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Saadh MJ, Ahmed HH, Sanghvi G, Bin Awang Isa MZ, Singh P, Kaur K, Kumar MR, Husseen B. Recent advances in the delivery of microRNAs via exosomes derived from MSCs, and their role in regulation of ferroptosis. Pathol Res Pract 2025; 270:155984. [PMID: 40315562 DOI: 10.1016/j.prp.2025.155984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 04/09/2025] [Accepted: 04/18/2025] [Indexed: 05/04/2025]
Abstract
Mesenchymal stem cell (MSC) therapy, with its unique properties, has garnered interest in cancer treatment. Exosomes (EXOs)-derived from MSC retain the paracrine components of MSCs and demonstrate increased stability, minimal immunogenicity, and low risk of unintended tumorigenesis. Enhanced endocytosis methods make them versatile delivery vehicles for therapeutic cargo. MSC-EXOs can either promote or inhibit carcinogenesis, mediated by paracrine factors and various RNA molecules, particularly microRNAs (miRNAs). The prospect of using MSC-EXOs as a delivery tool for antitumor miRNAs in solid tumor therapy is promising. Exosomes' intrinsic tumor-targeting abilities and low immunogenicity make them ideal for delivering miRNAs, which have shown potential as cancer therapeutics. miRNAs within MSC-EXOs molecules can stimulate tumor growth or induce non-apoptotic cell death pathways, such as ferroptosis, depending on context. Ferroptosis is a kind of controlled cell death that is associated with the pathophysiology of several illnesses and includes iron metabolism. There is growing evidence that miRNAs carried by exosomes derived from MSCs may control ferroptosis in tumor cells by altering key genes related to antioxidant defense, lipid peroxidation, and iron metabolism. Understanding their complex mechanisms in the tumor microenvironment and optimizing their cargo are critical steps toward harnessing their full therapeutic potential. This review provides a comprehensive overview of MSC-EXOs and their role in cancer treatment. We also discuss the potential of MSC-EXOs as delivery vehicles for miRNAs to enhance therapeutic efficacy, as well as the role of exosomal miRNAs in the induction of ferroptosis.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan.
| | | | - Gaurav Sanghvi
- Marwadi University Research Center, Department of Microbiology, Faculty of Science, Marwadi University, Rajkot, Gujarat 360003, India
| | | | - Priyanka Singh
- NIMS School of Allied Sciences and Technology, NIMS University, Jaipur, Rajasthan 303121, India
| | - Kiranjeet Kaur
- Chandigarh Pharmacy College, Chandigarh Group of colleges-Jhanjeri, Mohali, Punjab 140307, India
| | - M Ravi Kumar
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh 531162, India
| | - Beneen Husseen
- Medical laboratory technique college, the Islamic University, Najaf, Iraq; Medical laboratory technique college, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
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Lange-Consiglio A, Tagliasacchi F, Cremonesi F, Gusmara C, Pollera C, Scarpa P, Gaspari G, Riccaboni P. Characterization of Urine-Derived Stromal/Stem Cells from Healthy Dogs and Dogs Affected by Chronic Kidney Disease (CKD). Animals (Basel) 2025; 15:242. [PMID: 39858242 PMCID: PMC11758669 DOI: 10.3390/ani15020242] [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: 12/04/2024] [Revised: 01/02/2025] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
Urine-derived mesenchymal stromal/stem cells (USCs) could be a valuable source of cells in regenerative medicine because urine can be easily collected non-invasively. In this paper, USCs were isolated from both healthy dogs and dogs affected by chronic kidney disease (CKD), and the efficacy of collection methods (spontaneous micturition, bladder catheterization, and cystocentesis) were compared. Isolated cells were cultured in the presence of platelet-rich plasma and studied for their proliferative capacity (growth curve, doubling time, and colony forming unit), differentiation properties, expression of mesenchymal markers, and Klotho protein. Morphologically, all cells were elongated and fibroblast-like. USCs isolated from samples collected by spontaneous micturition and bladder catheterization failed to proliferate, whilst USCs obtained by cystocentesis showed a doubling time of 2.04 days in healthy dogs and 1.7 days in dogs with CKD (p < 0.05). Cells were able to differentiate into osteogenic, chondrogenic, and adipogenic lines, showed positive expression to mesenchymal/stem markers, negative expression to hematopoietic markers, and major histocompatibility complex (MHCII) antigen. Klotho protein expression was confirmed. This study confirmed that USCs from healthy and CKD dogs can act as stem cells, with those from sick dogs having greater proliferative ability with the potential for use as autologous therapies.
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Affiliation(s)
- Anna Lange-Consiglio
- Reproduction Laboratory, Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, 26900 Lodi, Italy; (A.L.-C.); (F.C.)
| | - Filippo Tagliasacchi
- Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, 26900 Lodi, Italy; (F.T.); (C.G.); (C.P.); (P.S.); (P.R.)
| | - Fausto Cremonesi
- Reproduction Laboratory, Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, 26900 Lodi, Italy; (A.L.-C.); (F.C.)
| | - Claudia Gusmara
- Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, 26900 Lodi, Italy; (F.T.); (C.G.); (C.P.); (P.S.); (P.R.)
- Laboratorio di Malattie Infettive degli Animali (MiLab), Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, 26900 Lodi, Italy
| | - Claudia Pollera
- Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, 26900 Lodi, Italy; (F.T.); (C.G.); (C.P.); (P.S.); (P.R.)
| | - Paola Scarpa
- Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, 26900 Lodi, Italy; (F.T.); (C.G.); (C.P.); (P.S.); (P.R.)
| | - Giulia Gaspari
- Reproduction Laboratory, Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, 26900 Lodi, Italy; (A.L.-C.); (F.C.)
| | - Pietro Riccaboni
- Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, 26900 Lodi, Italy; (F.T.); (C.G.); (C.P.); (P.S.); (P.R.)
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Wang L, Zhang J, Ye S, Lu F. LncRNA H19 improves mesenchymal characteristics of buffalo (Bubalus bubalis) bone marrow-derived mesenchymal stem cells under hypoxic conditions. Res Vet Sci 2025; 182:105461. [PMID: 39612735 DOI: 10.1016/j.rvsc.2024.105461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 10/15/2024] [Accepted: 11/07/2024] [Indexed: 12/01/2024]
Abstract
As adult stem cells with various advantages, Bone marrow-derived mesenchymal stem cells (BMSCs) are valuable resources for veterinary treatment and animal reproduction. Previous studies have shown that hypoxia can induce epithelial-mesenchymal transition (EMT) and improve mesenchymal characteristics of BMSCs in vitro culture. However, the mechanism by which hypoxia improves the interstitial characteristics of buffalo BMSCs (bBMSCs) remains unclear. In this study, the effects of hypoxia on the mesenchymal characteristics of bBMSCs and the expression level of lncRNA H19 were examined, and then the effects of lncRNA H19 on maintaining the mesenchymal characteristics of bBMSCs under hypoxic culture conditions (5 % oxygen) as well as its mechanism also were explored, so as to further understand the molecular mechanism of mesenchymal characteristics maintenance of bBMSCs. The results showed that hypoxic culture conditions promoted EMT of bBMSCs, with lncRNA H19 expression up-regulated. When lncRNA H19 was knocked down in hypoxia, the expression level of Vimentin was down-regulated, the expression level of E-Cadherin was up-regulated, and EMT was inhibited. Meanwhile, the genes (p-PI3K and p-AKT1) involved in PI3K/AKT signaling pathway were inhibited by lncRNA H19 Knockdown. IGF-1 (10 ng/mL), an activator of PI3K/AKT signaling pathway, was added to rescued the inhibition of PI3K/AKT signaling pathway caused by lncRNA H19 Knockdown, with the effects of lncRNA H19 on EMT related genes also partially reversed. These findings not only provide theoretical guidance to elucidate the detailed regulation mechanism of hypoxia on mesenchymal nature maintenance of bBMSCs, but also provide positive support to further establish the stable in vitro culture system of bBMSCs.
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Affiliation(s)
- Lulu Wang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi Key Laboratory of Animal Breeding and Diease Control, Guangxi University, Nanning 530005, China
| | - Jun Zhang
- Laboratory Animal Center, Guangxi Medical University, Nanning 530021, China
| | - Sheng Ye
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi Key Laboratory of Animal Breeding and Diease Control, Guangxi University, Nanning 530005, China
| | - Fenghua Lu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi Key Laboratory of Animal Breeding and Diease Control, Guangxi University, Nanning 530005, China.
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Cheng X, Li YL, Wang H, Zhang RJ, Fan KY, Qi XT, Zheng GP, Dong HL. Mesenchymal stem cell therapy in atherosclerosis: A bibliometric and visual analysis. World J Stem Cells 2024; 16:1062-1085. [PMID: 39734478 PMCID: PMC11669984 DOI: 10.4252/wjsc.v16.i12.1062] [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: 05/03/2024] [Revised: 10/15/2024] [Accepted: 11/18/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are capable of self-renewal and differentiation, and extensive studies have demonstrated their therapeutic potential in atherosclerosis (AS). AIM To conduct a bibliometric analysis of studies on the use of MSC therapy for AS over the past two decades, assess key trends and provide insights for future research directions. METHODS We systematically searched the Web of Science Core Collection database for articles published between 1999 and 2023, yielding a total of 556 articles. Visual representation and bibliometric analysis of information and trends were facilitated using CiteSpace, the R package 'bibliometrix' and VOSviewer. RESULTS The analyzed articles were predominantly from 52 countries/regions, with prominent contributions from China and the United States. A cohort of 3057 authors contributed to these publications, with the works of Libby P distinguished by their influence and citation count. Int J Mol Sci has emerged as the journal with the highest publication volume, prominently disseminating influential papers and identifying citation outbreaks. Furthermore, our analysis identified current research hotspots within the field, focusing on vascular progenitor cells, inflammatory mechanisms, and extracellular vesicles. Emerging research frontiers, such as extracellular vesicles and oxidative stress, have been highlighted as areas of burgeoning interest. Finally, we offer perspectives on the status of research and future directions of MSC therapy in AS. CONCLUSION This comprehensive analysis provides valuable insights for advancing scientific research on MSC therapy for AS. By elucidating pivotal trends and research directions, this study aimed to foster innovation and promote the progress of disciplines in this field, thereby contributing to advancing scientific knowledge and clinical practice.
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Affiliation(s)
- Xing Cheng
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Ya-Ling Li
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Heng Wang
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney 2145, New South Wales, Australia
| | - Rui-Jing Zhang
- Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Ke-Yi Fan
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Xiao-Tong Qi
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Guo-Ping Zheng
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney 2145, New South Wales, Australia
| | - Hong-Lin Dong
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China.
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Cheng T, Mao M, Liu Y, Xie L, Shi F, Liu H, Li X. The potential therapeutic effect of human umbilical cord mesenchymal stem cell-derived exosomes in bronchopulmonary dysplasia. Life Sci 2024; 357:123047. [PMID: 39260518 DOI: 10.1016/j.lfs.2024.123047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 08/25/2024] [Accepted: 09/07/2024] [Indexed: 09/13/2024]
Abstract
Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm infants, with its incidence rising due to improved survival rates of these infants. BPD results from a combination of prenatal and postnatal factors, such as mechanical ventilation, oxygen toxicity, and infections, all of which significantly impact the prognosis and growth of affected infants. Current treatment options for BPD are largely supportive and do not address the underlying pathology. Exosomes are cell-derived bilayer-enclosed membrane structures enclosing proteins, lipids, RNAs, growth factors, cytokines and metabolites. They have become recognized as crucial regulators of intercellular communication in various physiological and pathological processes. Previous studies have revealed the therapeutic potential of human umbilical cord mesenchymal stem cells-derived exosomes (HUCMSCs-Exos) in promoting tissue repair and regeneration. Therefore, HUCMSCs-Exos maybe a promising and effective therapeutic modality for BPD. In this review, we firstly provide a comprehensive overview of BPD, including its etiology and the mechanisms of lung injury. Then we detail the isolation, characterization, and contents of HUCMSCs-Exos, and discuss their potential mechanisms of HUCMSCs-Exos in BPD treatment. Additionally, we summarize current clinical trials and discuss the challenges in translating these findings from bench to bedside. This review aims to lay the groundwork for future clinical applications of HUCMSCs-Exos in treating BPD.
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Affiliation(s)
- Tianyu Cheng
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Min Mao
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yang Liu
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Liang Xie
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Fang Shi
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Hanmin Liu
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China.
| | - Xin Li
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China; NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China; The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China; Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China.
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Fasciano S, Wheba A, Ddamulira C, Wang S. Recent advances in scaffolding biomaterials for cultivated meat. BIOMATERIALS ADVANCES 2024; 162:213897. [PMID: 38810509 DOI: 10.1016/j.bioadv.2024.213897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 02/07/2024] [Accepted: 05/15/2024] [Indexed: 05/31/2024]
Abstract
The emergence of cultivated meat provides a sustainable and ethical alternative to traditional animal agriculture, highlighting its increasing importance in the food industry. Biomaterial scaffolds are critical components in cultivated meat production for enabling cell adhesion, proliferation, differentiation, and orientation. While there's extensive research on scaffolding biomaterials, applying them to cultivated meat production poses distinct challenges, with each material offering its own set of advantages and disadvantages. This review summarizes the most recent scaffolding biomaterials used in the last five years for cell-cultured meat, detailing their respective advantages and disadvantages. We suggest future research directions and provide recommendations for scaffolds that support scalable, cost-effective, and safe high-quality meat production. Additionally, we highlight commercial challenges cultivated meat faces, encompassing bioreactor design, cell culture mediums, and regulatory and food safety issues. In summary, this review provides a comprehensive guide and valuable insights for researchers and companies in the field of cultivated meat production.
