in vivo models of ARDS, reducing bacterial pneumonia and ischemia-reperfusion injury while promoting the repair of ventilator-induced lung injury. This article reviews the current basic research findings and clinical applications of MSCs in the treatment of ARDS in order to emphasize the clinical prospects of MSCs.
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Affiliation(s)
- Tian-Yu Liang
- Emergency and Critical Care Center, Intensive Care Unit, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou 310014, Zhejiang Province, China
| | - Li-Hai Lu
- Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Si-Yu Tang
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Zi-Hao Zheng
- Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Kai Shi
- Department of Respiratory Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, Zhejiang Province, China
| | - Jing-Quan Liu
- Emergency and Critical Care Center, Intensive Care Unit, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou 310014, Zhejiang Province, China.
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18
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Rostkowska E, Poleszak E, Wojciechowska K, Dos Santos Szewczyk K. Dermatological Management of Aged Skin. COSMETICS 2023. [DOI: 10.3390/cosmetics10020055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023] Open
Abstract
The subject of the work concerns the dermatological management of patients mainly with aged skin. The purpose of the work was to present the basic techniques and preparations which are performed by dermatologists in the treatment of aged skin. There are dermatological treatments related to the treatment of skin diseases and cosmetic treatments which are mainly related to skin care. In this work, the method of literature research was applied. On the basis of books and journal articles on dermatological and cosmetic procedures for aged skin, an analysis of treatment types was made. Then, the results of this analysis were presented in the paper under discussion. The paper presents information on the skin and its properties. The structure and functions of the skin, aging processes and characteristics of aged skin were discussed. Then, the possibilities of reducing the visible signs of skin aging through the use of invasive and non-invasive dermatological and cosmetological treatments were given, and the most important components of preparations used supportively in combating skin aging processes were discussed.
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19
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Feng Z, Jin M, Liang J, Kang J, Yang H, Guo S, Sun X. Insight into the effect of biomaterials on osteogenic differentiation of mesenchymal stem cells: A review from a mitochondrial perspective. Acta Biomater 2023; 164:1-14. [PMID: 36972808 DOI: 10.1016/j.actbio.2023.03.032] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 03/02/2023] [Accepted: 03/21/2023] [Indexed: 03/29/2023]
Abstract
Bone damage may be triggered by a variety of factors, and the damaged area often requires a bone graft. Bone tissue engineering can serve as an alternative strategy for repairing large bone defects. Mesenchymal stem cells (MSCs), the progenitor cells of connective tissue, have become an important tool for tissue engineering due to their ability to differentiate into a variety of cell types. The precise regulation of the growth and differentiation of the stem cells used for bone regeneration significantly affects the efficiency of this type of tissue engineering. During the process of osteogenic induction, the dynamics and function of localized mitochondria are altered. These changes may also alter the microenvironment of the therapeutic stem cells and result in mitochondria transfer. Mitochondrial regulation not only affects the induction/rate of differentiation, but also influences its direction, determining the final identity of the differentiated cell. To date, bone tissue engineering research has mainly focused on the influence of biomaterials on phenotype and nuclear genotype, with few studies investigating the role of mitochondria. In this review, we provide a comprehensive summary of researches into the role of mitochondria in MSCs differentiation and critical analysis regarding smart biomaterials that are able to "programme" mitochondria modulation was proposed. STATEMENT OF SIGNIFICANCE: : • This review proposed the precise regulation of the growth and differentiation of the stem cells used to seed bone regeneration. • This review addressed the dynamics and function of localized mitochondria during the process of osteogenic induction and the effect of mitochondria on the microenvironment of stem cells. • This review summarized biomaterials which affect the induction/rate of differentiation, but also influences its direction, determining the final identity of the differentiated cell through the regulation of mitochondria.
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Affiliation(s)
- Ziyi Feng
- Department of Plastic Surgery, The First Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang, 110002 Liaoning Province, China
| | - Meiqi Jin
- School of Intelligent Medicine, China Medical University, No.77, Puhe Road, Shenyang, 110122, Liaoning Province, China
| | - Junzhi Liang
- Center of Reproductive Medicine, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping, Shenyang, 110004 Liaoning Province, China
| | - Junning Kang
- Department of Neurosurgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping, Shenyang, 110004 Liaoning Province, China
| | - Huazhe Yang
- School of Intelligent Medicine, China Medical University, No.77, Puhe Road, Shenyang, 110122, Liaoning Province, China.
| | - Shu Guo
- Department of Plastic Surgery, The First Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang, 110002 Liaoning Province, China.
| | - Xiaoting Sun
- School of Forensic Medicine, China Medical University, No.77, Puhe Road, Shenyang, 110122, Liaoning Province, China.
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20
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Ma X, Liu B, Fan L, Liu Y, Zhao Y, Ren T, Li Y, Li Y. Native and engineered exosomes for inflammatory disease. NANO RESEARCH 2022; 16:6991-7006. [PMID: 36591564 PMCID: PMC9793369 DOI: 10.1007/s12274-022-5275-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/28/2022] [Accepted: 10/31/2022] [Indexed: 05/24/2023]
Abstract
Exosomes are extracellular vesicles which carry specific molecular information from donor cells and act as an intercellular communication vehicle, which have emerged as a novel cell-free strategy for the treatment of many diseases including inflammatory disease. Recently, rising studies have developed exosome-based strategies for novel inflammation therapy due to their biocompatibility and bioactivity. Researchers not only use native exosomes as therapeutic agents for inflammation, but also strive to make up for the natural defects of exosomes through engineering methods to improve and update the property of exosomes for enhanced therapeutic effects. The engineered exosomes can improve cargo-loading efficiency, targeting ability, stability, etc., to achieve combined and diverse treatment strategies in inflammation diseases. Herein, a comprehensive overview of the recent advances in application studies of native and engineered exosomes as well as the engineered methods is provided. Meanwhile, potential application prospects, possible challenges, and the development of clinical researches of exosome treatment strategy are concluded from plentiful examples, which may be able to provide guidance and suggestions for the future research and application of exosomes.
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Affiliation(s)
- Xiaoyi Ma
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Bingbing Liu
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Limin Fan
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Yiqiong Liu
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Yuge Zhao
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Tianbin Ren
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Yan Li
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Yongyong Li
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
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21
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Yudintceva N, Mikhailova N, Fedorov V, Samochernych K, Vinogradova T, Muraviov A, Shevtsov M. Mesenchymal Stem Cells and MSCs-Derived Extracellular Vesicles in Infectious Diseases: From Basic Research to Clinical Practice. Bioengineering (Basel) 2022; 9:662. [PMID: 36354573 PMCID: PMC9687734 DOI: 10.3390/bioengineering9110662] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/30/2022] [Accepted: 11/04/2022] [Indexed: 08/10/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are attractive in various fields of regenerative medicine due to their therapeutic potential and complex unique properties. Basic stem cell research and the global COVID-19 pandemic have given impetus to the development of cell therapy for infectious diseases. The aim of this review was to systematize scientific data on the applications of mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) in the combined treatment of infectious diseases. Application of MSCs and MSC-EVs in the treatment of infectious diseases has immunomodulatory, anti-inflammatory, and antibacterial effects, and also promotes the restoration of the epithelium and stimulates tissue regeneration. The use of MSC-EVs is a promising cell-free treatment strategy that allows solving the problems associated with the safety of cell therapy and increasing its effectiveness. In this review, experimental data and clinical trials based on MSCs and MSC-EVs for the treatment of infectious diseases are presented. MSCs and MSC-EVs can be a promising tool for the treatment of various infectious diseases, particularly in combination with antiviral drugs. Employment of MSC-derived EVs represents a more promising strategy for cell-free treatment, demonstrating a high therapeutic potential in preclinical studies.
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Affiliation(s)
- Natalia Yudintceva
- Institute of Cytology of the Russian Academy of Sciences (RAS), St. Petersburg 194064, Russia
- Personalized Medicine Centre, Almazov National Medical Research Centre, St. Petersburg 197341, Russia
| | - Natalia Mikhailova
- Institute of Cytology of the Russian Academy of Sciences (RAS), St. Petersburg 194064, Russia
| | - Viacheslav Fedorov
- Personalized Medicine Centre, Almazov National Medical Research Centre, St. Petersburg 197341, Russia
| | - Konstantin Samochernych
- Personalized Medicine Centre, Almazov National Medical Research Centre, St. Petersburg 197341, Russia
| | - Tatiana Vinogradova
- Saint-Petersburg State Research Institute of Phthisiopulmonology of the Ministry of Health of the Russian Federation, St. Petersburg 191036, Russia
| | - Alexandr Muraviov
- Saint-Petersburg State Research Institute of Phthisiopulmonology of the Ministry of Health of the Russian Federation, St. Petersburg 191036, Russia
| | - Maxim Shevtsov
- Institute of Cytology of the Russian Academy of Sciences (RAS), St. Petersburg 194064, Russia
- Personalized Medicine Centre, Almazov National Medical Research Centre, St. Petersburg 197341, Russia
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22
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Pathophysiology of Sepsis and Genesis of Septic Shock: The Critical Role of Mesenchymal Stem Cells (MSCs). Int J Mol Sci 2022; 23:ijms23169274. [PMID: 36012544 PMCID: PMC9409099 DOI: 10.3390/ijms23169274] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/14/2022] [Accepted: 08/15/2022] [Indexed: 11/17/2022] Open
Abstract
The treatment of sepsis and septic shock remains a major public health issue due to the associated morbidity and mortality. Despite an improvement in the understanding of the physiological and pathological mechanisms underlying its genesis and a growing number of studies exploring an even higher range of targeted therapies, no significant clinical progress has emerged in the past decade. In this context, mesenchymal stem cells (MSCs) appear more and more as an attractive approach for cell therapy both in experimental and clinical models. Pre-clinical data suggest a cornerstone role of these cells and their secretome in the control of the host immune response. Host-derived factors released from infected cells (i.e., alarmins, HMGB1, ATP, DNA) as well as pathogen-associated molecular patterns (e.g., LPS, peptidoglycans) can activate MSCs located in the parenchyma and around vessels to upregulate the expression of cytokines/chemokines and growth factors that influence, respectively, immune cell recruitment and stem cell mobilization. However, the way in which MSCs exert their beneficial effects in terms of survival and control of inflammation in septic states remains unclear. This review presents the interactions identified between MSCs and mediators of immunity and tissue repair in sepsis. We also propose paradigms related to the plausible roles of MSCs in the process of sepsis and septic shock. Finally, we offer a presentation of experimental and clinical studies and open the way to innovative avenues of research involving MSCs from a prognostic, diagnostic, and therapeutic point of view in sepsis.
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Organ-Specific Differentiation of Human Adipose-Derived Stem Cells in Various Organs of Xenotransplanted Rats: A Pilot Study. LIFE (BASEL, SWITZERLAND) 2022; 12:life12081116. [PMID: 35892918 PMCID: PMC9330795 DOI: 10.3390/life12081116] [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: 06/23/2022] [Revised: 07/19/2022] [Accepted: 07/22/2022] [Indexed: 11/17/2022]
Abstract
Adipose-derived stem cells (ADSCs) are potential therapeutics considering their self-renewal capacity and ability to differentiate into all somatic cell types in vitro. The ideal ADSC-based therapy is a direct injection into the relevant organs. The objective of this study was to investigate the viability and safety of intra-organ human ADSC (h-ADSC) xenotransplants in vivo. Subcutaneous adipose tissue from the abdominal area of 10 patients was sampled. h-ADSCs were isolated from adipose tissue samples and identified using immunofluorescence antibodies. Multi-differentiation potential assays for adipocytes, osteocytes, and chondrocytes were performed. Cultured h-ADSCs at passage 4 were transplanted into multiple organs of 17 rats, including the skin, subcutaneous layer, liver, kidney, pancreas, and spleen. The h-ADSC-injected organs excised after 100 days were examined, and the survival of h-ADSCs was measured by quantitative real-time polymerase chain reaction (qRT-PCR) using specific human and rat target genes. h-ADSCs confirmed by stem cell phenotyping were induced to differentiate into adipogenic, osteogenic, and chondrogenic lineages in vitro. All rats were healthy and exhibited no side effects during the study; the transplanted h-ADSCs did not cause inflammation and were indiscernible from the native organ cells. The presence of transplanted h-ADSCs was confirmed using qRT-PCR. However, the engrafted survival rates varied as follows: subcutaneous fat (70.6%), followed by the liver (52.9%), pancreas (50.0%), kidney (29.4%), skin (29.4%), and spleen (12.5%). h-ADSCs were successfully transplanted into a rat model, with different survival rates depending on the organ.
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24
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Yang G, Fan X, Mazhar M, Yang S, Xu H, Dechsupa N, Wang L. Mesenchymal Stem Cell Application and Its Therapeutic Mechanisms in Intracerebral Hemorrhage. Front Cell Neurosci 2022; 16:898497. [PMID: 35769327 PMCID: PMC9234141 DOI: 10.3389/fncel.2022.898497] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 05/18/2022] [Indexed: 12/15/2022] Open
Abstract
Intracerebral hemorrhage (ICH), a common lethal subtype of stroke accounting for nearly 10–15% of the total stroke disease and affecting two million people worldwide, has a high mortality and disability rate and, thus, a major socioeconomic burden. However, there is no effective treatment available currently. The role of mesenchymal stem cells (MSCs) in regenerative medicine is well known owing to the simplicity of acquisition from various sources, low immunogenicity, adaptation to the autogenic and allogeneic systems, immunomodulation, self-recovery by secreting extracellular vesicles (EVs), regenerative repair, and antioxidative stress. MSC therapy provides an increasingly attractive therapeutic approach for ICH. Recently, the functions of MSCs such as neuroprotection, anti-inflammation, and improvement in synaptic plasticity have been widely researched in human and rodent models of ICH. MSC transplantation has been proven to improve ICH-induced injury, including the damage of nerve cells and oligodendrocytes, the activation of microglia and astrocytes, and the destruction of blood vessels. The improvement and recovery of neurological functions in rodent ICH models were demonstrated via the mechanisms such as neurogenesis, angiogenesis, anti-inflammation, anti-apoptosis, and synaptic plasticity. Here, we discuss the pathological mechanisms following ICH and the therapeutic mechanisms of MSC-based therapy to unravel new cues for future therapeutic strategies. Furthermore, some potential strategies for enhancing the therapeutic function of MSC transplantation have also been suggested.
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Affiliation(s)
- Guoqiang Yang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- Department of Acupuncture and Rehabilitation, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Xuehui Fan
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention of Cardiovascular Diseases, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany
| | - Maryam Mazhar
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Sijin Yang
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Houping Xu
- Preventive Treatment Center, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Nathupakorn Dechsupa
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- *Correspondence: Nathupakorn Dechsupa,
| | - Li Wang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
- Li Wang,
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25
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Zhang L, Zhao Q, Cang H, Wang Z, Hu X, Pan R, Yang Y, Chen Y. Acute Myeloid Leukemia Cells Educate Mesenchymal Stromal Cells toward an Adipogenic Differentiation Propensity with Leukemia Promotion Capabilities. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:2105811. [PMID: 35686138 PMCID: PMC9165478 DOI: 10.1002/advs.202105811] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 02/16/2022] [Indexed: 05/14/2023]
Abstract
Mesenchymal stromal cells (MSCs) are essential elements of the bone marrow (BM) microenvironment, which have been widely implicated in pathways that contribute to leukemia growth and resistance. Recent reports showed genotypic and phenotypic alterations in leukemia patient-derived MSCs, indicating that MSCs might be educated/reprogrammed. However, the results have been inconclusive, possibly due to the heterogeneity of leukemia. Here, the authors report that acute myeloid leukemia (AML) induces MSCs towards an adipogenic differentiation propensity. RNAseq analysis reveal significant upregulation of gene expression enriched in the adipocyte differentiation process and reduction in osteoblast differentiation. The alteration is accompanied by a metabolic switch from glycolysis to a more oxidative phosphorylation-dependent manner. Mechanistic studies identify that AML cell-derived exosomes play a vital role during the AML cell-mediated MSCs education/reprogramming process. Pre-administration of mice BM microenvironment with AML-derived exosomes greatly enhance leukemia engraftment in vivo. The quantitative proteomic analysis identified a list of exosomal protein components that are differently expressed in AML-derived exosomes, which represent an opportunity for novel therapeutic strategies based on the targeting of exosome-based AML cells-MSCs communication. Collectively, the data show that AML-educated MSCs tend to differentiate into adipocytes contributing to disease progression, which suggests complex interactions of leukemia with microenvironment components.