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Affiliation(s)
- Samantha Fasciano
- Department of Cellular and Molecular Biology, University of New Haven, West Haven, CT, 06516, USA
| | - Anas Wheba
- Department of Chemistry, Chemical and Biomedical Engineering, University of New Haven, West Haven, CT, 06516, USA
| | - Christopher Ddamulira
- Department of Chemistry, Chemical and Biomedical Engineering, University of New Haven, West Haven, CT, 06516, USA
| | - Shue Wang
- Department of Chemistry, Chemical and Biomedical Engineering, University of New Haven, West Haven, CT, 06516, USA.
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Humenik F, Vdoviaková K, Krešáková L, Danko J, Giretová M, Medvecký Ľ, Lengyel P, Babík J. The Combination of Chitosan-Based Biomaterial and Cellular Therapy for Successful Treatment of Diabetic Foot-Pilot Study. Int J Mol Sci 2024; 25:8388. [PMID: 39125958 PMCID: PMC11313444 DOI: 10.3390/ijms25158388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 07/29/2024] [Accepted: 07/29/2024] [Indexed: 08/12/2024] Open
Abstract
Diabetic foot ulceration is one of the most common complications in patients treated for diabetes mellitus. The presented pilot study describes the successful treatment of diabetic ulceration of the heel with ongoing osteomyelitis in a 39-year-old patient after using a combination of modified chitosan-based biomaterial in combination with autologous mesenchymal stem cells isolated from bone marrow and dermal fibroblasts. The isolated population of bone marrow mesenchymal stem cells fulfilled all of the attributes given by the International Society for Stem Cell Research, such as fibroblast-like morphology, the high expression of positive surface markers (CD29: 99.1 ± 0.4%; CD44: 99.8 ± 0.2% and CD90: 98.0 ± 0.6%) and the ability to undergo multilineage differentiation. Likewise, the population of dermal fibroblasts showed high positivity for the widely accepted markers collagen I, collagen III and vimentin, which was confirmed by immunocytochemical staining. Moreover, we were able to describe newly formed blood vessels shown by angio CT and almost complete closure of the skin defect after 8 months of the treatment.
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Affiliation(s)
- Filip Humenik
- Department of Morphological Sciences, University of Veterinary Medicine and Pharmacy in Košice, 041 81 Košice, Slovakia; (K.V.); (L.K.); (J.D.)
| | - Katarína Vdoviaková
- Department of Morphological Sciences, University of Veterinary Medicine and Pharmacy in Košice, 041 81 Košice, Slovakia; (K.V.); (L.K.); (J.D.)
| | - Lenka Krešáková
- Department of Morphological Sciences, University of Veterinary Medicine and Pharmacy in Košice, 041 81 Košice, Slovakia; (K.V.); (L.K.); (J.D.)
| | - Ján Danko
- Department of Morphological Sciences, University of Veterinary Medicine and Pharmacy in Košice, 041 81 Košice, Slovakia; (K.V.); (L.K.); (J.D.)
| | - Mária Giretová
- Division of Functional and Hybrid Systems, Institute of Materials Research of SAS, 040 01 Košice, Slovakia; (M.G.); (Ľ.M.)
| | - Ľubomír Medvecký
- Division of Functional and Hybrid Systems, Institute of Materials Research of SAS, 040 01 Košice, Slovakia; (M.G.); (Ľ.M.)
| | - Peter Lengyel
- Clinic of Burns and Reconstructive Medicine, AGEL Hospital, 040 15 Košice-Šaca, Slovakia; (P.L.); (J.B.)
| | - Ján Babík
- Clinic of Burns and Reconstructive Medicine, AGEL Hospital, 040 15 Košice-Šaca, Slovakia; (P.L.); (J.B.)
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Bandarra-Tavares H, Franchi-Mendes T, Ulpiano C, Morini S, Kaur N, Harris-Becker A, Vemuri MC, Cabral JMS, Fernandes-Platzgummer A, da Silva CL. Dual production of human mesenchymal stromal cells and derived extracellular vesicles in a dissolvable microcarrier-based stirred culture system. Cytotherapy 2024; 26:749-756. [PMID: 38506771 DOI: 10.1016/j.jcyt.2024.03.001] [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: 07/26/2023] [Revised: 01/29/2024] [Accepted: 03/02/2024] [Indexed: 03/21/2024]
Abstract
BACKGROUND & AIMS Cell therapies based on mesenchymal stromal cells (MSCs) have gained an increasing therapeutic interest in the context of multiple disorders. Nonetheless, this field still faces important challenges, particularly concerning suitable manufacturing platforms. Here, we aimed at establishing a scalable culture system to expand umbilical cord-derived Wharton's jelly MSC (MSC(WJ)) and their derived extracellular vesicles (EVs) by using dissolvable microcarriers combined with xeno(geneic)-free culture medium. METHODS MSC(WJ) isolated from three donors were cultured at a starting density of 1 × 106 cells per spinner flask, i.e., 2.8 × 103 cells per cm2 of dissolvable microcarrier surface area. After a 6-day expansion period of MSC(WJ), extracellular vesicles (EVs) were produced for 24 h. RESULTS Taking advantage of an intermittent agitation regimen, we observed high adhesion rates to the microcarriers (over 90% at 24 h) and achieved 15.8 ± 0.7-fold expansion after 6 days of culture. Notably, dissolution of the microcarriers was achieved through a pectinase-based solution to recover the cell product, reducing the hurdles of downstream processing. MSC identity was validated by detecting the characteristic MSC immunophenotype and by multilineage differentiation assays. Considering the growing interest in MSC-derived EVs, which are known to be mediators of the therapeutic features of MSC, this platform also was evaluated for EV production. Upon a 24-h period of conditioning, secreted EVs were isolated by ultrafiltration followed by anion-exchange chromatography and exhibited the typical cup-shaped morphology, small size distribution (162.6 ± 30.2 nm) and expressed EV markers (CD63, CD9 and syntenin-1). CONCLUSIONS Taken together, we established a time-effective and robust scalable platform that complies with clinical-grade standards for the dual production of MSC(WJ) and their derived EV.
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Affiliation(s)
- Hélder Bandarra-Tavares
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal; Associate Laboratory i4HB - Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Teresa Franchi-Mendes
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal; Associate Laboratory i4HB - Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Cristiana Ulpiano
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal; Associate Laboratory i4HB - Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Sara Morini
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal; Associate Laboratory i4HB - Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Navjot Kaur
- Cell and Gene Therapy, Thermo Fisher Scientific, Cell Biology, Frederick, Maryland, USA
| | - Abigail Harris-Becker
- Cell and Gene Therapy, Thermo Fisher Scientific, Cell Biology, Frederick, Maryland, USA
| | - Mohan C Vemuri
- Cell and Gene Therapy, Thermo Fisher Scientific, Cell Biology, Frederick, Maryland, USA
| | - Joaquim M S Cabral
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal; Associate Laboratory i4HB - Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Ana Fernandes-Platzgummer
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal; Associate Laboratory i4HB - Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Cláudia L da Silva
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal; Associate Laboratory i4HB - Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.
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Shi L, Chen L, Gao X, Sun X, Jin G, Yang Y, Shao Y, Zhu F, Zhou G. Comparison of different sources of mesenchymal stem cells: focus on inflammatory bowel disease. Inflammopharmacology 2024; 32:1721-1742. [PMID: 38615278 DOI: 10.1007/s10787-024-01468-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 03/22/2024] [Indexed: 04/15/2024]
Abstract
Inflammatory bowel disease (IBD) poses a significant challenge in modern medicine, with conventional treatments limited by efficacy and associated side effects, necessitating innovative therapeutic approaches. Mesenchymal stem cells (MSC) have emerged as promising candidates for IBD treatment due to their immunomodulatory properties and regenerative potential. This thesis aims to explore and compare various sources of MSC and evaluate their efficacy in treating IBD. This study comprehensively analyses MSC derived from multiple sources, including bone marrow, adipose tissue, umbilical cord, and other potential reservoirs. Core elements of this investigation include assessing differences in cell acquisition, immunomodulatory effects, and differentiation capabilities among these MSC sources, as well as comparing their clinical trial outcomes in IBD patients to their therapeutic efficacy in animal models. Through meticulous evaluation and comparative analysis, this thesis aims to elucidate disparities in the efficacy of different MSC sources for IBD treatment, thereby identifying the most promising therapeutic applications. The findings of this study are intended to advance our understanding of MSC biology and offer valuable insights for selecting the most effective MSC sources for personalized IBD therapy. Ultimately, this research endeavor will optimise therapeutic strategies for managing inflammatory bowel disease through the utilization of MSC.
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Affiliation(s)
- Lihao Shi
- Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Leilei Chen
- Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Xizhuang Gao
- Clinical Medical College of Jining Medical University, Jining Medical University, Jining, Shandong, 272000, People's Republic of China
| | - Xufan Sun
- Clinical Medical College of Jining Medical University, Jining Medical University, Jining, Shandong, 272000, People's Republic of China
| | - Guiyuan Jin
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, People's Republic of China
| | - Yonghong Yang
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, People's Republic of China
| | - Yiming Shao
- Department of Burns and Plastic Surgery, Affiliated Hospital of Jining Medical University, Jining, China
| | - Fengqin Zhu
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, 272000, People's Republic of China
| | - Guangxi Zhou
- Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, 272000, People's Republic of China.
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10
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Hazell AS. Stem Cell Therapy and Thiamine Deficiency-Induced Brain Damage. Neurochem Res 2024; 49:1450-1467. [PMID: 38720090 DOI: 10.1007/s11064-024-04137-5] [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: 02/24/2023] [Revised: 01/18/2024] [Accepted: 03/15/2024] [Indexed: 05/21/2024]
Abstract
Wernicke's encephalopathy (WE) is a major central nervous system disorder resulting from thiamine deficiency (TD) in which a number of brain regions can develop serious damage including the thalamus and inferior colliculus. Despite decades of research into the pathophysiology of TD and potential therapeutic interventions, little progress has been made regarding effective treatment following the development of brain lesions and its associated cognitive issues. Recent developments in our understanding of stem cells suggest they are capable of repairing damage and improving function in different maladys. This article puts forward the case for the potential use of stem cell treatment as a therapeutic strategy in WE by first examining the effects of TD on brain functional integrity and its consequences. The second half of the paper will address the future benefits of treating TD with these cells by focusing on their nature and their potential to effectively treat neurodegenerative diseases that share some overlapping pathophysiological features with TD. At the same time, some of the obstacles these cells will have to overcome in order to become a viable therapeutic strategy for treating this potentially life-threatening illness in humans will be highlighted.
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Affiliation(s)
- Alan S Hazell
- Department of Medicine, University of Montreal, 2335 Bennett Avenue, Montreal, QC, H1V 2T6, Canada.
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11
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Wang S, Jia Z, Dai M, Feng X, Tang C, Liu L, Cao L. Advances in natural and synthetic macromolecules with stem cells and extracellular vesicles for orthopedic disease treatment. Int J Biol Macromol 2024; 268:131874. [PMID: 38692547 DOI: 10.1016/j.ijbiomac.2024.131874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 04/16/2024] [Accepted: 04/24/2024] [Indexed: 05/03/2024]
Abstract
Serious orthopedic disorders resulting from myriad diseases and impairments continue to pose a considerable challenge to contemporary clinical care. Owing to its limited regenerative capacity, achieving complete bone tissue regeneration and complete functional restoration has proven challenging with existing treatments. By virtue of cellular regenerative and paracrine pathways, stem cells are extensively utilized in the restoration and regeneration of bone tissue; however, low survival and retention after transplantation severely limit their therapeutic effect. Meanwhile, biomolecule materials provide a delivery platform that improves stem cell survival, increases retention, and enhances therapeutic efficacy. In this review, we present the basic concepts of stem cells and extracellular vesicles from different sources, emphasizing the importance of using appropriate expansion methods and modification strategies. We then review different types of biomolecule materials, focusing on their design strategies. Moreover, we summarize several forms of biomaterial preparation and application strategies as well as current research on biomacromolecule materials loaded with stem cells and extracellular vesicles. Finally, we present the challenges currently impeding their clinical application for the treatment of orthopedic diseases. The article aims to provide researchers with new insights for subsequent investigations.
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Affiliation(s)
- Supeng Wang
- The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, China; Jiujiang City Key Laboratory of Cell Therapy, The First Hospital of Jiujiang City, Jiujiang 332000, China; Ningxia Medical University, Ningxia 750004, China
| | - Zhiqiang Jia
- The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, China
| | - Minghai Dai
- The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, China
| | - Xujun Feng
- Jiujiang City Key Laboratory of Cell Therapy, The First Hospital of Jiujiang City, Jiujiang 332000, China
| | - Chengxuan Tang
- The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, China
| | - Liangle Liu
- The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, China.
| | - Lingling Cao
- Jiujiang City Key Laboratory of Cell Therapy, The First Hospital of Jiujiang City, Jiujiang 332000, China.