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Affiliation(s)
- Luwen Zhang
- Department of Genetics, and Department of Genetic and Metabolic DiseaseThe Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHangzhouZhejiang310052China
- Zhejiang Provincial Key Laboratory of Genetic and Developmental DisordersInstitute of Genetics, Zhejiang UniversityHangzhouZhejiang310058China
| | - Qiong Zhao
- Department of Genetics, and Department of Genetic and Metabolic DiseaseThe Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHangzhouZhejiang310052China
- Zhejiang Provincial Key Laboratory of Genetic and Developmental DisordersInstitute of Genetics, Zhejiang UniversityHangzhouZhejiang310058China
| | - Hui Cang
- Department of Genetics, and Department of Genetic and Metabolic DiseaseThe Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHangzhouZhejiang310052China
- Zhejiang Provincial Key Laboratory of Genetic and Developmental DisordersInstitute of Genetics, Zhejiang UniversityHangzhouZhejiang310058China
| | - Ziqiang Wang
- Department of Genetics, and Department of Genetic and Metabolic DiseaseThe Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHangzhouZhejiang310052China
- Zhejiang Provincial Key Laboratory of Genetic and Developmental DisordersInstitute of Genetics, Zhejiang UniversityHangzhouZhejiang310058China
| | - Xiaojia Hu
- Department of Genetics, and Department of Genetic and Metabolic DiseaseThe Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHangzhouZhejiang310052China
- Zhejiang Provincial Key Laboratory of Genetic and Developmental DisordersInstitute of Genetics, Zhejiang UniversityHangzhouZhejiang310058China
| | - Ruolang Pan
- Zhejiang Provincial Key Laboratory of Cell‐Based Drug and Applied Technology DevelopmentInstitute for Cell‐Based Drug Development of Zhejiang ProvinceS‐Evans BiosciencesHangzhouZhejiang310023China
| | - Yang Yang
- Bone Marrow Transplantation Center, Institute of Hematology, The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang310004China
| | - Ye Chen
- Department of Genetics, and Department of Genetic and Metabolic DiseaseThe Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHangzhouZhejiang310052China
- Zhejiang Provincial Key Laboratory of Genetic and Developmental DisordersInstitute of Genetics, Zhejiang UniversityHangzhouZhejiang310058China
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Prajwal GS, Jeyaraman N, Kanth V K, Jeyaraman M, Muthu S, Rajendran SNS, Rajendran RL, Khanna M, Oh EJ, Choi KY, Chung HY, Ahn BC, Gangadaran P. Lineage Differentiation Potential of Different Sources of Mesenchymal Stem Cells for Osteoarthritis Knee. Pharmaceuticals (Basel) 2022; 15:386. [PMID: 35455383 PMCID: PMC9028477 DOI: 10.3390/ph15040386] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 03/11/2022] [Accepted: 03/17/2022] [Indexed: 02/05/2023] Open
Abstract
Tissue engineering and regenerative medicine (TERM) have paved a way for treating musculoskeletal diseases in a minimally invasive manner. The regenerative medicine cocktail involves the usage of mesenchymal stem/stromal cells (MSCs), either uncultured or culture-expanded cells along with growth factors, cytokines, exosomes, and secretomes to provide a better regenerative milieu in degenerative diseases. The successful regeneration of cartilage depends on the selection of the appropriate source of MSCs, the quality, quantity, and frequency of MSCs to be injected, and the selection of the patient at an appropriate stage of the disease. However, confirmation on the most favorable source of MSCs remains uncertain to clinicians. The lack of knowledge in the current cellular treatment is uncertain in terms of how beneficial MSCs are in the long-term or short-term (resolution of pain) and improved quality of life. Whether MSCs treatments have any superiority, exists due to sources of MSCs utilized in their potential to objectively regenerate the cartilage at the target area. Many questions on source and condition remain unanswered. Hence, in this review, we discuss the lineage differentiation potentials of various sources of MSCs used in the management of knee osteoarthritis and emphasize the role of tissue engineering in cartilage regeneration.
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Affiliation(s)
- Gollahalli Shivashankar Prajwal
- Research Fellow, Fellowship in Orthopaedic Rheumatology (FEIORA), Dr. Ram Manohar Lohiya National Law University, Lucknow 226010, Uttar Pradesh, India; (G.S.P.); (N.J.)
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 110048, Uttar Pradesh, India; (S.M.); (M.K.)
- Department of Orthopaedics, Mallika Spine Centre, Guntur 522001, Andhra Pradesh, India
| | - Naveen Jeyaraman
- Research Fellow, Fellowship in Orthopaedic Rheumatology (FEIORA), Dr. Ram Manohar Lohiya National Law University, Lucknow 226010, Uttar Pradesh, India; (G.S.P.); (N.J.)
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 110048, Uttar Pradesh, India; (S.M.); (M.K.)
- Department of Orthopaedics, Atlas Hospitals, Tiruchirappalli 620002, Tamil Nadu, India
| | - Krishna Kanth V
- Department of Orthopaedics, Government Medical College, Mahabubabad 506104, Telangana, India;
| | - Madhan Jeyaraman
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 110048, Uttar Pradesh, India; (S.M.); (M.K.)
- Department of Orthopaedics, Faculty of Medicine—Sri Lalithambigai Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai 600095, Tamil Nadu, India
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201306, Uttar Pradesh, India
- Orthopaedic Research Group, Coimbatore 641001, Tamil Nadu, India
| | - Sathish Muthu
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 110048, Uttar Pradesh, India; (S.M.); (M.K.)
- Department of Orthopaedics, Government Medical College, Mahabubabad 506104, Telangana, India;
- Department of Orthopaedics, Faculty of Medicine—Sri Lalithambigai Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai 600095, Tamil Nadu, India
- Orthopaedic Research Group, Coimbatore 641001, Tamil Nadu, India
| | - Sree Naga Sowndary Rajendran
- Department of Medicine, Sri Venkateshwaraa Medical College Hospital and Research Centre, Puducherry 605102, Puducherry, India;
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea;
| | - Manish Khanna
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 110048, Uttar Pradesh, India; (S.M.); (M.K.)
- Department of Orthopaedics, Government Medical College and Hospital, Dindigul 624001, Tamil Nadu, India
- Department of Orthopaedics, Prasad Institute of Medical Sciences, Lucknow 226010, Uttar Pradesh, India
| | - Eun Jung Oh
- Department of Plastic and Reconstructive Surgery, CMRI, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea; (E.J.O.); (K.Y.C.); (H.Y.C.)
| | - Kang Young Choi
- Department of Plastic and Reconstructive Surgery, CMRI, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea; (E.J.O.); (K.Y.C.); (H.Y.C.)
| | - Ho Yun Chung
- Department of Plastic and Reconstructive Surgery, CMRI, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea; (E.J.O.); (K.Y.C.); (H.Y.C.)
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea;
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea;
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, Korea
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27
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Zhang W, Lin J, Shi P, Su D, Cheng X, Yi W, Yan J, Chen H, Cheng F. Small Extracellular Vesicles Derived From MSCs Have Immunomodulatory Effects to Enhance Delivery of ASO-210 for Psoriasis Treatment. Front Cell Dev Biol 2022; 10:842813. [PMID: 35359454 PMCID: PMC8960430 DOI: 10.3389/fcell.2022.842813] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 02/21/2022] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have been increasingly used for treating autoimmune diseases due to their immune modulation functions, but inefficient homing to the target tissue and safety issues limits their wide application. Recently, increasing studies demonstrate small extracellular vesicles (sEVs) as key mediators of MSCs to exert their immunomodulatory effects. In this study, we found that sEVs derived from human umbilical cord MSCs stimulated by IFN-γ (IFNγ-sEVs) inhibited proliferation and activation of peripheral blood mononuclear cells and T cells in vitro. Furthermore, we confirmed that IFNγ-sEVs reduced psoriasis symptoms including thickness, erythema, and scales of skin lesions; exhausted Th17 cells, increased Th2 cells; and reduced enrichment of inflammatory cytokines such as IL-17A, IFN-γ, IL-6, and TNF-α in both spleen and skin lesions in vivo. Importantly, IFNγ-sEVs significantly improved the delivery efficiency and stability of ASO-210, the antisense oligonucleotides of miR-210 block the immune imbalance and subsequent psoriasis development. Our results reveal MSC-sEVs as promising cell-free therapeutic agents and ideal delivery vehicles of antisense oligonucleotides for psoriasis treatment.
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Affiliation(s)
- Weixian Zhang
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
| | - Jingxiong Lin
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
| | - Peilin Shi
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
| | - Dandan Su
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
| | - Xiaoli Cheng
- Department of Pharmacy, Shenzhen Baoan Maternal and Child Health Hospital, Shenzhen, China
| | - Wenkai Yi
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China
| | - Jian Yan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China
| | - Hongbo Chen
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
- *Correspondence: Fang Cheng, ; Hongbo Chen,
| | - Fang Cheng
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
- *Correspondence: Fang Cheng, ; Hongbo Chen,
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28
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Therapeutic Potential of Human Fetal Mesenchymal Stem Cells in Musculoskeletal Disorders: A Narrative Review. Int J Mol Sci 2022; 23:ijms23031439. [PMID: 35163361 PMCID: PMC8835918 DOI: 10.3390/ijms23031439] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/24/2022] [Accepted: 01/24/2022] [Indexed: 01/15/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for diverse diseases and injuries. The biological and clinical advantages of human fetal MSCs (hfMSCs) have recently been reported. In terms of promising therapeutic approaches for diverse diseases and injuries, hfMSCs have gained prominence as healing tools for clinical therapies. Therefore, this review assesses not the only biological advantages of hfMSCs for healing human diseases and regeneration, but also the research evidence for the engraftment and immunomodulation of hfMSCs based on their sources and biological components. Of particular clinical relevance, the present review also suggests the potential therapeutic feasibilities of hfMSCs for musculoskeletal disorders, including osteoporosis, osteoarthritis, and osteogenesis imperfecta.