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12
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Yuan H, Zhang P, Xin Y, Liu Z, Gao B. Single cell RNA-seq identifies a FOS/JUN-related monocyte signature associated with clinical response of heart failure patients with mesenchymal stem cell therapy. Aging (Albany NY) 2024; 16:5651-5675. [PMID: 38517374 PMCID: PMC11006470 DOI: 10.18632/aging.205670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 02/07/2024] [Indexed: 03/23/2024]
Abstract
Heart failure (HF) is a serious global health issue that demands innovative treatment approaches. In this study, we collected samples from 4 HF patients before and after MSC therapy and performed scRNA-seq. After the MSC therapy, the proportion of CD14+ monocytes decreased significantly in both the treatment response and non-response groups, with a more pronounced decrease in the treatment response group. The therapy-response and non-response group were clearly separated in the UMAP plot, while the CD14+ monocytes in the therapy-response group before and after MSC therapy were very similar, but there were significant differences in the non-response group. By further performing NMF analysis, we identified 11 subsets of CD14+ monocytes. More importantly, we identified a therapy-related CD14+ monocyte subpopulation. The predictive model based on CD14+ monocytes constructed by machine learning algorithms showed good performance. Moreover, genes such as FOS were highly enriched in the therapy-related CD14+ monocytes. The SCENIC analysis revealed potential regulatory factors for this treatment-responsive CD14+ monocytes, and FOS/JUN were identified as potential core indicators/regulators. Finally, HF patients were divided into three groups by NMF analysis, and the therapy-responsive CD14+ monocyte characteristics were differentially activated among the three groups. Together, this study identifies treatment-responsive CD14+ monocytes as a crucial biomarker for assessing the suitability of MSC therapy and determining which HF patients could benefit from it. This provides new clues for further investigating the therapeutic mechanisms of MSC therapy, offering beneficial insights for personalized treatment and improving prognosis in HF patients.
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Affiliation(s)
- Hui Yuan
- Department of Cardiac Surgery, Lanzhou University Second Hospital, Lanzhou 730030, Gansu, China
- Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Pengfei Zhang
- Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Yuanfeng Xin
- Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Zhongmin Liu
- Department of Cardiac Surgery, Lanzhou University Second Hospital, Lanzhou 730030, Gansu, China
- Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Bingren Gao
- Department of Cardiac Surgery, Lanzhou University Second Hospital, Lanzhou 730030, Gansu, China
- Cardiopulmonary Vascular Center, Haikang Hospital, Xingguang Island, West Coast New Area, Qingdao 266400, Shandong, China
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13
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Sabeti MA, Saqib Ihsan M, Adami D, Hassani SN, Moushekhian S, Shafieian R, Salari Sedigh H, Ghoddusi J. Cell-Based Regenerative Endodontics for the Treatment of Irreversible Pulpitis: AnIn VivoInvestigation. J Endod 2024; 50:344-350. [PMID: 38142887 DOI: 10.1016/j.joen.2023.11.014] [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: 09/15/2023] [Revised: 11/21/2023] [Accepted: 11/24/2023] [Indexed: 12/26/2023]
Abstract
INTRODUCTION This study aims to investigate the ability of umbilical cord mesenchymal stem cells (UC-MSC) to enhance the regeneration of pulp-dentin complex in immature permanent teeth with irreversible pulpitis. METHODS A total of 32 mandibular premolar teeth with immature apices in 5 dogs were used in this in-vivo randomized controlled trial (RCT). Eight healthy teeth without pre-existing pathosis served as the positive control samples and received no treatment, while in another 8 teeth, the pulp was completely extirpated (negative control). Class V cavities were prepared to induce inflammation in the remaining 16 teeth (groups 3 and 4) and the pulp was extirpated 2-4 mm short of the radiographic apex. Of the 16, the 8 teeth in group 4 received 1 mL of cord blood stem cells with a hydrogel scaffold. Blood clots were covered with mineral trioxide aggregates at the cementoenamel junction in the experimental groups, and teeth were filled with RMGI and composite. Three months later, block sections were removed for histologic evaluations for the evaluation of postoperative apical closure, degree of inflammation, and presence of normal pulp tissue. The data were statistically analyzed with the chi-square test (P < .05). RESULTS All teeth with complete pulp extirpation demonstrated pulpal necrosis with no postoperative closure of their apices, while apical closure was seen in all the teeth in the remaining groups. There was a statistically significant (P < .001) difference in the presence of inflammation and normal pulp tissue between the experimental groups. The teeth in group 3 showed normal pulp tissue extending to the level of MTA, but there was inflammation within the canal space. In contrast, the teeth in the UC-MSC group demonstrated organized, normal pulp tissue with no inflammation. CONCLUSION Based on these results, the regeneration of the pulp-dentin complex is possible with no inflammation when UC-MSCs are used and 2-4 mm of the apical pulp remains intact in immature teeth with irreversible pulpitis.
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Affiliation(s)
- Mohammad A Sabeti
- Advanced Specialty Program in Endodontics, Department of Preventive and Restorative Dental Sciences, University of California, San Francisco School of Dentistry, San Francisco, California.
| | - Mohammad Saqib Ihsan
- Advanced Specialty Program in Endodontics, Department of Preventive and Restorative Dental Sciences, University of California, San Francisco School of Dentistry, San Francisco, California
| | - Dina Adami
- Advanced Specialty Program in Endodontics, Department of Preventive and Restorative Dental Sciences, University of California, San Francisco School of Dentistry, San Francisco, California
| | - Seyedeh-Nafiseh Hassani
- Head of Stem Cells and Developmental Biology Department and Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Royan Institute for Stem Cell Biology & Technology ACECR, Tehran, Iran
| | - Siavash Moushekhian
- Dental Research Center, Department of Endodontics, Faculty of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reihaneh Shafieian
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamideh Salari Sedigh
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Jamileh Ghoddusi
- Dental Research Center, Department of Endodontics, Faculty of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
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Pampanella L, Petrocelli G, Abruzzo PM, Zucchini C, Canaider S, Ventura C, Facchin F. Cytochalasins as Modulators of Stem Cell Differentiation. Cells 2024; 13:400. [PMID: 38474364 PMCID: PMC10931372 DOI: 10.3390/cells13050400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 02/16/2024] [Accepted: 02/22/2024] [Indexed: 03/14/2024] Open
Abstract
Regenerative medicine aims to identify new research strategies for the repair and restoration of tissues damaged by pathological or accidental events. Mesenchymal stem cells (MSCs) play a key role in regenerative medicine approaches due to their specific properties, such as the high rate of proliferation, the ability to differentiate into several cell lineages, the immunomodulatory potential, and their easy isolation with minimal ethical issues. One of the main goals of regenerative medicine is to modulate, both in vitro and in vivo, the differentiation potential of MSCs to improve their use in the repair of damaged tissues. Over the years, much evidence has been collected about the ability of cytochalasins, a large family of 60 metabolites isolated mainly from fungi, to modulate multiple properties of stem cells (SCs), such as proliferation, migration, and differentiation, by altering the organization of the cyto- and the nucleo-skeleton. In this review, we discussed the ability of two different cytochalasins, cytochalasins D and B, to influence specific SC differentiation programs modulated by several agents (chemical or physical) or intra- and extra-cellular factors, with particular attention to human MSCs (hMSCs).
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Affiliation(s)
- Luca Pampanella
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (P.M.A.); (C.Z.); (F.F.)
| | - Giovannamaria Petrocelli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (P.M.A.); (C.Z.); (F.F.)
| | - Provvidenza Maria Abruzzo
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (P.M.A.); (C.Z.); (F.F.)
| | - Cinzia Zucchini
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (P.M.A.); (C.Z.); (F.F.)
| | - Silvia Canaider
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (P.M.A.); (C.Z.); (F.F.)
| | - Carlo Ventura
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (P.M.A.); (C.Z.); (F.F.)
- National Laboratory of Molecular Biology and Stem Cell Bioengineering of the National Institute of Biostructures and Biosystems (NIBB) c/o Eldor Lab, Via Corticella 183, 40129 Bologna, Italy
| | - Federica Facchin
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (P.M.A.); (C.Z.); (F.F.)
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15
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Malvicini R, De Lazzari G, Tolomeo AM, Santa-Cruz D, Ullah M, Cirillo C, Grumati P, Pacienza N, Muraca M, Yannarelli G. Influence of the isolation method on characteristics and functional activity of mesenchymal stromal cell-derived extracellular vesicles. Cytotherapy 2024; 26:157-170. [PMID: 38069981 DOI: 10.1016/j.jcyt.2023.11.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 11/07/2023] [Accepted: 11/07/2023] [Indexed: 02/03/2024]
Abstract
BACKGROUND AIMS Extracellular vesicle (EV) isolation methods are based on different physicochemical properties and may result in the purification of distinct EV populations. We compared two different isolation methods suitable for producing clinical-grade mesenchymal stromal cell-derived EVs (MSC-EVs)-ion exchange chromatography (IEX) and ultrafiltration (UF)-and evaluated their impact on the composition and functional properties of EVs. METHODS EVs were purified from conditioned culture medium using an anion exchange resin (IEX) or Amicon filters with a 100-kDa cutoff (UF) (MilliporeSigma, Burlington, MA, USA). We assessed nanoparticle size and distribution by nanoparticle tracking analysis (NTA) and tunable resistive pulse sensing (TRPS) and morphology by transmission electron microscopy. We also measured protein, lipid and total RNA concentration and immunophenotyped both EV populations by flow cytometry (MACSPlex assay; Miltenyi Biotec, Bergisch Gladbach, Germany). Moreover, immunomodulatory activity was tested using a standardized macrophage polarization assay and T-cell stimulation assay. Finally, proteomic analysis and cytokine quantification were carried out to better characterize both EV populations. RESULTS We found by both TRPS and NTA that IEX and UF yielded a comparable amount of total particles with similar size and distribution. In addition, a similar quantity of lipids was obtained with the two procedures. However, IEX yielded 10-fold higher RNA quantity and a larger amount of proteins than UF. MSC-EVs isolated from IEX and UF were positive for the exosome markers CD9, CD63 and CD81 and showed a comparable surface marker expression pattern. Both populations demonstrated immunomodulatory activity in vitro, as they prevented acquisition of the M1 phenotype in lipopolysaccharide-stimulated macrophages and inhibited acquisition of the activation markers CD69 and CD25 on T cells, but the IEX-EVs exerted a significantly greater immunomodulatory effect on both macrophages and T cells compared with UF-EVs. Proteomic analysis and gene ontology enrichment analysis revealed no major differences between the preparations. Finally, cytokine quantification revealed that IEX-EVs were more enriched in some crucial anti-inflammatory and immunomodulatory cytokines (e.g., IL-2, IL-10, transforming growth factor beta and vascular endothelial growth factor) compared with UF-EVs. CONCLUSIONS MSC-EVs isolated by IEX and UF displayed similar physicochemical, phenotypic and functional characteristics. In our conditions, both EV populations demonstrated important anti-inflammatory activity in macrophages and T cells. However, IEX-EVs were more potent than UF-EVs, which may indicate the superiority of this method for the production of clinical-grade EVs.
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Affiliation(s)
- Ricardo Malvicini
- Laboratorio de Regulación Génica y Células Madre, Instituto de Medicina Traslacional, Trasplante y Bioingeniería, Universidad Favaloro-Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina; Department of Women's and Children's Health, University of Padua, Padua, Italy; Laboratory of Extracellular Vesicles as Therapeutic Tools, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padua, Italy; LIFELAB Program, Consorzio per la Ricerca Sanitaria, Padua, Italy.
| | - Giada De Lazzari
- Department of Women's and Children's Health, University of Padua, Padua, Italy; Laboratory of Extracellular Vesicles as Therapeutic Tools, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padua, Italy
| | - Anna Maria Tolomeo
- Laboratory of Extracellular Vesicles as Therapeutic Tools, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padua, Italy; LIFELAB Program, Consorzio per la Ricerca Sanitaria, Padua, Italy; Department of Cardiac, Thoracic and Vascular Science and Public Health, University of Padova, Padua, Italy
| | - Diego Santa-Cruz
- Laboratorio de Regulación Génica y Células Madre, Instituto de Medicina Traslacional, Trasplante y Bioingeniería, Universidad Favaloro-Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Mujib Ullah
- Institute for Immunity and Transplantation, Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Palo Alto, California, USA
| | - Carmine Cirillo
- Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy
| | - Paolo Grumati
- Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy; Department of Clinical Medicine and Surgery, University of Napoli Federico II, Naples, Italy
| | - Natalia Pacienza
- Laboratorio de Regulación Génica y Células Madre, Instituto de Medicina Traslacional, Trasplante y Bioingeniería, Universidad Favaloro-Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Maurizio Muraca
- Department of Women's and Children's Health, University of Padua, Padua, Italy; Laboratory of Extracellular Vesicles as Therapeutic Tools, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padua, Italy; LIFELAB Program, Consorzio per la Ricerca Sanitaria, Padua, Italy
| | - Gustavo Yannarelli
- Laboratorio de Regulación Génica y Células Madre, Instituto de Medicina Traslacional, Trasplante y Bioingeniería, Universidad Favaloro-Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
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16
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Cao C, Maska B, Malik MA, Tagett R, Kaigler D. Immunomodulatory differences between mesenchymal stem cells from different oral tissues. Heliyon 2024; 10:e23317. [PMID: 38192855 PMCID: PMC10771986 DOI: 10.1016/j.heliyon.2023.e23317] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 11/24/2023] [Accepted: 11/30/2023] [Indexed: 01/10/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have recently been identified as having potentially therapeutic immunomodulatory properties. MSCs isolated from different oral tissues have similar morphology and immunophenotypes, however, direct comparisons of their gene expression and immunomodulatory properties have not been conducted. We isolated alveolar bone-derived MSCs (aBMSCs), dental pulp stem cells (DPSCs) and gingiva-derived MSCs (GMSCs) from the same patients and compared their immunophenotypes and transcriptomes. Additionally, we compared their production of soluble immunomodulatory cytokines as well as their immunoregulatory properties in coculture with THP-1 human monocytic cells. RNA sequencing revealed distinct gene expression in DPSCs while aBMSCs and GMSCs had less differentially expressed genes. DPSCs also had significantly less secretion of osteopontin compared to aBMSCs and GMSCs. Finally, DPSCs did not exhibit an immunosuppresive effect on THP-1 cells to the same degree as aBMSCs and GMSCs. These findings demonstrate that MSCs from different oral tissues have distinct transcriptomes and immunoregulatory properties.
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Affiliation(s)
- Chen Cao
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
| | - Bartosz Maska
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
| | - Malika A. Malik
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
| | - Rebecca Tagett
- Bioinformatics Core, Medical School, University of Michigan, Ann Arbor, MI, USA
| | - Darnell Kaigler
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
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17
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Han W, Zhang H, Feng L, Dang R, Wang J, Cui C, Jiang P. The emerging role of exosomes in communication between the periphery and the central nervous system. MedComm (Beijing) 2023; 4:e410. [PMID: 37916034 PMCID: PMC10616655 DOI: 10.1002/mco2.410] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 09/18/2023] [Accepted: 09/21/2023] [Indexed: 11/03/2023] Open
Abstract
Exosomes, membrane-enclosed vesicles, are secreted by all types of cells. Exosomes can transport various molecules, including proteins, lipids, functional mRNAs, and microRNAs, and can be circulated to various recipient cells, leading to the production of local paracrine or distal systemic effects. Numerous studies have proved that exosomes can pass through the blood-brain barrier, thus, enabling the transfer of peripheral substances into the central nervous system (CNS). Consequently, exosomes may be a vital factor in the exchange of information between the periphery and CNS. This review will discuss the structure, biogenesis, and functional characterization of exosomes and summarize the role of peripheral exosomes deriving from tissues like the lung, gut, skeletal muscle, and various stem cell types in communicating with the CNS and influencing the brain's function. Then, we further discuss the potential therapeutic effects of exosomes in brain diseases and the clinical opportunities and challenges. Gaining a clearer insight into the communication between the CNS and the external areas of the body will help us to ascertain the role of the peripheral elements in the maintenance of brain health and illness and will facilitate the design of minimally invasive techniques for diagnosing and treating brain diseases.
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Affiliation(s)
- Wenxiu Han
- Translational Pharmaceutical LaboratoryJining First People's HospitalShandong First Medical UniversityJiningP. R. China
- Institute of Translational PharmacyJining Medical Research AcademyJiningP. R. China
| | - Hailiang Zhang
- Translational Pharmaceutical LaboratoryJining First People's HospitalShandong First Medical UniversityJiningP. R. China
- Institute of Translational PharmacyJining Medical Research AcademyJiningP. R. China
| | - Lei Feng
- Department of NeurosurgeryJining First People's HospitalShandong First Medical UniversityJiningP. R. China
| | - Ruili Dang
- Translational Pharmaceutical LaboratoryJining First People's HospitalShandong First Medical UniversityJiningP. R. China
- Institute of Translational PharmacyJining Medical Research AcademyJiningP. R. China
| | - Jing Wang
- Translational Pharmaceutical LaboratoryJining First People's HospitalShandong First Medical UniversityJiningP. R. China
- Institute of Translational PharmacyJining Medical Research AcademyJiningP. R. China
| | - Changmeng Cui
- Department of NeurosurgeryAffiliated Hospital of Jining Medical UniversityJiningP. R. China
| | - Pei Jiang
- Translational Pharmaceutical LaboratoryJining First People's HospitalShandong First Medical UniversityJiningP. R. China
- Institute of Translational PharmacyJining Medical Research AcademyJiningP. R. China
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18
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Yabe M, Karakida T, Onuma K, Yamamoto R, Chiba-Ohkuma R, Asada S, Yamakoshi Y, Gomi K. Synergistic effect of FGF-2 and TGF-β1 on the mineralization of human umbilical cord perivascular cells. Arch Oral Biol 2023; 156:105826. [PMID: 37898061 DOI: 10.1016/j.archoralbio.2023.105826] [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: 07/13/2023] [Revised: 10/05/2023] [Accepted: 10/15/2023] [Indexed: 10/30/2023]
Abstract
OBJECTIVE Human umbilical cord perivascular cells (HUCPVCs) are derived from the human umbilical cord perivascular tissue and are expected to replace mesenchymal stromal cells in the future. We investigated the synergistic effects of fibroblast growth factor 2 (FGF-2) and transforming growth factor-beta 1 (TGF-β1) on HUCPVC mineralization. DESIGN We prepared HUCPVCs with (FGF(+)HUCPVCs) or without FGF-2 (FGF(-)HUCPVCs) in the presence of activated vitamin D3, a bone morphogenic protein inhibitor, and TGF-β1. We examined the cell proliferative capacity, expression of various hard tissue-forming cell gene markers, and mineralization induction ability and identified the crystalline phases of the mineralized nodules. RESULTS FGF(+)HUCPVCs exhibited higher intracellular alkaline phosphatase (ALP) gene expression and ALP activity, and their cell proliferation rate was higher than that of FGF(-)HUCPVCs. The expression levels of osteoblast marker genes increased in FGF(+)HUCPVCs, whereas those of elastic fiber and muscle cell markers increased in FGF(-)HUCPVCs. The expression of genes related to matrix vesicle-mediated mineralization was increased in FGF(+)HUCPVCs. While FGF(-)HUCPVCs displayed myofibroblast-like properties and could not induce mineralization, FGF(+)HUCPVCs demonstrated the ability to produce mineralized nodules. The resulting mineralized nodules consisted of hydroxyapatite as the major phase and minor amounts of octacalcium phosphate. The mineralized nodules exhibited the morphological characteristics of bone hydroxyapatite, composed of fibrous hydroxyapatite nanorods and polycrystalline sheets. CONCLUSION We found that FGF-2 synergizes with TGF-β1 and is a key factor in the differentiation of HUCPVCs into osteoblast-like cells. Thus, HUCPVCs can potentially serve as a new stem cell source for future bone regeneration and dental treatments.
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Affiliation(s)
- Masahiro Yabe
- Department of Periodontology, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Japan
| | - Takeo Karakida
- Department of Biochemistry and Molecular Biology, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Japan
| | - Kazuo Onuma
- Department of Biochemistry and Molecular Biology, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Japan
| | - Ryuji Yamamoto
- Department of Biochemistry and Molecular Biology, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Japan
| | - Risako Chiba-Ohkuma
- Department of Biochemistry and Molecular Biology, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Japan
| | - Sakurako Asada
- Department of Periodontology, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Japan
| | - Yasuo Yamakoshi
- Department of Biochemistry and Molecular Biology, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Japan.
| | - Kazuhiro Gomi
- Department of Periodontology, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Japan
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19
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Abstract
Bioprinting, as a groundbreaking technology, enables the fabrication of biomimetic tissues and organs with highly complex structures, multiple cell types, mechanical heterogeneity, and diverse functional gradients. With the growing demand for organ transplantation and the limited number of organ donors, bioprinting holds great promise for addressing the organ shortage by manufacturing completely functional organs. While the bioprinting of complete organs remains a distant goal, there has been considerable progress in the development of bioprinted transplantable tissues and organs for regenerative medicine. This review article recapitulates the current achievements of organ 3D bioprinting, primarily encompassing five important organs in the human body (i.e., the heart, kidneys, liver, pancreas, and lungs). Challenges from cellular techniques, biomanufacturing technologies, and organ maturation techniques are also deliberated for the broad application of organ bioprinting. In addition, the integration of bioprinting with other cutting-edge technologies including machine learning, organoids, and microfluidics is envisioned, which strives to offer the reader the prospect of bioprinting in constructing functional organs.
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Affiliation(s)
- Yang Wu
- School of Mechanical Engineering and Automation, Harbin Institute of Technology, Shenzhen 518055, China.
| | - Minghao Qin
- School of Mechanical Engineering and Automation, Harbin Institute of Technology, Shenzhen 518055, China.
| | - Xue Yang
- School of Mechanical Engineering and Automation, Harbin Institute of Technology, Shenzhen 518055, China.
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20
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Schwarzl T, Keogh A, Shaw G, Krstic A, Clayton E, Higgins DG, Kolch W, Barry F. Transcriptional profiling of early differentiation of primary human mesenchymal stem cells into chondrocytes. Sci Data 2023; 10:758. [PMID: 37923731 PMCID: PMC10624874 DOI: 10.1038/s41597-023-02686-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 10/25/2023] [Indexed: 11/06/2023] Open
Abstract
Articular cartilage has only very limited regenerative capacities in humans. Tissue engineering techniques for cartilage damage repair are limited in the production of hyaline cartilage. Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells and can be differentiated into mature cartilage cells, chondrocytes, which could be used for repairing damaged cartilage. Chondrogenesis is a highly complex, relatively inefficient process lasting over 3 weeks in vitro. Methods: In order to better understand chondrogenic differentiation, especially the commitment phase, we have performed transcriptional profiling of MSC differentiation into chondrocytes from early timepoints starting 15 minutes after induction to 16 hours and fully differentiated chondrocytes at 21 days in triplicates.
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Affiliation(s)
- Thomas Schwarzl
- European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117, Heidelberg, Germany
| | - Andrea Keogh
- Previously: Regenerative Medicine Institute (REMEDI), Biosciences, National University of Ireland Galway, University Road, Galway, Ireland
| | - Georgina Shaw
- Regenerative Medicine Institute (REMEDI), Biosciences, National University of Ireland Galway, University Road, Galway, Ireland
| | - Aleksandar Krstic
- Systems Biology Ireland (SBI), School of Medicine, University College Dublin, Dublin, 4, Ireland
| | - Elizabeth Clayton
- Previously: Regenerative Medicine Institute (REMEDI), Biosciences, National University of Ireland Galway, University Road, Galway, Ireland
| | - Desmond G Higgins
- Systems Biology Ireland (SBI), School of Medicine, University College Dublin, Dublin, 4, Ireland
- Conway Institute of Biomolecular and Biomedical Research, University College Dublin (UCD), Belfield, Dublin, 4, Ireland
| | - Walter Kolch
- Systems Biology Ireland (SBI), School of Medicine, University College Dublin, Dublin, 4, Ireland.
- Conway Institute of Biomolecular and Biomedical Research, University College Dublin (UCD), Belfield, Dublin, 4, Ireland.
| | - Frank Barry
- Regenerative Medicine Institute (REMEDI), Biosciences, National University of Ireland Galway, University Road, Galway, Ireland
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21
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Garcia MF, Tiwari KK, Gendreau JL, Burgess PL, Taupin P, Martin ED. Mesenchymal Stem Cells and Regenerative Therapy with Bilateral Gracilis Flaps for Perineal Reconstruction of a Wound Infection in the Setting of Anal Squamous Cell Carcinoma. Adv Skin Wound Care 2023; 36:1-7. [PMID: 37471451 DOI: 10.1097/asw.0000000000000009] [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: 07/22/2023]
Abstract
ABSTRACT Many patients are affected by HIV/AIDS, and these conditions are highly prevalent worldwide. Patients with HIV/AIDS can experience debilitating wound infections that often require flap reconstruction and become challenging for surgeons to treat. In the past 5 years, mesenchymal stem cells have been tested and used as regenerative therapy to promote the growth of tissues throughout the body because of their ability to successfully promote cellular mitogenesis. To the authors' knowledge, the use of mesenchymal stem cell grafting following necrosis of a myocutaneous gracilis flap (as part of perineal wound reconstruction) has never been reported in the literature.In addition, the use of mesenchymal stem cells and regenerative medicine combined in the setting of squamous cell carcinoma of the anus with prior radiation (along with comorbid AIDS) has not been previously documented.In this report, the authors outline the case of a 60-year-old patient who had a recipient bed (perineum) complication from prior radiation therapy. Complicating the clinical picture, the patient also developed a Pseudomonal organ space infection of the pelvis leading to the failure of a vertical rectus abdominis myocutaneous flap and myocutaneous gracilis flaps. As a result, the patient underwent serial operative debridements for source control, with the application of mesenchymal stem cells, fetal bovine dermis, porcine urinary bladder xenograft, and other regenerative medicine products, achieving a highly successful clinical outcome. A procedural description for future use and replication of this method is provided.
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Affiliation(s)
- Matthew F Garcia
- At Dwight D. Eisenhower Army Medical Center, Fort Gordon, Georgia, USA, Matthew F. Garcia, MD, is Transitional Year Resident; Kirti K. Tiwari, MS, is Chief, Research Operations; Julian L. Gendreau, MD, is Transitional Year Resident; and Pamela L. Burgess, MD, is Chief, General Surgery. Philippe Taupin, PhD, is Senior Manager, Medical Affairs, Integra LifeSciences, Princeton, New Jersey. Also at Dwight D. Eisenhower Army Medical Center, Eric D. Martin, DO, is Chief, Cardiovascular Surgery. Dr Taupin is an employee of Integra LifeSciences Corporation. The authors have disclosed no other financial relationships related to this article. Submitted March 5, 2022; accepted in revised form September 9, 2022
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22
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Kahrizi MS, Mousavi E, Khosravi A, Rahnama S, Salehi A, Nasrabadi N, Ebrahimzadeh F, Jamali S. Recent advances in pre-conditioned mesenchymal stem/stromal cell (MSCs) therapy in organ failure; a comprehensive review of preclinical studies. Stem Cell Res Ther 2023; 14:155. [PMID: 37287066 DOI: 10.1186/s13287-023-03374-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 05/10/2023] [Indexed: 06/09/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs)-based therapy brings the reassuring capability to regenerative medicine through their self-renewal and multilineage potency. Also, they secret a diversity of mediators, which are complicated in moderation of deregulated immune responses, and yielding angiogenesis in vivo. Nonetheless, MSCs may lose biological performance after procurement and prolonged expansion in vitro. Also, following transplantation and migration to target tissue, they encounter a harsh milieu accompanied by death signals because of the lack of proper tensegrity structure between the cells and matrix. Accordingly, pre-conditioning of MSCs is strongly suggested to upgrade their performances in vivo, leading to more favored transplantation efficacy in regenerative medicine. Indeed, MSCs ex vivo pre-conditioning by hypoxia, inflammatory stimulus, or other factors/conditions may stimulate their survival, proliferation, migration, exosome secretion, and pro-angiogenic and anti-inflammatory characteristics in vivo. In this review, we deliver an overview of the pre-conditioning methods that are considered a strategy for improving the therapeutic efficacy of MSCs in organ failures, in particular, renal, heart, lung, and liver.