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29
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Effects of scandium chloride on osteogenic and adipogenic differentiation of mesenchymal stem cells. J RARE EARTH 2022. [DOI: 10.1016/j.jre.2020.11.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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30
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Lee KE, Kang CM, Jeon M, Kim SO, Lee JH, Choi HJ. General gene expression patterns and stemness of the gingiva and dental pulp. J Dent Sci 2022; 17:284-292. [PMID: 35028049 PMCID: PMC8739237 DOI: 10.1016/j.jds.2021.02.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 02/26/2021] [Indexed: 12/01/2022] Open
Abstract
Background/purpose Due to the unique properties of healing processes and cellular differentiation, the gingiva and dental pulp have attracted attention as a potential source of mesenchymal stem cells (MSCs). The purpose of this study was to obtain molecular-level information on these tissues in terms of their function and differentiation processes and investigate stemness. Materials and methods Healthy gingival tissues were collected from patients (n = 9; aged 7–12 years) who underwent simple surgical procedures, and normal dental pulp tissues were obtained from patients (n = 25; aged 11–25 years) undergoing tooth extraction for orthodontic reasons. Complementary DNA microarray, qRT-qPCR, and immunohistochemical staining were performed to assess general and MSC gene expression patterns. Results In the gingival tissue, genes related to keratinization, the formation of epithelial cells and ectoderm, and immune and/or inflammatory responses were highly expressed. Meanwhile, in the dental pulp tissue, genes related to ion transport, neuronal development and axon guidance, bone and enamel mineralization, extracellular matrix organization, and angiogenesis were highly expressed. When focusing on the expression of MSC genes, induced pluripotent stem (iPS) cell genes, such as Sox2, c-Myc, and KLF4, were expressed at higher levels in the gingival tissue, whereas dental stem cell genes, such as NT5E and VCAM1, were expressed in dental pulp tissue. Conclusion We found different general and MSC gene expression patterns between the gingival and dental pulp tissue. These results have implications for future regenerative medicine, considering the application of gingival tissue as a potential source of iPS cells.
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Affiliation(s)
- Ko Eun Lee
- Department of Pediatric Dentistry, Yonsei University College of Dentistry, Seoul, Republic of Korea
| | - Chung-Min Kang
- Department of Pediatric Dentistry, Yonsei University College of Dentistry, Seoul, Republic of Korea
| | - Mijeong Jeon
- Oral Science Research Center, College of Dentistry, Yonsei University, Seoul, Republic of Korea
| | - Seong-Oh Kim
- Department of Pediatric Dentistry, Yonsei University College of Dentistry, Seoul, Republic of Korea
| | - Jae-Ho Lee
- Department of Pediatric Dentistry, Yonsei University College of Dentistry, Seoul, Republic of Korea
| | - Hyung-Jun Choi
- Department of Pediatric Dentistry, Yonsei University College of Dentistry, Seoul, Republic of Korea
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31
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Goutas A, Trachana V. Stem cells' centrosomes: How can organelles identified 130 years ago contribute to the future of regenerative medicine? World J Stem Cells 2021; 13:1177-1196. [PMID: 34630857 PMCID: PMC8474719 DOI: 10.4252/wjsc.v13.i9.1177] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/03/2021] [Accepted: 08/09/2021] [Indexed: 02/06/2023] Open
Abstract
At the core of regenerative medicine lies the expectation of repair or replacement of damaged tissues or whole organs. Donor scarcity and transplant rejection are major obstacles, and exactly the obstacles that stem cell-based therapy promises to overcome. These therapies demand a comprehensive understanding of the asymmetric division of stem cells, i.e. their ability to produce cells with identical potency or differentiated cells. It is believed that with better understanding, researchers will be able to direct stem cell differentiation. Here, we describe extraordinary advances in manipulating stem cell fate that show that we need to focus on the centrosome and the centrosome-derived primary cilium. This belief comes from the fact that this organelle is the vehicle that coordinates the asymmetric division of stem cells. This is supported by studies that report the significant role of the centrosome/cilium in orchestrating signaling pathways that dictate stem cell fate. We anticipate that there is sufficient evidence to place this organelle at the center of efforts that will shape the future of regenerative medicine.
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Affiliation(s)
- Andreas Goutas
- Department of Biology, Faculty of Medicine, University of Thessaly, Larisa 41500, Biopolis, Greece
| | - Varvara Trachana
- Department of Biology, Faculty of Medicine, University of Thessaly, Larisa 41500, Biopolis, Greece.
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Khorsandi K, Hosseinzadeh R, Abrahamse H, Fekrazad R. Biological Responses of Stem Cells to Photobiomodulation Therapy. Curr Stem Cell Res Ther 2021; 15:400-413. [PMID: 32013851 DOI: 10.2174/1574888x15666200204123722] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 10/26/2019] [Accepted: 11/14/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Stem cells have attracted the researchers interest, due to their applications in regenerative medicine. Their self-renewal capacity for multipotent differentiation, and immunomodulatory properties make them unique to significantly contribute to tissue repair and regeneration applications. Recently, stem cells have shown increased proliferation when irradiated with low-level laser therapy or Photobiomodulation Therapy (PBMT), which induces the activation of intracellular and extracellular chromophores and the initiation of cellular signaling. The purpose of this study was to evaluate this phenomenon in the literature. METHODS The literature investigated the articles written in English in four electronic databases of PubMed, Scopus, Google Scholar and Cochrane up to April 2019. Stem cell was searched by combining the search keyword of "low-level laser therapy" OR "low power laser therapy" OR "low-intensity laser therapy" OR "photobiomodulation therapy" OR "photo biostimulation therapy" OR "LED". In total, 46 articles were eligible for evaluation. RESULTS Studies demonstrated that red to near-infrared light is absorbed by the mitochondrial respiratory chain. Mitochondria are significant sources of reactive oxygen species (ROS). Mitochondria play an important role in metabolism, energy generation, and are also involved in mediating the effects induced by PBMT. PBMT may result in the increased production of (ROS), nitric oxide (NO), adenosine triphosphate (ATP), and cyclic adenosine monophosphate (cAMP). These changes, in turn, initiate cell proliferation and induce the signal cascade effect. CONCLUSION The findings of this review suggest that PBMT-based regenerative medicine could be a useful tool for future advances in tissue engineering and cell therapy.
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Affiliation(s)
- Khatereh Khorsandi
- Department of Photodynamic, Medical Laser Research Center, YARA Institute, ACECR, Tehran, Iran;
and Photo Dynamic Therapy (INPMPDT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Reza Hosseinzadeh
- Department of Medical Laser, Medical Laser Research Center, YARA Institute, ACECR, Tehran, Iran
| | - Heidi Abrahamse
- Laser Research Centre, NRF SARChI Chair: Laser Applications in Health, Faculty of Health Sciences, University of Johannesburg, Johannesburg, South Africa
| | - Reza Fekrazad
- Department of Periodontology, Dental Faculty - Radiation Sciences Research Center, Laser Research
Center in Medical Sciences, AJA University of Medical Sciences, Tehran, Iran,International Network for Photo Medicine and Photo Dynamic Therapy (INPMPDT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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Li J, Xiao L, He D, Luo Y, Sun H. Mechanism of White Matter Injury and Promising Therapeutic Strategies of MSCs After Intracerebral Hemorrhage. Front Aging Neurosci 2021; 13:632054. [PMID: 33927608 PMCID: PMC8078548 DOI: 10.3389/fnagi.2021.632054] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 03/18/2021] [Indexed: 12/15/2022] Open
Abstract
Intracerebral hemorrhage (ICH) is the most fatal subtype of stroke with high disability and high mortality rates, and there is no effective treatment. The predilection site of ICH is in the area of the basal ganglia and internal capsule (IC), where exist abundant white matter (WM) fiber tracts, such as the corticospinal tract (CST) in the IC. Proximal or distal white matter injury (WMI) caused by intracerebral parenchymal hemorrhage is closely associated with poor prognosis after ICH, especially motor and sensory dysfunction. The pathophysiological mechanisms involved in WMI are quite complex and still far from clear. In recent years, the neuroprotection and repairment capacity of mesenchymal stem cells (MSCs) has been widely investigated after ICH. MSCs exert many unique biological effects, including self-recovery by producing growth factors and cytokines, regenerative repair, immunomodulation, and neuroprotection against oxidative stress, providing a promising cellular therapeutic approach for the treatment of WMI. Taken together, our goal is to discuss the characteristics of WMI following ICH, including the mechanism and potential promising therapeutic targets of MSCs, aiming at providing new clues for future therapeutic strategies.
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Affiliation(s)
- Jing Li
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Linglong Xiao
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Dian He
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yunhao Luo
- Division of Laboratory Medicine, Clinical Biobank Center, Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Haitao Sun
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Division of Laboratory Medicine, Clinical Biobank Center, Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Key Laboratory of Mental Health of The Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou, China
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Fagalde P, Reininger D. Oral tissues regeneration using intraoral mesenchymal stem cells. J Clin Exp Dent 2021; 13:e268-e277. [PMID: 33680329 PMCID: PMC7920558 DOI: 10.4317/jced.56810] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 07/02/2020] [Indexed: 01/01/2023] Open
Abstract
Background Oral pathologies or some treatments can cause facial and functional alterations, being fundament to retrieve those functions restoring the original anatomy of the lost tissues. On this purpose, various techniques have been studied, one of these was the tissue engineering. Mesenchymal stem cells (MSC) are multipotent adult stem cells. The MSC in the oral cavity have been striking for regenerative therapies by its high plasticity, good interaction with scaffolds and growth factors, good proliferation and differentiation, they are also easy to obtain. Objective: The objective of this study was to describe the current uses of the intraoral MSC for the regeneration of the tissues of the oral cavity.
Material and Methods An electronic research was made in the databases PubMed, Cochrane Library, Google Scholar, Scopus and EBSCO between 2000 to 2018.
Results 21 articles were included. 13 were studies in vivo and 8 were studies in humans. The site mostly used as a giver site was the dental pulp. Intraoral MSC are able to regenerate the pulp dentin complex, alveolar bone and periodontium.