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Affiliation(s)
| | - Elnaz Mousavi
- Department of Endodontics, School of Dentistry, Guilan University of Medical Sciences, Rasht, Iran
| | - Armin Khosravi
- Department of Periodontics, Dental School, Islamic Azad University, Isfahan (Khorasgan) Branch, Isfahan, Iran
| | - Sara Rahnama
- Department of Pediatric Dentistry, School of Dentistry, Semnan University of Medical Sciences, Semnan, Iran
| | - Ali Salehi
- Department of Oral and Maxillofacial Radiology, School of Dentistry, Islamic Azad University, Isfahan (Khorasgan) Branch, Isfahan, Iran
| | - Navid Nasrabadi
- Department of Endodontics, School of Dentistry, Birjand University of Medical Sciences, Birjand, Iran
| | - Farnoosh Ebrahimzadeh
- Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Samira Jamali
- Department of Endodontics, Stomatological Hospital, College of Stomatology, Xi'an Jiaotong University, Shaanxi, People's Republic of China.
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23
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Zhang Y, Wang P, Jin MX, Zhou YQ, Ye L, Zhu XJ, Li HF, Zhou M, Li Y, Li S, Liang KY, Wang Y, Gao Y, Pan MX, Zhou SQ, Peng Q. Schisandrin B Improves the Hypothermic Preservation of Celsior Solution in Human Umbilical Cord Mesenchymal Stem Cells. Tissue Eng Regen Med 2023; 20:447-459. [PMID: 36947320 PMCID: PMC10219924 DOI: 10.1007/s13770-023-00531-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 02/14/2023] [Accepted: 02/17/2023] [Indexed: 03/23/2023] Open
Abstract
BACKGROUND Human umbilical cord mesenchymal stem cells (hUCMSCs) have emerged as promising therapy for immune and inflammatory diseases. However, how to maintain the activity and unique properties during cold storage and transportation is one of the key factors affecting the therapeutic efficiency of hUCMSCs. Schisandrin B (SchB) has many functions in cell protection as a natural medicine. In this study, we investigated the protective effects of SchB on the hypothermic preservation of hUCMSCs. METHODS hUCMSCs were isolated from Wharton's jelly. Subsequently, hUCMSCs were exposed to cold storage (4 °C) and 24-h re-warming. After that, cells viability, surface markers, immunomodulatory effects, reactive oxygen species (ROS), mitochondrial integrity, apoptosis-related and antioxidant proteins expression level were evaluated. RESULTS SchB significantly alleviated the cells injury and maintained unique properties such as differentiation potential, level of surface markers and immunomodulatory effects of hUCMSCs. The protective effects of SchB on hUCMSCs after hypothermic storage seemed associated with its inhibition of apoptosis and the anti-oxidative stress effect mediated by nuclear factor erythroid 2-related factor 2 signaling. CONCLUSION These results demonstrate SchB could be used as an agent for hypothermic preservation of hUCMSCs.
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Affiliation(s)
- Ying Zhang
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, China
| | - Peng Wang
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, China
| | - Mei-Xian Jin
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, China
| | - Ying-Qi Zhou
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, China
| | - Liang Ye
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, China
| | - Xiao-Juan Zhu
- Department of Anesthesiology, First People's Hospital of Kashi, Kashi, 844000, China
| | - Hui-Fang Li
- Department of Anesthesiology, First People's Hospital of Kashi, Kashi, 844000, China
| | - Ming Zhou
- Department of Anesthesiology, First People's Hospital of Kashi, Kashi, 844000, China
| | - Yang Li
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, China
| | - Shao Li
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, China
| | - Kang-Yan Liang
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, China
| | - Yi Wang
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, China
| | - Yi Gao
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, China
| | - Ming-Xin Pan
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, China
| | - Shu-Qin Zhou
- Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, China.
| | - Qing Peng
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, China.
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24
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Ohshima H, Mishima K. Oral biosciences: The annual review 2022. J Oral Biosci 2023; 65:1-12. [PMID: 36740188 DOI: 10.1016/j.job.2023.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 01/25/2023] [Indexed: 02/05/2023]
Abstract
BACKGROUND The Journal of Oral Biosciences is devoted to advancing and disseminating fundamental knowledge concerning every aspect of oral biosciences. HIGHLIGHT This review features review articles in the fields of "Bone Cell Biology," "Tooth Development & Regeneration," "Tooth Bleaching," "Adipokines," "Milk Thistle," "Epithelial-Mesenchymal Transition," "Periodontitis," "Diagnosis," "Salivary Glands," "Tooth Root," "Exosome," "New Perspectives of Tooth Identification," "Dental Pulp," and "Saliva" in addition to the review articles by the winner of the "Lion Dental Research Award" ("Plastic changes in nociceptive pathways contributing to persistent orofacial pain") presented by the Japanese Association for Oral Biology. CONCLUSION The review articles in the Journal of Oral Biosciences have inspired its readers to broaden their knowledge about various aspects of oral biosciences. The current editorial review introduces these exciting review articles.
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Affiliation(s)
- Hayato Ohshima
- Division of Anatomy and Cell Biology of the Hard Tissue, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, 2-5274 Gakkocho-dori, Chuo-ku, Niigata 951-8514, Japan.
| | - Kenji Mishima
- Division of Pathology, Department of Oral Diagnostic Sciences, Showa University School of Dentistry, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
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25
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Oliinyk D, Eigenberger A, Felthaus O, Haerteis S, Prantl L. Chorioallantoic Membrane Assay at the Cross-Roads of Adipose-Tissue-Derived Stem Cell Research. Cells 2023; 12:cells12040592. [PMID: 36831259 PMCID: PMC9953848 DOI: 10.3390/cells12040592] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 02/09/2023] [Accepted: 02/10/2023] [Indexed: 02/15/2023] Open
Abstract
With a history of more than 100 years of different applications in various scientific fields, the chicken chorioallantoic membrane (CAM) assay has proven itself to be an exceptional scientific model that meets the requirements of the replacement, reduction, and refinement principle (3R principle). As one of three extraembryonic avian membranes, the CAM is responsible for fetal respiration, metabolism, and protection. The model provides a unique constellation of immunological, vascular, and extracellular properties while being affordable and reliable at the same time. It can be utilized for research purposes in cancer biology, angiogenesis, virology, and toxicology and has recently been used for biochemistry, pharmaceutical research, and stem cell biology. Stem cells and, in particular, mesenchymal stem cells derived from adipose tissue (ADSCs) are emerging subjects for novel therapeutic strategies in the fields of tissue regeneration and personalized medicine. Because of their easy accessibility, differentiation profile, immunomodulatory properties, and cytokine repertoire, ADSCs have already been established for different preclinical applications in the files mentioned above. In this review, we aim to highlight and identify some of the cross-sections for the potential utilization of the CAM model for ADSC studies with a focus on wound healing and tissue engineering, as well as oncological research, e.g., sarcomas. Hereby, the focus lies on the combination of existing evidence and experience of such intersections with a potential utilization of the CAM model for further research on ADSCs.
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Affiliation(s)
- Dmytro Oliinyk
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
- Correspondence:
| | - Andreas Eigenberger
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | - Oliver Felthaus
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | - Silke Haerteis
- Institute for Molecular and Cellular Anatomy, Faculty for Biology and Preclinical Medicine, University of Regensburg, Universitätsstraße 31, 93053 Regensburg, Germany
| | - Lukas Prantl
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
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26
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Human Umbilical Cord-Derived Mesenchymal Stem Cells Alleviate Psoriasis Through TNF-α/NF-κB/MMP13 Pathway. Inflammation 2023; 46:987-1001. [PMID: 36749439 DOI: 10.1007/s10753-023-01785-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/18/2023] [Accepted: 01/19/2023] [Indexed: 02/08/2023]
Abstract
Psoriasis is a chronic, immune-mediated disease that affects 2-3% of the global population. Recently, mesenchymal stem cells (MSCs) have been used to alleviate psoriasis. However, the therapeutic mechanisms of MSCs remain unclear. Matrix metalloproteinase-13 (MMP13), a member of the MMPs family, is the key enzyme in the cleavage of type II collagen and plays a pivotal role in extracellular matrix (ECM) remodeling. Here, it was found that Mmp13 was upregulated in the skin lesions of an imiquimod-induced mouse model, which was downregulated after intravenous infusion of human umbilical cord MSCs (hUC-MSCs). Knockdown of MMP13 inhibited the proliferation of keratinocytes and arrested the cell cycle in G1 stage. In addition, hUC-MSCs were co-cultured with THP-1 or PMA-stimulated THP-1 directly in vitro to simulate the fate of systematically infused hUC-MSCs. The level of TNF-α was decreased in the supernatant of co-cultured hUC-MSCs and THP-1 or PMA-stimulated THP-1. Moreover, it was identified that TNF-α upregulated MMP13 through the NF-κB pathway in keratinocytes. In conclusion, we propose that systematically infused hUC-MSCs exert a therapeutic effect on psoriasis through the TNF-α/NF-κB/MMP13 pathway.
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27
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Wang Q, Wang Y, Chang C, Ma F, Peng D, Yang S, An Y, Deng Q, Wang Q, Gao F, Wang F, Tang H, Qi X, Jiang X, Cai D, Zhou G. Comparative analysis of mesenchymal stem/stromal cells derived from human induced pluripotent stem cells and the cognate umbilical cord mesenchymal stem/stromal cells. Heliyon 2023; 9:e12683. [PMID: 36647346 PMCID: PMC9840238 DOI: 10.1016/j.heliyon.2022.e12683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 12/05/2022] [Accepted: 12/22/2022] [Indexed: 01/06/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) show tremendous potential for regenerative medicine due to their self-renewal, multi-differentiation and immunomodulatory capabilities. Largely studies had indicated conventional tissue-derived MSCs have considerable limited expandability and donor variability which hinders further application. Induced pluripotent stem cell (iPSCs)-derived MSCs (iMSCs) have created exciting source for standardized cellular therapy. However, the cellular and molecular differences between iMSCs and the cognate tissue-derived MSCs remains poorly explored. In this study, we first successfully reprogrammed human umbilical cords-derived mesenchymal stem/stromal cells (UMSCs) into iPSCs by using the cocktails of mRNA. Subsequently, iPSCs were further differentiated into iMSCs in xeno-free induction medium. Then, iMSCs were compared with the donor matched UMSCs by assessing proliferative state, differentiation capability, immunomodulatory potential through immunohistochemical analysis, flow cytometric analysis, transcriptome sequencing analysis, and combine with coculture with immune cell population. The results showed that iMSCs exhibited high expression of MSCs positive-makers CD73, CD90, CD105 and lack expression of negative-maker cocktails CD34, CD45, CD11b, CD19, HLA-DR; also successfully differentiated into osteocytes, chondrocytes and adipocytes. Further, the iMSCs were similar with their parental UMSCs in cell proliferative state detected by the CCK-8 assay, and in cell rejuvenation state assessed by β-Galactosidase staining and telomerase activity related mRNA and protein analysis. However, iMSCs exhibited similarity to resident MSCs in Homeobox (Hox) genes expression profile and presented better neural differentiation potential by activation of NESTIN related pathway. Moreover, iMSCs owned enhanced immunosuppression capacity through downregulation pools of pro-inflammatory factors, including IL6, IL1B etc. and upregulation anti-inflammatory factors NOS1, TGFB etc. signals. In summary, our study provides an attractive cell source for basic research and offers fundamental biological insight of iMSCs-based therapy.
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Affiliation(s)
- Quanlei Wang
- Key Laboratory of Regenerative Medicine of Ministry of Education, Biology Postdoctoral Research Station, Jinan University, Guangzhou, China,Cheerland Danlun Biopharma Co. Ltd., Dapeng New District, Shenzhen, China,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 Science Center, Shenzhen University, Shenzhen, China
| | - Yuwei Wang
- Cheerland Danlun Biopharma Co. Ltd., Dapeng New District, Shenzhen, China,The SZU-Cheerland Institute for Advanced and Innovative Medicine, Shenzhen, China
| | - Chongfei Chang
- Cheerland Danlun Biopharma Co. Ltd., Dapeng New District, Shenzhen, China
| | - Feilong Ma
- Cheerland Danlun Biopharma Co. Ltd., Dapeng New District, Shenzhen, China
| | - Dongxiu Peng
- Cheerland Danlun Biopharma Co. Ltd., Dapeng New District, Shenzhen, China
| | - Shun Yang
- Cheerland Danlun Biopharma Co. Ltd., Dapeng New District, Shenzhen, China
| | | | - Qiuting Deng
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Qixiao Wang
- Department of Oral and Maxillofacial Surgery, The First People's Hospital of Huaihua, University of South China, Huaihua, Hunan, China
| | - Fei Gao
- China Food and Drug Administration, Beijing, China
| | - Fei Wang
- The SZU-Cheerland Institute for Advanced and Innovative Medicine, Shenzhen, China
| | - Huiru Tang
- Cheerland Danlun Biopharma Co. Ltd., Dapeng New District, Shenzhen, China
| | - Xufeng Qi
- Key Laboratory of Regenerative Medicine of Ministry of Education, Biology Postdoctoral Research Station, Jinan University, Guangzhou, China
| | - Xiaoming Jiang
- The SZU-Cheerland Institute for Advanced and Innovative Medicine, Shenzhen, China,Corresponding author. The SZU-Cheerland Institute for Advanced and Innovative Medicine, Shenzhen, China.
| | - Dongqing Cai
- Key Laboratory of Regenerative Medicine of Ministry of Education, Biology Postdoctoral Research Station, Jinan University, Guangzhou, China,Corresponding author. Key Laboratory of Regenerative Medicine of Ministry of Education, Biology Postdoctoral Research Station, Jinan University, Guangzhou, China.
| | - Guangqian Zhou
- Cheerland Danlun Biopharma Co. Ltd., Dapeng New District, Shenzhen, China,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 Science Center, Shenzhen University, Shenzhen, China,The SZU-Cheerland Institute for Advanced and Innovative Medicine, Shenzhen, China,Corresponding author. The SZU-Cheerland Institute for Advanced and Innovative Medicine, Shenzhen, China.