Conclusions Intraoral MSC come from easy access areas, less traumatic interventions and have high potential to regenerate intraoral tissues in comparison to MSC from other sites of the body which allows a more predictable oral tissues regeneration. Key words:Oral stem cells, oral cavity, regeneration, tissue engineering.
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Affiliation(s)
| | - David Reininger
- DDS, PhD, Master in Oral Surgery and Implantology, Assistant professor, Universidad Mayor, Chile
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Abstract
Ischemic brain injury is a common cause of long-term neurological deficits in children as well as adults, and no efficient treatments could reverse the sequelae in clinic till now. Stem cells have the capacity of self-renewal and multilineage differentiation. The therapeutic efficacy of stem cell transplantation for ischemic brain injury have been tested for many years. The grafts could survive and mature in the ischemic brain environment. Stem cell transplantation could improve functional recovery of ischemic brain injury models in pre-clinical trials. The potential mechanisms included cell replacement, release of neurotrophic and anti-inflammatory factors, immunoregulation as well as activation of endogenous neurogenesis. Besides, many clinical trials were conducted and some of trials already had preliminary results. From the current published data, cell transplantation for clinical application is safe and feasible. No severe adverse events and tumorigenesis were reported. While the therapeutic efficacy of stem cell therapy in clinic still needs more evidences. In this review, we overviewed the studies about stem cell therapy for ischemic brain injury. Different types of stem cells used for transplantation as well as the therapeutic mechanisms were discussed in detail. The related pre-clinical and clinical trials were summarized into two separate tables. In addition, we also discussed the unsolved problems and concerns about stem cell therapy for ischemic brain injury that need to be overcome before clinic transformation.
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Affiliation(s)
- Xiao-Li Ji
- Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China.,Key Laboratory of Neonatal Diseases, Ministry of Health, Children's Hospital of Fudan University, Shanghai, China
| | - Ling Ma
- Stem Cell Research Center, Institute of Pediatrics, Children's Hospital, Fudan University, Shanghai, China
| | - Wen-Hao Zhou
- Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China.,Key Laboratory of Neonatal Diseases, Ministry of Health, Children's Hospital of Fudan University, Shanghai, China
| | - Man Xiong
- Stem Cell Research Center, Institute of Pediatrics, Children's Hospital, Fudan University, Shanghai, China
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Human amniotic membrane as a delivery vehicle for stem cell-based therapies. Life Sci 2021; 272:119157. [PMID: 33524418 DOI: 10.1016/j.lfs.2021.119157] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/20/2021] [Accepted: 01/21/2021] [Indexed: 12/11/2022]
Abstract
Stem cell-based therapy is known as a regenerative approach for a variety of diseases and tissue injuries. These cells exert their therapeutic effects through paracrine secretions namely extracellular vesicles. To achieve higher therapeutic potential, a variety of delivery routes have been tested in clinical and preclinical studies. Direct cell injection, intra-venous administration, and intra-arterial infusion are widely used methods of stem cells delivery but these methods are associated with several complications. As one of the most popular biological delivery systems, amniotic membrane has been widely utilized to support cell proliferation and differentiation therefore facilitating tissue regeneration without endangering the stem cells' viability. It is composed of several extracellular matrix components and growth factors. Due to these characteristics, amniotic membrane can mimic the stem cell's niche and can be an ideal carrier for stem cell transplantation. Here, we provide an overview of the recent progress, challenges, and future perspectives in the use of amniotic membrane as a delivery platform for stem cells.
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Interferon-γ enhances the therapeutic effect of mesenchymal stem cells on experimental renal fibrosis. Sci Rep 2021; 11:850. [PMID: 33441701 PMCID: PMC7807061 DOI: 10.1038/s41598-020-79664-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) administered for therapeutic purposes can be activated by interferon-γ (IFN-γ) secreted from natural killer cells in injured tissues and exert anti-inflammatory effects. These processes require a substantial period of time, leading to a delayed onset of MSCs’ therapeutic effects. In this study, we investigated whether pretreatment with IFN-γ could potentiate the anti-fibrotic ability of MSCs in rats with ischemia–reperfusion injury (IRI) and unilateral ureter obstruction. Administration of MSCs treated with IFN-γ strongly reduced infiltration of inflammatory cells and ameliorated interstitial fibrosis compared with control MSCs without IFN-γ treatment. In addition, conditioned medium obtained from IFN-γ-treated MSCs decreased fibrotic changes in cultured cells induced by transforming growth factor-β1 more efficiently than that from control MSCs. Most notably, secretion of prostaglandin E2 from MSCs was significantly increased by treatment with IFN-γ. Increased prostaglandin E2 in conditioned medium obtained from IFN-γ-treated MSCs induced polarization of immunosuppressive CD163 and CD206-positive macrophages. In addition, knockdown of prostaglandin E synthase weakened the anti-fibrotic effects of MSCs treated with IFN-γ in IRI rats, suggesting the involvement of prostaglandin E2 in the beneficial effects of IFN-γ. Administration of MSCs treated with IFN-γ might represent a promising therapy to prevent the progression of renal fibrosis.
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Wu Y, Zhang X, Zhao Q, Tan B, Chen X, Liao J. Role of Hydrogels in Bone Tissue Engineering: How Properties Shape Regeneration. J Biomed Nanotechnol 2020; 16:1667-1686. [PMID: 33485397 DOI: 10.1166/jbn.2020.2997] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Bone defect that resulted from trauma, tumors, and other reasons is believed as a common clinical problem, which exists mainly in post-traumatic healing. Additionally, autologous/allogeneic transplantation, bone tissue engineering attracts increasing attention due to the existing problem of the limited donor. The applications of biomaterials can be considered as a rising and promising strategy for bone regeneration. Especially, hydrogel is featured with hydrophilic characteristic, good biocompatibility, and porous structure, which shows unique properties for bone regeneration. The main properties of hydrogel such as surface property, adhesive property, mechanical property, porosity, and degradation property, generally present influences on the migration, proliferation, and differentiation of mesenchymal stem cells exclusively or in combination, which consequently affect the regeneration of bones. This review mainly focuses on the theme: "how properties of hydrogel shape bone regeneration." Moreover, the latest progress achieved in the above mentioned direction is further discussed. Despite the fascinating advances researchers have made, certain potential challenges continue to exist in the research field, which need to be addressed for accelerating the clinical translation of hydrogel in bone regeneration.
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Mostafa-He G, Ewaiss Has M, Sabry D, Ibrahim Al R. Anti-diabetic Therapeutic Efficacy of Mesenchymal Stem Cells-derived Exosomes. INT J PHARMACOL 2020. [DOI: 10.3923/ijp.2020.437.446] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Jena D, Kharche SD, Singh SP, Rani S, Dige MS, Ranjan R, Singh SK, Kumar H. Growth and proliferation of caprine bone marrow mesenchymal stem cells on different culture media. Tissue Cell 2020; 67:101446. [PMID: 33099198 DOI: 10.1016/j.tice.2020.101446] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 09/21/2020] [Accepted: 09/22/2020] [Indexed: 01/26/2023]
Abstract
The growth and proliferation of mesenchymal stem cells are very sensitive in in vitro and a number of factors like media play a significant role in that context. In this study we assessed effect of different media on growth and proliferation of bone marrow derived mesenchymal stem cells (BMMSCs). The BMMSCs were isolated from caprine bone marrow and were subjected to magnetic activated cell sorting against CD90+, CD105+, CD271+and CD34- along with FC blocker. After characterisation, 2 × 104 cells were seeded in 12 well culture plates in four different media viz. MesenCult, MesenPRO, StemPro and complete DMEM (15 % FBS) to study their growth kinetic for 6 days from passage 0 (P0) to passage 3 (P3). The population doubling time (PDT) was derived from growth curve using logarithmic formula. The results showed that the BMMSCs growth and proliferation was highest in MesenCult media in P0 which varied significantly (p < 0.05) from rest of media and from P1 to P3, it was MesenPRO which yielded maximum cells (p < 0.05). The PDT was also in line with growth curve findings. In conclusion, the MesenPRO media had higher growth and proliferation rate from P1 to P3 although MesenCult had higher cell numbers in P0. In conclusion, the use of MesenPRO media could be a better option than conventional media when mesenchymal stem cells are used in clinical applications and other therapeutic purposes taking consideration to its higher growth and proliferation rate. And MesenCult would be a great option to harvest MSCs from P0.