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Shafique S, Ali SR, Rajput SN, Salim A, Khan I. Cardiac Transcription Regulators Differentiate Human Umbilical Cord Mesenchymal Stem Cells into Cardiac Cells. Altern Lab Anim 2023; 51:12-29. [PMID: 36484201 DOI: 10.1177/02611929221143774] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Stem cell-based therapy presents an attractive alternative to conventional therapies for degenerative diseases. Numerous studies have investigated the capability of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) to contribute to the regeneration of cardiomyocytes, and the results have encouraged further basic and clinical studies on the MSC-based treatment of cardiomyopathies. This study aimed to determine the potential of cardiomyogenic transcription factors in differentiating hUC-MSCs into cardiac-like cells in vitro. MSCs were isolated from umbilical cord tissue and were transduced with the transcription factor genes, GATA-4 and Nkx 2.5, via infection with lentiviruses, to promote differentiation into the cardiomyogenic lineage. Gene and protein expression were analysed with qPCR and immunocytochemical staining. After transduction, differentiated cardiac-like cells showed significant expression of cardiac genes and proteins, namely GATA-4, Nkx-2.5, cardiac troponin I (cTnI) and myosin heavy chain (MHC). The cardiomyogenic-induced group significantly overexpressed cardiac-specific genes (GATA-4, Nkx-2.5, cTnI, MHC, α-actinin and Wnt2). Expression of the calcium channel gene was also significantly increased, while the sodium channel gene was downregulated in the transduced hUC-MSCs, as compared to non-transduced cells. The results suggest that GATA-4 and Nkx-2.5 interact synergistically in the activation of downstream cardiac transcription factors, demonstrating the functional convergence of hUC-MSC differentiation into cardiac-like cells. These findings could potentially be utilised in the efficient production of cardiac-like cells from stem cells; these cardiac-like cells could then be used in various applications, such as for in vivo implantation in infarcted myocardium, and for drug screening in toxicity testing.
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Affiliation(s)
- Shumaila Shafique
- 208246Dr Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Syeda Roohina Ali
- 208246Dr Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Shafiqa Naeem Rajput
- 208246Dr Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Asmat Salim
- 208246Dr Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Irfan Khan
- 208246Dr Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
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29
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Sadeghi B, Ringdén O, Gustafsson B, Castegren M. Mesenchymal stromal cells as treatment for acute respiratory distress syndrome. Case Reports following hematopoietic cell transplantation and a review. Front Immunol 2022; 13:963445. [PMID: 36426365 PMCID: PMC9680556 DOI: 10.3389/fimmu.2022.963445] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 10/18/2022] [Indexed: 11/09/2022] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a life-threatening lung disease. It may occur during the pancytopenia phase following allogeneic hematopoietic cell transplantation (HCT). ARDS is rare following HCT. Mesenchymal stromal cells (MSCs) have strong anti-inflammatory effect and first home to the lung following intravenous infusion. MSCs are safe to infuse and have almost no side effects. During the Covid-19 pandemic many patients died from ARDS. Subsequently MSCs were evaluated as a therapy for Covid-19 induced ARDS. We report three patients, who were treated with MSCs for ARDS following HCT. Two were treated with MSCs derived from the bone marrow (BM). The third patient was treated with MSCs obtained from the placenta, so-called decidua stromal cells (DSCs). In the first patient, the pulmonary infiltrates cleared after infusion of BM-MSCs, but he died from multiorgan failure. The second patient treated with BM-MSCs died of aspergillus infection. The patient treated with DSCs had a dramatic response and survived. He is alive after 7 years with a Karnofsky score of 100%. We also reviewed experimental and clinical studies using MSCs or DSCs for ARDS. Several positive reports are using MSCs for sepsis and ARDS in experimental animals. In man, two prospective randomized placebo-controlled studies used adipose and BM-MSCs, respectively. No difference in outcome was seen compared to placebo. Some pilot studies used MSCs for Covid-19 ARDS. Positive results were achieved using umbilical cord and DSCs however, optimal source of MSCs remains to be elucidated using randomized trials.
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Affiliation(s)
- Behnam Sadeghi
- Translational Cell Therapy Research (TCR), Division of Paediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- *Correspondence: Behnam Sadeghi,
| | - Olle Ringdén
- Translational Cell Therapy Research (TCR), Division of Paediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Britt Gustafsson
- Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
| | - Markus Castegren
- Center for Clinical Research, Sörmland, Uppsala University, Uppsala, Sweden
- Department of Anesthesiology and Intensive Care, CLINTEC, Karolinska Institutet, Stockholm, Sweden
- Section of Infectious Diseases, Department of Medical Science, Uppsala University, Uppsala, Sweden
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30
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Chetty S, Yarani R, Swaminathan G, Primavera R, Regmi S, Rai S, Zhong J, Ganguly A, Thakor AS. Umbilical cord mesenchymal stromal cells-from bench to bedside. Front Cell Dev Biol 2022; 10:1006295. [PMID: 36313578 PMCID: PMC9597686 DOI: 10.3389/fcell.2022.1006295] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 09/27/2022] [Indexed: 11/27/2022] Open
Abstract
In recent years, mesenchymal stromal cells (MSCs) have generated a lot of attention due to their paracrine and immuno-modulatory properties. mesenchymal stromal cells derived from the umbilical cord (UC) are becoming increasingly recognized as having increased therapeutic potential when compared to mesenchymal stromal cells from other sources. The purpose of this review is to provide an overview of the various compartments of umbilical cord tissue from which mesenchymal stromal cells can be isolated, the differences and similarities with respect to their regenerative and immuno-modulatory properties, as well as the single cell transcriptomic profiles of in vitro expanded and freshly isolated umbilical cord-mesenchymal stromal cells. In addition, we discuss the therapeutic potential and biodistribution of umbilical cord-mesenchymal stromal cells following systemic administration while providing an overview of pre-clinical and clinical trials involving umbilical cord-mesenchymal stromal cells and their associated secretome and extracellular vesicles (EVs). The clinical applications of umbilical cord-mesenchymal stromal cells are also discussed, especially in relation to obstacles and potential solutions for their effective translation from bench to bedside.
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Affiliation(s)
- Shashank Chetty
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
| | - Reza Yarani
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
- Translational Type 1 Diabetes Research, Department of Clinical, Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Ganesh Swaminathan
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
| | - Rosita Primavera
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
| | - Shobha Regmi
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
| | - Sravanthi Rai
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
| | - Jim Zhong
- Department of Diagnostic and Interventional Radiology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Abantika Ganguly
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
| | - Avnesh S Thakor
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
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31
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Asgari Taei A, Khodabakhsh P, Nasoohi S, Farahmandfar M, Dargahi L. Paracrine Effects of Mesenchymal Stem Cells in Ischemic Stroke: Opportunities and Challenges. Mol Neurobiol 2022; 59:6281-6306. [PMID: 35922728 DOI: 10.1007/s12035-022-02967-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 07/17/2022] [Indexed: 10/16/2022]
Abstract
It is well acknowledged that neuroprotective effects of transplanted mesenchymal stem cells (MSCs) in ischemic stroke are attributed to their paracrine-mediated actions or bystander effects rather than to cell replacement in infarcted areas. This therapeutic plasticity is due to MSCs' ability to secrete a broad range of bioactive molecules including growth factors, trophic factors, cytokines, chemokines, and extracellular vesicles, overall known as the secretome. The secretome derivatives, such as conditioned medium (CM) or purified extracellular vesicles (EVs), exert remarkable advantages over MSC transplantation in stroke treating. Here, in this review, we used published information to provide an overview on the secretome composition of MSCs, underlying mechanisms of therapeutic effects of MSCs, and preclinical studies on MSC-derived products application in stroke. Furthermore, we discussed current advantages and challenges for successful bench-to-bedside translation.
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Affiliation(s)
- Afsaneh Asgari Taei
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pariya Khodabakhsh
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sanaz Nasoohi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Farahmandfar
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Leila Dargahi
- Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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32
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de Souza Dobuchak D, Stricker PEF, de Oliveira NB, Mogharbel BF, da Rosa NN, Dziedzic DSM, Irioda AC, Athayde Teixeira de Carvalho K. The Neural Multilineage Differentiation Capacity of Human Neural Precursors from the Umbilical Cord-Ready to Bench for Clinical Trials. MEMBRANES 2022; 12:873. [PMID: 36135892 PMCID: PMC9500740 DOI: 10.3390/membranes12090873] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/03/2022] [Accepted: 09/07/2022] [Indexed: 06/16/2023]
Abstract
Mesenchymal stem cells (MSC) are promising for regenerative medicine as they have a vast differentiation capacity, immunomodulatory properties and can be isolated from different tissues. Among them, the umbilical cord is considered a good source of MSC, as its collection poses no risk to donors and is unrelated to ethical issues. Furthermore, umbilical cord mesenchymal stem cells (UC-MSC) can differentiate into several cell lines, including neural lineages that, in the future, may become an alternative in the treatment of neurodegenerative diseases. This study used a natural functional biopolymer matrix (NFBX) as a membrane to differentiate UC-MSC into neurospheres and their Neural precursors without using neurogenic growth factors or gene transfection. Through the characterization of Neural precursors and differentiated cells, it was possible to demonstrate the broad potential for the differentiation of cells obtained through cultivation on this membrane. To demonstrate these Neural precursors' potential for future studies in neurodegenerative diseases, the Neural precursors from Wharton's jelly were differentiated into Schwann cells, oligodendrocytes, cholinergic-, dopaminergic- and GABAergic-like neurons.
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33
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Tian Y, Fang J, Zeng F, Chen Y, Pei Y, Gu F, Ding C, Niu G, Gu B. The role of hypoxic mesenchymal stem cells in tumor immunity. Int Immunopharmacol 2022; 112:109172. [PMID: 36087506 DOI: 10.1016/j.intimp.2022.109172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 08/06/2022] [Accepted: 08/14/2022] [Indexed: 11/09/2022]
Abstract
The emerging evidence has shown that mesenchymal stem cells (MSCs) not only exert a significant role in the occurrence and development of tumors, but also have immunosuppressive potential in tumor immunity. Hypoxia is a sign of solid tumors, but how functions of hypoxic MSCs alter in the tumor microenvironment (TME) remains less well and comprehensively described. Herein, we mostly describe and investigate recent advances in our comprehension of the emerging effects of different tissue derived MSCs in hypoxia condition on tumor progression and development, as well as bidirectional influence between hypoxic MSCs and immune cells of the TME. Furthermore, we also discuss the potential drug-resistant and therapeutic role of hypoxic MSCs. It can be envisaged that novel and profound insights into the functionality of hypoxic MSCs and the underlying mechanisms in tumor and tumor immunity will promote the meaningful and promising treatment strategies against tumor.
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Affiliation(s)
- Yiqing Tian
- Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu, PR China
| | - Jian Fang
- The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei 230022, Anhui, PR China
| | - Fanpeng Zeng
- Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu, PR China
| | - Yongqiang Chen
- Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu, PR China
| | - Yunfeng Pei
- Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu, PR China
| | - Feng Gu
- Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu, PR China
| | - Chen Ding
- Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu, PR China.
| | - Guoping Niu
- Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu, PR China.
| | - Bing Gu
- Laboratory Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510000, PR China.
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34
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Luo Q, Tang Y, Jiang Z, Bao H, Fu Q, Zhang H. hUCMSCs reduce theca interstitial cells apoptosis and restore ovarian function in premature ovarian insufficiency rats through regulating NR4A1-mediated mitochondrial mechanisms. Reprod Biol Endocrinol 2022; 20:125. [PMID: 35986315 PMCID: PMC9389823 DOI: 10.1186/s12958-022-00992-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 08/03/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Human umbilical cord mesenchymal stem cells (hUCMSCs, retrospectively registered) have a lot of promise for treating theca interstitial cells(TICs) dysfunction in premature ovarian insufficiency (POI). The mechanisms, however, are still unknown. METHODS To examine the therapeutic and find the cause, we used both in vivo cisplatin-induced POI rat model and in vitro TICs model. HUCMSCs were injected into the tail veins of POI rats in an in vivo investigation. Then, using ELISA, HE staining, TUNEL apoptosis test kit, immunohistochemistry and western blot, researchers examined hormonal levels, ovarian morphology, TICs apoptosis, NR4A1 and Cyp17a1 in response to cisplatin treatment and hUCMSCs. TICs were obtained from the ovaries of rats and treated with the cisplatin, hUCMSCs supernatant, and the antagonist of NR4A1--DIM-C-pPhOH. ELISA, immunofluorescence, flow cytometry, JC-1 labeling and western blot analysis were used to detect T levels, Cyp17a1, NR4A1, and the anti-apoptotic protein Bcl-2, as well as pro-apoptotic proteins Bax, caspase-9, caspase-3, and cytochrome C(cytc). RESULTS We discovered that hUCMSCs restored the ovarian function, particularly TICs function based on measures of Cyp17a1 and T expression. NR4A1 was found in ovarian TICs of each group and NR4A1 expression was lower in the POI rats but higher following hUCMSCs therapy. The apoptosis of TICs generated by cisplatin was reduced after treatment with hUCMSCs. In vitro, NR4A1 was expressed in the nucleus of TICs, and NR4A1 as well as phospho-NR4A1 were decreased, following the apoptosis of TICs was emerged after cisplatin treatment. Interestingly, the localization of NR4A1 was translocated from the nucleus to the cytoplasm due to cisplatin. HUCMSCs were able to boost NR4A1 and phospho-NR4A1 expression while TICs' apoptosis and JC-1 polymorimonomor fluorescence ratios reduced. Furthermore, Bcl-2 expression dropped following cisplatin treatment, whereas Bax, cytc, caspase-9, and caspase-3 expression rose; however, hUCMSCs treatment reduced their expression. In addition, DIM-C-pPhOH had no effect on the NR4A1 expression, but it did increase the expression of apoptosis-related factors such as Bax, cytc, caspase-9, and caspase-3, causing the apoptosis of TICs. CONCLUSIONS These data show that hUCMSCs therapy improves ovarian function in POI rats by inhibiting TICs apoptosis through regulating NR4A1 -mediated mitochondrial mechanisms.