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Affiliation(s)
- Dayanidhi Jena
- Dept. of Veterinary Clinical Complex, Faculty of Veterinary & Animal Sciences, Banaras Hindu University, Varanasi, U.P., 231001, India
| | - Suresh Dinkar Kharche
- ICAR-Central Institute for Research on Goats (CIRG), Makhdoom, Farah, 281122, Mathura, U.P., India.
| | - Shiva Pratap Singh
- ICAR-Central Institute for Research on Goats (CIRG), Makhdoom, Farah, 281122, Mathura, U.P., India
| | - Sonam Rani
- ICAR-Central Institute for Research on Goats (CIRG), Makhdoom, Farah, 281122, Mathura, U.P., India
| | - Mahesh Shivanand Dige
- ICAR-Central Institute for Research on Goats (CIRG), Makhdoom, Farah, 281122, Mathura, U.P., India
| | - Ravi Ranjan
- ICAR-Central Institute for Research on Goats (CIRG), Makhdoom, Farah, 281122, Mathura, U.P., India
| | - Sanjay Kumar Singh
- ICAR-Indian Veterinary Research Institute, Bareilly, U.P., 243122, India
| | - Harendra Kumar
- ICAR-Indian Veterinary Research Institute, Bareilly, U.P., 243122, India
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Luo L, Zhou Y, Zhang C, Huang J, Du J, Liao J, Bergholt NL, Bünger C, Xu F, Lin L, Tong G, Zhou G, Luo Y. Feeder-free generation and transcriptome characterization of functional mesenchymal stromal cells from human pluripotent stem cells. Stem Cell Res 2020; 48:101990. [PMID: 32950887 DOI: 10.1016/j.scr.2020.101990] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 08/23/2020] [Accepted: 09/05/2020] [Indexed: 01/18/2023] Open
Abstract
Induced mesenchymal stromal cells (iMSCs) derived from human pluripotent stem cells (PSCs) are attractive cells for regenerative medicine. However, the transcriptome of iMSCs and signature genes that can distinguish MSCs from fibroblasts and other cell types are rarely explored. In this study, we reported an optimized feeder-free method for the generation of iMSCs from human pluripotent stem cells. These iMSCs display a typical MSC morphology, express classic MSC markers (CD29, CD44, CD73, CD90, CD105, CD166), are negative for lymphocyte markers (CD11b, CD14, CD31, CD34, CD45, HLA-DR), and are potent for osteogenic and chondrogenic differentiation. Using genome-wide transcriptome profiling, we created an easily accessible transcriptome reference for the process of differentiating PSCs into iMSCs. The iMSC transcriptome reference revealed clear patterns in the silencing of pluripotency genes, activation of lineage commitment genes, and activation of mesenchymal genes during iMSC generation. All previously known positive and negative markers for MSCs were confirmed by our iMSC transcriptomic reference, and most importantly, gene classification and time course analysis identified 52 genes including FN1, TGFB1, TAGLN and SERPINE1, which showed significantly higher expression in MSCs (over 3 folds) than fibroblasts and other cell types. Taken together, these results provide a useful method and important resources for developing and understanding iMSCs in regenerative medicine.
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Affiliation(s)
- Lidan Luo
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen 518033, China; Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
| | - Yan Zhou
- Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark; Department of Medical Cell Biology and Genetics, Guangdong Key Laboratory of Genomic Stability and Disease Prevention, Shenzhen Key Laboratory of Anti-aging and Regenerative Medicine, and Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopaedic Diseases, Health Sciences Center, Shenzhen University, Shenzhen 518060, China; Lungene Technologies Co., Ltd, Shenzhen, China.
| | - Chenxi Zhang
- Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, BGI-Shenzhen, Shenzhen 518083, China.
| | - Jinrong Huang
- Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, BGI-Shenzhen, Shenzhen 518083, China; Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark.
| | - Jie Du
- Department of Medical Cell Biology and Genetics, Guangdong Key Laboratory of Genomic Stability and Disease Prevention, Shenzhen Key Laboratory of Anti-aging and Regenerative Medicine, and Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopaedic Diseases, Health Sciences Center, Shenzhen University, Shenzhen 518060, China; Lungene Technologies Co., Ltd, Shenzhen, China.
| | - Jinqi Liao
- Department of Medical Cell Biology and Genetics, Guangdong Key Laboratory of Genomic Stability and Disease Prevention, Shenzhen Key Laboratory of Anti-aging and Regenerative Medicine, and Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopaedic Diseases, Health Sciences Center, Shenzhen University, Shenzhen 518060, China; Lungene Technologies Co., Ltd, Shenzhen, China.
| | | | - Cody Bünger
- Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
| | - Fengping Xu
- Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, BGI-Shenzhen, Shenzhen 518083, China.
| | - Lin Lin
- Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
| | - Guangdong Tong
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen 518033, China.
| | - Guangqian Zhou
- Department of Medical Cell Biology and Genetics, Guangdong Key Laboratory of Genomic Stability and Disease Prevention, Shenzhen Key Laboratory of Anti-aging and Regenerative Medicine, and Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopaedic Diseases, Health Sciences Center, Shenzhen University, Shenzhen 518060, China.
| | - Yonglun Luo
- Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, BGI-Shenzhen, Shenzhen 518083, China; Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
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Song N, Scholtemeijer M, Shah K. Mesenchymal Stem Cell Immunomodulation: Mechanisms and Therapeutic Potential. Trends Pharmacol Sci 2020; 41:653-664. [PMID: 32709406 PMCID: PMC7751844 DOI: 10.1016/j.tips.2020.06.009] [Citation(s) in RCA: 550] [Impact Index Per Article: 110.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 06/26/2020] [Accepted: 06/26/2020] [Indexed: 02/08/2023]
Abstract
Mesenchymal stem/stromal cells (MSCs) are multipotent cells that are emerging as the most promising means of allogeneic cell therapy. MSCs have inherent immunomodulatory characteristics, trophic activity, high invitro self-renewal ability, and can be readily engineered to enhance their immunomodulatory functions. MSCs affect the functions of most immune effector cells via direct contact with immune cells and local microenvironmental factors. Previous studies have confirmed that the immunomodulatory effects of MSCs are mainly communicated via MSC-secreted cytokines; however, apoptotic and metabolically inactivated MSCs have more recently been shown to possess immunomodulatory potential, in which regulatory T cells and monocytes play a key role. We review the immunomodulatory aspects of naïve and engineered MSCs, and discuss strategies for increasing the potential of successfully using MSCs in clinical settings.
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Affiliation(s)
- Na Song
- Center for Stem Cell Therapeutics and Imaging (CSTI), Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China
| | - Martijn Scholtemeijer
- Center for Stem Cell Therapeutics and Imaging (CSTI), Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Khalid Shah
- Center for Stem Cell Therapeutics and Imaging (CSTI), Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
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Dilogo IH, Rahmatika D, Pawitan JA, Liem IK, Kurniawati T, Kispa T, Mujadid F. Allogeneic umbilical cord-derived mesenchymal stem cells for treating critical-sized bone defects: a translational study. EUROPEAN JOURNAL OF ORTHOPAEDIC SURGERY AND TRAUMATOLOGY 2020; 31:265-273. [PMID: 32804289 DOI: 10.1007/s00590-020-02765-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 08/05/2020] [Indexed: 01/01/2023]
Abstract
INTRODUCTION The current 'gold-standard' treatment of critical-sized bone defects (CSBDs) is autografts; however, they have drawbacks including lack of massive bone source donor site morbidity, incomplete remodeling, and the risk of infection. One potential treatment for treating CSBDs is bone marrow-derived mesenchymal stem cells (BM-MSCs). Previously, there were no studies regarding the use of human umbilical cord-mesenchymal stem cells (hUC-MSCs) for treating BDs. We aim to investigate the use of allogeneic hUC-MSCs for treating CSBDs. METHOD We included subjects who were diagnosed with non-union fracture with CSBDs who agreed to undergo hUC-MSCs implantation. All patients were given allogeneic hUC-MSCs. All MSCs were obtained and cultured using the multiple-harvest explant method. Subjects were evaluated functionally using the Lower Extremity Functional Scale (LEFS) and radiologically by volume defect reduction. RESULT A total of seven (3 male, 4 female) subjects were recruited for this study. The subjects age ranged from 14 to 62 years. All seven subjects had increased LEFS during the end of the follow-up period, indicating improved functional ability. The follow-up period ranged from 12 to 36 months. One subject had wound dehiscence and infection, and two subjects developed partial union. CONCLUSION Umbilical cord mesenchymal stem cells are a potential new treatment for CSBDs. Additional studies with larger samples and control groups are required to further investigate the safety and efficacy of umbilical cord-derived mesenchymal stem cells for treating CSBDs.
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Affiliation(s)
- Ismail Hadisoebroto Dilogo
- Department of Orthopaedic and Traumatology, Dr. Cipto Mangunkusumo General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
- Stem Cell Medical Technology Integrated Service Unit, Cipto Mangunkusumo Central Hospital, Faculty of Medicine, Universitas Indonesia, CMU 2 Building 5th Floor, Jl. Diponegoro 71, Jakarta Pusat, Indonesia.
- Stem Cell and Tissue Engineering Research Center, IMERI, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
| | - Dina Rahmatika
- Stem Cell Medical Technology Integrated Service Unit, Cipto Mangunkusumo Central Hospital, Faculty of Medicine, Universitas Indonesia, CMU 2 Building 5th Floor, Jl. Diponegoro 71, Jakarta Pusat, Indonesia
| | - Jeanne Adiwinata Pawitan
- Stem Cell Medical Technology Integrated Service Unit, Cipto Mangunkusumo Central Hospital, Faculty of Medicine, Universitas Indonesia, CMU 2 Building 5th Floor, Jl. Diponegoro 71, Jakarta Pusat, Indonesia
- Department Histology, Faculty of Medicine, Universitas Indonesia, Jl. Salemba 6, Jakarta, Indonesia
- Stem Cell and Tissue Engineering Research Center, IMERI, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Isabella Kurnia Liem
- Stem Cell Medical Technology Integrated Service Unit, Cipto Mangunkusumo Central Hospital, Faculty of Medicine, Universitas Indonesia, CMU 2 Building 5th Floor, Jl. Diponegoro 71, Jakarta Pusat, Indonesia
- Stem Cell and Tissue Engineering Research Center, IMERI, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jl. Salemba 6, Jakarta, Indonesia
| | - Tri Kurniawati
- Stem Cell Medical Technology Integrated Service Unit, Cipto Mangunkusumo Central Hospital, Faculty of Medicine, Universitas Indonesia, CMU 2 Building 5th Floor, Jl. Diponegoro 71, Jakarta Pusat, Indonesia
- Stem Cell and Tissue Engineering Research Center, IMERI, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Tera Kispa
- Stem Cell Medical Technology Integrated Service Unit, Cipto Mangunkusumo Central Hospital, Faculty of Medicine, Universitas Indonesia, CMU 2 Building 5th Floor, Jl. Diponegoro 71, Jakarta Pusat, Indonesia
| | - Fajar Mujadid
- Stem Cell Medical Technology Integrated Service Unit, Cipto Mangunkusumo Central Hospital, Faculty of Medicine, Universitas Indonesia, CMU 2 Building 5th Floor, Jl. Diponegoro 71, Jakarta Pusat, Indonesia
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Jin H, Xu Y, Qi Y, Wang X, Patel DK, Deb Dutta S, Chen R, Lim KT. Evaluation of Osteogenic/Cementogenic Modulating Potential of PAI-1 Transfected Media for Stem Cells. IEEE Trans Nanobioscience 2020; 19:446-456. [PMID: 32603295 DOI: 10.1109/tnb.2020.2984551] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
AIM OF THE STUDY In vitro evaluation of the effects of plasminogen activator inhibitor-1 (PAI-1) transfected-conditioned media (P-CM) on the differentiation of human periodontal ligament stem cells (hPDLSCs) and human periapical follicular stem cells (hPAFSCs). MATERIALS AND METHODS The hPDLSCs and hPAFSCs received from impacted third molars were treated with P-CM and viability, as well as differentiation of the cells were evaluated. Plasmids were constructed according to standard techniques, and all sequences were validated by proper enzyme digestion and sequencing. Chinese hamster ovarian (CHO) cells were transfected with pcDNA3.1-hPAI-1 plasmid to obtain P-CM, followed by western blotting and PAI-1-specific ELISA kit to evaluate the proteins of P-CM. The cell viability of hPDLSCs and hPAFSCs were analyzed using MTT assay after 48 h of incubation. Alizarin red S staining was performed to evaluate the differentiation of hPDLSCs and hPAFSCs. The reverse transcription-polymerase chain reaction was used to observe the expression levels of osteogenic/cementogenic marker genes. The human cytokine antibody array was applied for further analysis of cytokine expression in P-CM. RESULTS P-CM significantly promoted the differentiation of hPDLSCs and hPAFSCs and upregulated the expression of osteogenic/cementogenic marker genes in vitro. Furthermore, rhPAI-1 promoted mineralized nodules formation of hPDLSCs and hPAFSCs, and we identified that other proteins, RANTES and IL-6, were highly expressed in P-CM. CONCLUSIONS P-CM promoted the differentiation of hPDLSCs and hPAFSCs by upregulating the expression of RANTES and IL-6, and interaction between PAI-1 and RANTES/IL-6 signaling may be involved in P-CM-induced osteogenic/cementogenic differentiation.
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Wang G, Yuan J, Cai X, Xu Z, Wang J, Ocansey DKW, Yan Y, Qian H, Zhang X, Xu W, Mao F. HucMSC-exosomes carrying miR-326 inhibit neddylation to relieve inflammatory bowel disease in mice. Clin Transl Med 2020; 10:e113. [PMID: 32564521 PMCID: PMC7403704 DOI: 10.1002/ctm2.113] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 06/04/2020] [Accepted: 06/05/2020] [Indexed: 02/06/2023] Open
Abstract
Background Inflammatory bowel disease (IBD) is a group of chronic intestinal inflammation that is a risk factor for many gastrointestinal cancers. Exosomes are gradually gaining attention as an emerging treatment method for IBD due to their important biological characteristics. NF‐κB is an important pro‐inflammatory transcription factor kept inactive by IκB protein in the cytoplasm by masking the nuclear localization signal of NF‐κB. The deterioration of IκB is mainly ubiquitination, and this depends on neddylation. Methods In this study, we established a dextran sulfate sodium (DSS)‐induced IBD model in BABL/C mice to evaluate the effect of human umbilical cord mesenchymal stem cell‐derived exosomes (hucMSC‐exosomes, hucMSC‐Ex) on the repair of IBD. At the same time, human colorectal mucosa cells (FHC) were stimulated by LPS (lipopolysaccharide) in vitro to activate the inflammatory environment to study the mechanism of hucMSC‐Ex regulating neddylation. The microRNA (miRNA) obtained by sequencing and transfection with hucMSC‐Ex was used to verify the role of miR‐326/neddylation/IκB/NF‐κB signaling pathway in IBD repair. Results HucMSC‐Ex inhibited the process of neddylation in relieving DSS‐induced IBD in mice. The binding of NEDD8 (neural precursor cell‐expressed, developmentally downregulated gene 8) to cullin 1 and the activation of NF‐κB signaling pathway were suppressed along with reduced expression levels of neddylation‐related enzyme molecules. The same phenomenon was observed in FHC cells. The miRNA comparison results showed that miR‐326 was highly expressed in hucMSC‐Ex and played an important role in inhibiting the neddylation process. The therapeutic effect of hucMSC‐Ex with high expression of miR‐326 on IBD mice was significantly stronger than that of ordinary hucMSC‐Ex. Conclusions HucMSC‐Ex relieves DSS‐induced IBD in a mouse model by inhibiting neddylation through miR‐326.
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Affiliation(s)
- Gaoying Wang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China
| | - Jintao Yuan
- The People's Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Zhenjiang, Jiangsu, P. R. China
| | - Xiu Cai
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China
| | - Zhiwei Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China
| | - Jingyan Wang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China
| | - Dickson K W Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China
| | - Yongmin Yan
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China
| | - Hui Qian
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China
| | - Xu Zhang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China
| | - Wenrong Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P. R. China
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Karakaş N, Bay S, Türkel N, Öztunç N, Öncül M, Bilgen H, Shah K, Şahin F, Öztürk G. Neurons from human mesenchymal stem cells display both spontaneous and stimuli responsive activity. PLoS One 2020; 15:e0228510. [PMID: 32407317 PMCID: PMC7224507 DOI: 10.1371/journal.pone.0228510] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 04/06/2020] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells have the ability to transdifferentiate into neurons and therefore one of the potential adult stem cell source for neuronal tissue regeneration applications and understanding neurodevelopmental processes. In many studies on human mesenchymal stem cell (hMSC) derived neurons, success in neuronal differentiation was limited to neuronal protein expressions which is not statisfactory in terms of neuronal activity. Established neuronal networks seen in culture have to be investigated in terms of synaptic signal transmission ability to develop a culture model for human neurons and further studying the mechanism of neuronal differentiation and neurological pathologies. Accordingly, in this study, we analysed the functionality of bone marrow hMSCs differentiated into neurons by a single step cytokine-based induction protocol. Neurons from both primary hMSCs and hMSC cell line displayed spontaneous activity (≥75%) as demonstrated by Ca++ imaging. Furthermore, when electrically stimulated, hMSC derived neurons (hMd-Neurons) matched the response of a typical neuron in the process of maturation. Our results reveal that a combination of neuronal inducers enhance differentiation capacity of bone marrow hMSCs into high yielding functional neurons with spontaneous activity and mature into electrophysiologically active state. Conceptually, we suggest these functional hMd-Neurons to be used as a tool for disease modelling of neuropathologies and neuronal differentiation studies.