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Affiliation(s)
- Qianqian Luo
- Xu Rongxiang Regenerative Medicine Research Center, Binzhou Medical University, Yantai, 264003, Shandong, China
- Basic Medical College, Binzhou Medical University, Yantai, 264003, China
| | - Yu Tang
- Basic Medical College, Binzhou Medical University, Yantai, 264003, China
| | - Zhonglin Jiang
- Xu Rongxiang Regenerative Medicine Research Center, Binzhou Medical University, Yantai, 264003, Shandong, China
- Basic Medical College, Binzhou Medical University, Yantai, 264003, China
| | - Hongchu Bao
- Department of Clinical Medicine, Yantai Yuhuangding Hospital, Yantai, 264000, China
| | - Qiang Fu
- School of Pharmacology, Institute of Aging Medicine, Binzhou Medical University, Yantai, 264003, China.
| | - Hongqin Zhang
- Xu Rongxiang Regenerative Medicine Research Center, Binzhou Medical University, Yantai, 264003, Shandong, China.
- Basic Medical College, Binzhou Medical University, Yantai, 264003, China.
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35
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Chen J, Liu Q, He J, Li Y. Immune responses in diabetic nephropathy: Pathogenic mechanisms and therapeutic target. Front Immunol 2022; 13:958790. [PMID: 36045667 PMCID: PMC9420855 DOI: 10.3389/fimmu.2022.958790] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/28/2022] [Indexed: 11/14/2022] Open
Abstract
Diabetic nephropathy (DN) is a chronic, inflammatory disease affecting millions of diabetic patients worldwide. DN is associated with proteinuria and progressive slowing of glomerular filtration, which often leads to end-stage kidney diseases. Due to the complexity of this metabolic disorder and lack of clarity about its pathogenesis, it is often more difficult to diagnose and treat than other kidney diseases. Recent studies have highlighted that the immune system can inadvertently contribute to DN pathogenesis. Cells involved in innate and adaptive immune responses can target the kidney due to increased expression of immune-related localization factors. Immune cells then activate a pro-inflammatory response involving the release of autocrine and paracrine factors, which further amplify inflammation and damage the kidney. Consequently, strategies to treat DN by targeting the immune responses are currently under study. In light of the steady rise in DN incidence, this timely review summarizes the latest findings about the role of the immune system in the pathogenesis of DN and discusses promising preclinical and clinical therapies.
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Affiliation(s)
| | | | - Jinhan He
- *Correspondence: Jinhan He, ; Yanping Li,
| | - Yanping Li
- *Correspondence: Jinhan He, ; Yanping Li,
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36
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Vinukonda G, La Gamma EF. Emerging therapies for brain recovery after IVH in neonates: Cord blood derived Mesenchymal Stem Cells (MSC) and Unrestricted Somatic Stem Cells (USSC). Semin Perinatol 2022; 46:151598. [PMID: 35589461 DOI: 10.1016/j.semperi.2022.151598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
In this report, we summarize evidence on mechanisms of injury after intraventricular hemorrhage resulting in post-hemorrhagic white matter injury and hydrocephalus and correlate that with the possibility of cellular therapy. We describe how two stem cell lines (MSC & USSC) acting in a paracrine fashion offer promise for attenuating the magnitude of injury in animal models and for improved functional recovery by: lowering the magnitude of apoptosis and neuronal cell death, reducing inflammation, and thus, mitigating white matter injury that culminates in improved motor and neurocognitive outcomes. Animal models of IVH are analyzed for their similarity to the human condition and we discuss merits of each approach. Studies on stem cell therapy for IVH in human neonates is described. Lastly, we offer suggestions on what future studies are needed to better understand mechanisms of injury and recovery and argue that human trials need to be expanded in parallel to animal research.
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Affiliation(s)
- Govindaiah Vinukonda
- Department of Pediatrics, Cell Biology & Anatomy New York Medical College, Valhalla, NY
| | - Edmund F La Gamma
- Department of Pediatrics, Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY.
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The microenvironment of silk/gelatin nanofibrous scaffold improves proliferation and differentiation of Wharton's jelly-derived mesenchymal cells into islet-like cells. Gene 2022; 833:146586. [PMID: 35597530 DOI: 10.1016/j.gene.2022.146586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 05/03/2022] [Accepted: 05/16/2022] [Indexed: 11/22/2022]
Abstract
The use of umbilical cord-derived mesenchymal stem cells along with three-dimensional (3D) scaffolds in pancreatic tissue engineering can be considered as a treatment for diabetes. This study aimed to investigate the differentiation of Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) into pancreatic islet-insulin producing cells (IPCs) on silk/gelatin nanofibers as a 3D scaffold. Mesenchymal markers were evaluated at the mesenchymal stem cells (MSCs) level by flow cytometry. WJ-MSCs were then cultured on 3D scaffolds and treated with a differential medium. Immunocytochemical assays showed efficient differentiation of WJ-MSCs into IPCs. Also, Real-time PCR results showed a significant increase in the expression of pancreatic genes in the 3D culture group compared to the two-dimensional (2D) culture group. Despite these cases, the secretion of insulin and C-peptide in response to different concentrations of glucose in the 3D group was significantly higher than in the 2D culture. The results of our study showed that silk/gelatin scaffold with WJ-MSCs could be a good option in the production of IPCs in regenerative medicine and pancreatic tissue engineering.
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38
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Zhou JF, Xiong Y, Kang X, Pan Z, Zhu Q, Goldbrunner R, Stavrinou L, Lin S, Hu W, Zheng F, Stavrinou P. Application of stem cells and exosomes in the treatment of intracerebral hemorrhage: an update. Stem Cell Res Ther 2022; 13:281. [PMID: 35765072 PMCID: PMC9241288 DOI: 10.1186/s13287-022-02965-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 06/19/2022] [Indexed: 12/14/2022] Open
Abstract
Non-traumatic intracerebral hemorrhage is a highly destructive intracranial disease with high mortality and morbidity rates. The main risk factors for cerebral hemorrhage include hypertension, amyloidosis, vasculitis, drug abuse, coagulation dysfunction, and genetic factors. Clinically, surviving patients with intracerebral hemorrhage exhibit different degrees of neurological deficits after discharge. In recent years, with the development of regenerative medicine, an increasing number of researchers have begun to pay attention to stem cell and exosome therapy as a new method for the treatment of intracerebral hemorrhage, owing to their intrinsic potential in neuroprotection and neurorestoration. Many animal studies have shown that stem cells can directly or indirectly participate in the treatment of intracerebral hemorrhage through regeneration, differentiation, or secretion. However, considering the uncertainty of its safety and efficacy, clinical studies are still lacking. This article reviews the treatment of intracerebral hemorrhage using stem cells and exosomes from both preclinical and clinical studies and summarizes the possible mechanisms of stem cell therapy. This review aims to provide a reference for future research and new strategies for clinical treatment.
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Affiliation(s)
- Jian-Feng Zhou
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Yu Xiong
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Xiaodong Kang
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Zhigang Pan
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Qiangbin Zhu
- Department of Neurosurgery, Hui'an County Hospital of Fujian Province, Quanzhou, Fujian, China
| | - Roland Goldbrunner
- Department of Neurosurgery, Faculty of Medicine and University Hospital, Center for Neurosurgery, University of Cologne, Cologne, Germany
| | - Lampis Stavrinou
- 2nd Department of Neurosurgery, Athens Medical School, "Attikon" University Hospital, National and Kapodistrian University, Athens, Greece
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China. .,Diabetes and Metabolism Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia.
| | - Weipeng Hu
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China.
| | - Feng Zheng
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China.
| | - Pantelis Stavrinou
- Department of Neurosurgery, Faculty of Medicine and University Hospital, Center for Neurosurgery, University of Cologne, Cologne, Germany.,Neurosurgery, Metropolitan Hospital, Athens, Greece
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Human Amniotic Fluid Stem Cells Ameliorate Thioglycollate-Induced Peritonitis by Increasing Tregs in Mice. Int J Mol Sci 2022; 23:ijms23126433. [PMID: 35742877 PMCID: PMC9224120 DOI: 10.3390/ijms23126433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 06/06/2022] [Accepted: 06/07/2022] [Indexed: 11/16/2022] Open
Abstract
Mesenchymal stem cells (MSCs) affect immune cells and exert anti-inflammatory effects. Human amniotic fluid stem cells (hAFSCs), a type of MSCs, have a high therapeutic effect in animal models of inflammation-related diseases. hAFSCs can be easily isolated and cultured from amniotic fluid, which is considered a medical waste. Hence, amniotic fluid can be a source of cells for MSC therapy of inflammatory diseases. However, the effect of hAFSCs on acquired immunity in vivo, especially on regulatory T cells, has not yet been fully elucidated. Therefore, in this study, we aimed to understand the effects of hAFSCs on acquired immunity, particularly on regulatory T cells. We showed that hAFSCs ameliorated the thioglycollate-induced inflammation by forming aggregates with host immune cells, such as macrophages, T cells, and B cells in the peritoneal cavity. Further, the regulatory T cells increased in the peritoneal cavity. These results indicated that, in addition to helping the innate immunity, hAFSCs could also aid the acquired immune system in vivo against inflammation-related diseases by increasing regulatory T cells.
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Kay AG, Fox JM, Hewitson JP, Stone AP, Robertson S, James S, Wang XN, Kapasa E, Yang XB, Genever PG. CD317-Positive Immune Stromal Cells in Human "Mesenchymal Stem Cell" Populations. Front Immunol 2022; 13:903796. [PMID: 35734183 PMCID: PMC9207511 DOI: 10.3389/fimmu.2022.903796] [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: 03/24/2022] [Accepted: 05/04/2022] [Indexed: 12/31/2022] Open
Abstract
Heterogeneity of bone marrow mesenchymal stromal cells (MSCs, frequently referred to as "mesenchymal stem cells") clouds biological understanding and hampers their clinical development. In MSC cultures most commonly used in research and therapy, we have identified an MSC subtype characterized by CD317 expression (CD317pos (29.77 ± 3.00% of the total MSC population), comprising CD317dim (28.10 ± 4.60%) and CD317bright (1.67 ± 0.58%) MSCs) and a constitutive interferon signature linked to human disease. We demonstrate that CD317pos MSCs induced cutaneous tissue damage when applied a skin explant model of inflammation, whereas CD317neg MSCs had no effect. Only CD317neg MSCs were able to suppress proliferative cycles of activated human T cells in vitro, whilst CD317pos MSCs increased polarization towards pro-inflammatory Th1 cells and CD317neg cell lines did not. Using an in vivo peritonitis model, we found that CD317neg and CD317pos MSCs suppressed leukocyte recruitment but only CD317neg MSCs suppressed macrophage numbers. Using MSC-loaded scaffolds implanted subcutaneously in immunocompromised mice we were able to observe tissue generation and blood vessel formation with CD317neg MSC lines, but not CD317pos MSC lines. Our evidence is consistent with the identification of an immune stromal cell, which is likely to contribute to specific physiological and pathological functions and influence clinical outcome of therapeutic MSCs.
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Affiliation(s)
- Alasdair G. Kay
- York Biomedical Research Institute and Department of Biology, University of York, York, United Kingdom,*Correspondence: Paul G. Genever, ; Alasdair G. Kay,
| | - James M. Fox
- York Biomedical Research Institute and Department of Biology, University of York, York, United Kingdom
| | - James P. Hewitson
- York Biomedical Research Institute and Department of Biology, University of York, York, United Kingdom
| | - Andrew P. Stone
- York Biomedical Research Institute and Department of Biology, University of York, York, United Kingdom
| | - Sophie Robertson
- York Biomedical Research Institute and Department of Biology, University of York, York, United Kingdom
| | - Sally James
- York Biomedical Research Institute and Department of Biology, University of York, York, United Kingdom
| | - Xiao-nong Wang
- Translational and Clinical Research Institute, Newcastle University, Newcastle, United Kingdom
| | - Elizabeth Kapasa
- Department of Oral Biology, School of Dentistry, University of Leeds, St James’s University Hospital, Leeds, United Kingdom
| | - Xuebin B. Yang
- Department of Oral Biology, School of Dentistry, University of Leeds, St James’s University Hospital, Leeds, United Kingdom
| | - Paul G. Genever
- York Biomedical Research Institute and Department of Biology, University of York, York, United Kingdom,*Correspondence: Paul G. Genever, ; Alasdair G. Kay,
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Xie JL, Wang XR, Li MM, Tao ZH, Teng WW, Saijilafu. Mesenchymal Stromal Cell Therapy in Spinal Cord Injury: Mechanisms and Prospects. Front Cell Neurosci 2022; 16:862673. [PMID: 35722621 PMCID: PMC9204037 DOI: 10.3389/fncel.2022.862673] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 05/09/2022] [Indexed: 12/13/2022] Open
Abstract
Spinal cord injury (SCI) often leads to severe motor, sensory, and autonomic dysfunction in patients and imposes a huge economic cost to individuals and society. Due to its complicated pathophysiological mechanism, there is not yet an optimal treatment available for SCI. Mesenchymal stromal cells (MSCs) are promising candidate transplant cells for use in SCI treatment. The multipotency of MSCs, as well as their rich trophic and immunomodulatory abilities through paracrine signaling, are expected to play an important role in neural repair. At the same time, the simplicity of MSCs isolation and culture and the bypassing of ethical barriers to stem cell transplantation make them more attractive. However, the MSCs concept has evolved in a specific research context to encompass different populations of cells with a variety of biological characteristics, and failure to understand this can undermine the quality of research in the field. Here, we review the development of the concept of MSCs in order to clarify misconceptions and discuss the controversy in MSCs neural differentiation. We also summarize a potential role of MSCs in SCI treatment, including their migration and trophic and immunomodulatory effects, and their ability to relieve neuropathic pain, and we also highlight directions for future research.