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Affiliation(s)
- Nihal Karakaş
- Medical Biology Department, School of Medicine, İstanbul Medipol University, İstanbul, Turkey
- Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, İstanbul, Turkey
- * E-mail:
| | - Sadık Bay
- Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, İstanbul, Turkey
| | - Nezaket Türkel
- Genetics and Bioengineering Department, Faculty of Engineering, Yeditepe University, İstanbul, Turkey
| | - Nurşah Öztunç
- Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, İstanbul, Turkey
- Medical Biology and Genetics Program, Graduate School of Health Sciences, İstanbul Medipol University, İstanbul, Turkey
| | - Merve Öncül
- Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, İstanbul, Turkey
| | - Hülya Bilgen
- Center for Bone Marrow Transplantation, İstanbul Medipol University Hospital, İstanbul, Turkey
| | - Khalid Shah
- Center for Stem Cell Therapeutics and Imaging, Brigham and Woman’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Fikrettin Şahin
- Genetics and Bioengineering Department, Faculty of Engineering, Yeditepe University, İstanbul, Turkey
| | - Gürkan Öztürk
- Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, İstanbul, Turkey
- Physiology Department, International School of Medicine, İstanbul Medipol University, İstanbul, Turkey
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Different osteogenic differentiation potential of mesenchymal stem cells on three different polymeric substrates. Gene 2020; 740:144534. [DOI: 10.1016/j.gene.2020.144534] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 02/28/2020] [Accepted: 03/03/2020] [Indexed: 12/30/2022]
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Wang J, Fu X, Yan Y, Li S, Duan Y, Marie Inglis B, Si W, Zheng B. In vitro differentiation of rhesus macaque bone marrow- and adipose tissue-derived MSCs into hepatocyte-like cells. Exp Ther Med 2020; 20:251-260. [PMID: 32518605 PMCID: PMC7273898 DOI: 10.3892/etm.2020.8676] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 01/16/2020] [Indexed: 02/07/2023] Open
Abstract
Orthotopic liver or hepatocyte transplantation is effective for the treatment of acute liver injury and end-stage chronic liver disease. However, both of these therapies are hampered by the extreme shortage of organ donors. The clinical application of cell therapy through the substitution of hepatocytes with mesenchymal stem cells (MSCs) that have been differentiated into hepatocyte-like cells (HLCs) for liver disease treatment is expected to overcome this shortage. Bone marrow and adipose tissue are two major sources of MSCs [bone marrow-derived MSCs (BM-MSCs) and adipose tissue-derived MSCs (AT-MSCs), respectively]. However, knowledge about the variability in the differentiation potential between BM-MSCs and AT-MSCs is lacking. In the present study, the hepatogenic differentiation potential of rhesus macaque BM-MSCs and AT-MSCs was compared with the evaluation of morphology, immunophenotyping profiles, differentiation potential, glycogen deposition, urea secretion and hepatocyte-specific gene expression. The results indicated that BM-MSCs and AT-MSCs shared similar characteristics in terms of primary morphology, surface markers and trilineage differentiation potential (adipogenesis, osteogenesis and chondrogenesis). Subsequently, the hepatogenic differentiation potential of BM-MSCs and AT-MSCs was evaluated by morphology, glycogen accumulation, urea synthesis and expression of hepatocyte marker genes. The results indicated that rhesus BM-MSCs and AT-MSCs had hepatogenic differentiation ability. To the best of our knowledge, this is the first report to detect the hepatogenic differentiation potential of rhesus macaque BM-MSCs and AT-MSCs. The present study provides the basis for the selection of seed cells that can trans-differentiate into HLCs for cytotherapy of acute or chronic liver injuries in either clinical or veterinary practice.
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Affiliation(s)
- Junfeng Wang
- Department of Hepatic and Bile Duct Surgery, The First People's Hospital of Yunnan Province, Kunhua Hospital Affiliated to Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China.,Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China
| | - Xufeng Fu
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China.,Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, Ningxia Medical University, Yinchuan, Ningxia 741001, P.R. China.,School of Medicine, Yunnan University, Kunming, Yunnan 650091, P.R. China
| | - Yaping Yan
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China
| | - Shanshan Li
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China
| | - Yanchao Duan
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China
| | - Briauna Marie Inglis
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China
| | - Wei Si
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China
| | - Bingrong Zheng
- School of Medicine, Yunnan University, Kunming, Yunnan 650091, P.R. China
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Morganti C, Bonora M, Marchi S, Ferroni L, Gardin C, Wieckowski MR, Giorgi C, Pinton P, Zavan B. Citrate Mediates Crosstalk between Mitochondria and the Nucleus to Promote Human Mesenchymal Stem Cell In Vitro Osteogenesis. Cells 2020; 9:cells9041034. [PMID: 32326298 PMCID: PMC7226543 DOI: 10.3390/cells9041034] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 04/07/2020] [Accepted: 04/19/2020] [Indexed: 12/15/2022] Open
Abstract
Citrate, generated in the mitochondria, is a key metabolite that might link metabolism with signaling, chromatin structure and transcription to orchestrate mesenchymal stem cells (MSCs) fate determination. Based on a detailed morphological analysis of 3D reconstruction of mitochondria and nuclei in single cells, we identified contact sites between these organelles that drastically increase in volume and number during the early stage of mesenchymal stem cell differentiation. These contact sites create a microdomain that facilitates exchange of signals from mitochondria to the nucleus. Interestingly, we found that the citrate derived from mitochondria is necessary for osteogenic lineage determination. Indeed, inhibition of the citrate transporter system dramatically affected osteogenesis, reduced citrate levels that could be converted in α-ketoglutarate, and consequently affected epigenetic marker H3K9me3 associated with the osteogenesis differentiation process. These findings highlight that mitochondrial metabolites play key regulatory roles in the MSCs differentiation process. Further in-depth investigation is needed to provide novel therapeutic strategies in the field of regenerative medicine.
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Affiliation(s)
- Claudia Morganti
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (C.M.); (M.B.); (S.M.); (C.G.)
- Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA), University of Ferrara, 44121 Ferrara, Italy
| | - Massimo Bonora
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (C.M.); (M.B.); (S.M.); (C.G.)
- Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA), University of Ferrara, 44121 Ferrara, Italy
| | - Saverio Marchi
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (C.M.); (M.B.); (S.M.); (C.G.)
- Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA), University of Ferrara, 44121 Ferrara, Italy
| | - Letizia Ferroni
- Maria Cecilia Hospital, GVM Care & Research, Via Corriera 1, Cotignola, 48033 Ravenna, Italy; (L.F.); (C.G.)
| | - Chiara Gardin
- Maria Cecilia Hospital, GVM Care & Research, Via Corriera 1, Cotignola, 48033 Ravenna, Italy; (L.F.); (C.G.)
| | - Mariusz R. Wieckowski
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland;
| | - Carlotta Giorgi
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (C.M.); (M.B.); (S.M.); (C.G.)
- Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA), University of Ferrara, 44121 Ferrara, Italy
| | - Paolo Pinton
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (C.M.); (M.B.); (S.M.); (C.G.)
- Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA), University of Ferrara, 44121 Ferrara, Italy
- Maria Cecilia Hospital, GVM Care & Research, Via Corriera 1, Cotignola, 48033 Ravenna, Italy; (L.F.); (C.G.)
- Correspondence: (P.P.); (B.Z.)
| | - Barbara Zavan
- Maria Cecilia Hospital, GVM Care & Research, Via Corriera 1, Cotignola, 48033 Ravenna, Italy; (L.F.); (C.G.)
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology, University of Ferrara, 44121 Ferrara, Italy
- Correspondence: (P.P.); (B.Z.)
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50
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Fumagalli G, Monfrini M, Donzelli E, Rodriguez-Menendez V, Bonandrini B, Figliuzzi M, Remuzzi A, D’Amico G, Cavaletti G, Scuteri A. Protective Effect of Human Mesenchymal Stem Cells on the Survival of Pancreatic Islets. Int J Stem Cells 2020; 13:116-126. [PMID: 31887847 PMCID: PMC7119207 DOI: 10.15283/ijsc19094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 10/09/2019] [Accepted: 10/17/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Transplantation of pancreatic islets is an intriguing new therapeutic option to face the worldwide spread problem of Type-I diabetes. Currently, its clinical use is limited by several problems, mainly based on the high number of islets required to restore normoglycaemia and by the low survival of the transplanted tissue. A promising attempt to overcome the limits to such an approach was represented by the use of Mesenchymal Stem Cells (MSC). Despite the encouraging results obtained with murine-derived MSC, little is still known about their protective mechanisms. The aim of the present study was to verify the effectiveness, (besides murine MSC), of clinically relevant human-derived MSC (hMSC) on protecting pancreatic islets, thus also shedding light on the putative differences between MSC of different origin. METHODS AND RESULTS Threefold kinds of co-cultures were therefore in vitro set up (direct, indirect and mixed), to analyze the hMSC effect on pancreatic islet survival and function and to study the putative mechanisms involved. Although in a different way with respect to murine MSC, also human derived cells demonstrated to be effective on protecting pancreatic islet survival. This effect could be due to the release of some trophic factors, such as VEGF and Il-6, and by the reduction of inflammatory cytokine TNF-α. CONCLUSIONS Therefore, hMSC confirmed their great clinical potential to improve the feasibility of pancreatic islet transplantation therapy against diabetes.
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Affiliation(s)
- Giulia Fumagalli
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB), Italy
- PhD Program in Neuroscience, University of Milano-Bicocca, Monza (MB), Italy
| | - Marianna Monfrini
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB), Italy
| | - Elisabetta Donzelli
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB), Italy
- NeuroMi, Milan Center for Neurosciences, Milano, Italy
| | - Virginia Rodriguez-Menendez
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB), Italy
- NeuroMi, Milan Center for Neurosciences, Milano, Italy
| | - Barbara Bonandrini
- Department of Biomedical Engineering, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Marina Figliuzzi
- Department of Biomedical Engineering, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Andrea Remuzzi
- Department of Management, Information and Production Engineering, University of Bergamo, Dalmine (BG), Italy
| | - Giovanna D’Amico
- Centro Ricerca Tettamanti, Clinica Pediatrica, Università Milano-Bicocca, Monza (MB), Italy
| | - Guido Cavaletti
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB), Italy
- NeuroMi, Milan Center for Neurosciences, Milano, Italy
| | - Arianna Scuteri
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB), Italy
- NeuroMi, Milan Center for Neurosciences, Milano, Italy
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