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Affiliation(s)
- Ji-Le Xie
- Department of Orthopaedics, The First Affiliated Hospital, Soochow University, Suzhou, China,Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Xing-Ran Wang
- Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Mei-Mei Li
- Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Zi-Han Tao
- Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Wen-Wen Teng
- Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Saijilafu
- Department of Orthopaedics, The First Affiliated Hospital, Soochow University, Suzhou, China,Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China,*Correspondence: Saijilafu,
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Yang Y, Liu S, He C, Lv T, Zeng L, Zhang F, Chen H, Zhao RC. LncRNA LYPLAL1-AS1 rejuvenates human adipose-derived mesenchymal stem cell senescence via transcriptional MIRLET7B inactivation. Cell Biosci 2022; 12:45. [PMID: 35449031 PMCID: PMC9022335 DOI: 10.1186/s13578-022-00782-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 03/31/2022] [Indexed: 12/12/2022] Open
Abstract
Background Mesenchymal stem cell (MSC) senescence is a phenotype of aging. Long noncoding RNAs (lncRNAs) are emerging as potential key regulators of senescence. However, the role of lncRNAs in MSC senescence remains largely unknown. Results We performed transcriptome analysis in senescent human adipose-derived MSCs (hADSCs) and identified that the lncRNA LYPLAL1 antisense RNA1 (LYPLAL1-AS1) was significantly downregulated in senescent hADSCs. LYPLAL1-AS1 expression in peripheral blood was lower in middle-aged healthy donors than in young adult donors, and correlated negatively with age. Knockdown of LYPLAL1-AS1 accelerated hADSC senescence, while LYPLAL1-AS1 overexpression attenuated it. Chromatin isolation by RNA purification (ChIRP) sequencing indicated that LYPLAL1-AS1 bound to the MIRLET7B promoter region and suppressed its transcription activity, as demonstrated by dual-luciferase assay. miR-let-7b, the transcript of MIRLET7B, was upregulated during hADSC senescence and was regulated by LYPLAL1-AS1. Furthermore, miR-let-7b mimics promoted hADSC senescence, while the inhibitors repressed it. Finally, LYPLAL1-AS1 overexpression reversed miR-let-7b-induced hADSC senescence. Conclusions Our data demonstrate that LYPLAL1-AS1 rejuvenates hADSCs through the transcriptional inhibition of MIRLET7B. Our work provides new insights into the mechanism of MSC senescence and indicates lncRNA LYPLAL1-AS1 and miR-let-7b as potential therapeutic targets in aging. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-022-00782-x.
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Affiliation(s)
- Yanlei Yang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, China.,Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing Key Laboratory (No. BZO381), Beijing, China
| | - Suying Liu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, China
| | - Chengmei He
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, China
| | - Taibiao Lv
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, China
| | - Liuting Zeng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, China
| | - Fengchun Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, China.
| | - Hua Chen
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, China.
| | - Robert Chunhua Zhao
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing Key Laboratory (No. BZO381), Beijing, China. .,School of Life Sciences, Shanghai University, Shanghai, China.
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Li J, Wang Q, An Y, Chen X, Xing Y, Deng Q, Li Z, Wang S, Dai X, Liang N, Hou Y, Yang H, Shang Z. Integrative Single-Cell RNA-Seq and ATAC-Seq Analysis of Mesenchymal Stem/Stromal Cells Derived from Human Placenta. Front Cell Dev Biol 2022; 10:836887. [PMID: 35450295 PMCID: PMC9017713 DOI: 10.3389/fcell.2022.836887] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/09/2022] [Indexed: 12/20/2022] Open
Abstract
Mesenchymal stem/stromal cells derived from placenta (PMSCs) are an attractive source for regenerative medicine because of their multidifferentiation potential and immunomodulatory capabilities. However, the cellular and molecular heterogeneity of PMSCs has not been fully characterized. Here, we applied single-cell RNA sequencing (scRNA-seq) and assay for transposase-accessible chromatin sequencing (scATAC-seq) techniques to cultured PMSCs from human full-term placenta. Based on the inferred characteristics of cell clusters, we identify several distinct subsets of PMSCs with specific characteristics, including immunomodulatory-potential and highly proliferative cell states. Furthermore, integrative analysis of gene expression and chromatin accessibility showed a clearer chromatin accessibility signature than those at the transcriptional level on immunomodulatory-related genes. Cell cycle gene-related heterogeneity can be more easily distinguished at the transcriptional than the chromatin accessibility level in PMSCs. We further reveal putative subset-specific cis-regulatory elements regulating the expression of immunomodulatory- and proliferation-related genes in the immunomodulatory-potential and proliferative subpopulations, respectively. Moreover, we infer a novel transcription factor PRDM1, which might play a crucial role in maintaining immunomodulatory capability by activating PRDM1-regulon loop. Collectively, our study first provides a comprehensive and integrative view of the transcriptomic and epigenomic features of PMSCs, which paves the way for a deeper understanding of cellular heterogeneity and offers fundamental biological insight of PMSC subset-based cell therapy.
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Affiliation(s)
- Jinlu Li
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
| | - Quanlei Wang
- BGI-Shenzhen, Shenzhen, China
- Key Laboratory of Regenerative Medicine of Ministry of Education, Biology Postdoctoral Research Station, Jinan University, Guangzhou, China
| | | | | | - Yanan Xing
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
| | - Qiuting Deng
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
| | - Zelong Li
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
| | - Shengpeng Wang
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
| | - Xi Dai
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
| | | | | | - Huanming Yang
- BGI-Shenzhen, Shenzhen, China
- James D. Watson Institute of Genome Sciences, Hangzhou, China
| | - Zhouchun Shang
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
- BGI College, Northwest University, Xi’an, China
- *Correspondence: Zhouchun Shang,
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Abstract
Human mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells or medicinal signaling cells, are important adult stem cells for regenerative medicine, largely due to their regenerative characteristics such as self-renewal, secretion of trophic factors, and the capability of inducing mesenchymal cell lineages. MSCs also possess homing and trophic properties modulating immune system, influencing microenvironment around damaged tissues and enhancing tissue repair, thus offering a broad perspective in cell-based therapies. Therefore, it is not surprising that MSCs have been the broadly used adult stem cells in clinical trials. To gain better insights into the current applications of MSCs in clinical applications, we perform a comprehensive review of reported data of MSCs clinical trials conducted globally. We summarize the biological effects and mechanisms of action of MSCs, elucidating recent clinical trials phases and findings, highlighting therapeutic effects of MSCs in several representative diseases, including neurological, musculoskeletal diseases and most recent Coronavirus infectious disease. Finally, we also highlight the challenges faced by many clinical trials and propose potential solutions to streamline the use of MSCs in routine clinical applications and regenerative medicine.
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Zheng X, Gan S, Su C, Zheng Z, Liao Y, Shao J, Zhu Z, Chen W. Screening and preliminary identification of long non-coding RNAs critical for osteogenic differentiation of human umbilical cord mesenchymal stem cells. Bioengineered 2022; 13:6880-6894. [PMID: 35249446 PMCID: PMC8973756 DOI: 10.1080/21655979.2022.2044274] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Human umbilical cord mesenchymal stem cells (hUCMSCs) are attractive therapeutic cells for tissue engineering to treat bone defects. However, how the cells can differentiate into bone remains unclear. Long non-coding RNAs (lncRNAs) are non-coding RNAs that participate in many biological processes, including stem cell differentiation. In this study, we investigated the profiles and functions of lncRNAs in the osteogenic differentiation of hUCMSCs. We identified 343 lncRNAs differentially expressed during osteogenic differentiation, of which 115 were upregulated and 228 were downregulated. We further analyzed these lncRNAs using bioinformatic analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. GO and KEGG pathway analysis showed that ‘intracellular part’ and ‘Phosphatidylinositol signaling system’ were the most correlated molecular function and pathway, respectively. We selected the top 10 upregulated lncRNAs to construct six competing endogenous RNA networks. We validated the impact of the lncRNA H19 on osteogenic differentiation by overexpressing it in hUCMSCs. Overall, our results pave the way to detailed studies of the molecular mechanisms of hUCMSC osteogenic differentiation, and they provide a new theoretical basis to guide the therapeutic application of hUCMSCs.
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Affiliation(s)
- Xiao Zheng
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Pediatric Dentistry, Shenzhen Stomatology Hospital (Pingshan), Southern Medical University, Shenzhen, Guangdong, China
| | - Shuaiqi Gan
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Cheng Su
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Zheng Zheng
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yihan Liao
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Jingjing Shao
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Zhimin Zhu
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Wenchuan Chen
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.,Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
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Wu M, Chen L, Qi Y, Ci H, Mou S, Yang J, Yuan Q, Yao W, Wang Z, Sun J. Human umbilical cord mesenchymal stem cell promotes angiogenesis via integrin β1/ERK1/2/HIF-1α/VEGF-A signaling pathway for off-the-shelf breast tissue engineering. Stem Cell Res Ther 2022; 13:99. [PMID: 35255978 PMCID: PMC8900416 DOI: 10.1186/s13287-022-02770-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 01/24/2022] [Indexed: 01/02/2023] Open
Abstract
Background Mesenchymal stem cells (MSC)-based tissue engineered breast represent the visible future for breast reconstruction after mastectomy. However, autologous MSCs might not be appropriate for the large graft construction due to cell senescence during excessive cell expansion, thus hindering its further off-the-shelf application. The human umbilical cord mesenchymal stem cells (hUCMSCs) have been found to induce low immune response and can be easily stored, making them ideal for off-the-shelf tissue engineering application. Here, we explored the feasibility of using umbilical cord mesenchymal stem cells as tissue-engineered breast seed cells.
Methods The allogenic hUCMSCs were injected into transplanted fat tissue with or without breast scaffolds as an alternative for breast tissue engineering in vivo, and its potential mechanism of angiogenesis in vitro was explored. Results Transplantation of hUCMSCs promoted proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs) through paracrine mechanism by activating the integrin β1/ERK1/2/HIF-1α/VEGF-A signaling pathway. Histological examination of grafted fat revealed that the group which received hUCMSCs transplantation had more fat tissue [(93.60 ± 2.40) %] and fewer MAC2+CD206− M1 macrophages [(0.50 ± 0.47) cells/field] compared to the control group [fat tissue (45.42 ± 5.96) and macrophage cells/field (5.00 ± 2.23)]. Moreover, the hUCMSCs- labeled with a tracing dye differentiated into adipocytes and vascular endothelial cells in the adipose tissue. When applied to the tissue-engineered breast with a scaffold, the group treated with hUCMSCs had more adipose tissues and CD31+ cells than the control group. Conclusions These results demonstrate that allogeneic hUCMSCs promote the regeneration of adipose tissue and can be used to construct a tissue engineered breast. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02770-x.
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Affiliation(s)
- Mian Wu
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.,Department of Thyroid and Breast Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, People's Republic of China
| | - Lifeng Chen
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.,Wuhan Clinical Research Center for Superficial Organ Reconstruction, Wuhan, 430022, People's Republic of China
| | - Yuhan Qi
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Hai Ci
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.,Wuhan Clinical Research Center for Superficial Organ Reconstruction, Wuhan, 430022, People's Republic of China
| | - Shan Mou
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.,Wuhan Clinical Research Center for Superficial Organ Reconstruction, Wuhan, 430022, People's Republic of China
| | - Jie Yang
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.,Wuhan Clinical Research Center for Superficial Organ Reconstruction, Wuhan, 430022, People's Republic of China
| | - Qiaoyu Yuan
- Wuhan Optics Valley Zhongyuan Concord Cell Gene Technology Co., Ltd, Wuhan, People's Republic of China
| | - Weiqi Yao
- National Industrial Base for Stem Cell Engineering Products, Tianjin, People's Republic of China.,Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, People's Republic of China
| | - Zhenxing Wang
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China. .,Wuhan Clinical Research Center for Superficial Organ Reconstruction, Wuhan, 430022, People's Republic of China.
| | - Jiaming Sun
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China. .,Wuhan Clinical Research Center for Superficial Organ Reconstruction, Wuhan, 430022, People's Republic of China.
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Yoshimi R, Nakajima H. Current State and Issues of Regenerative Medicine for Rheumatic Diseases. Front Med (Lausanne) 2022; 9:813952. [PMID: 35155499 PMCID: PMC8831787 DOI: 10.3389/fmed.2022.813952] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 01/05/2022] [Indexed: 12/15/2022] Open
Abstract
The prognosis of rheumatic diseases is generally better than that of malignant diseases. However, some cases with poor prognoses resist conventional therapies and cause irreversible functional and organ damage. In recent years, there has been much research on regenerative medicine, which uses stem cells to restore the function of missing or dysfunctional tissues and organs. The development of regenerative medicine is also being attempted in rheumatic diseases. In diseases such as systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and rheumatoid arthritis, hematopoietic stem cell transplantation has been attempted to correct and reconstruct abnormalities in the immune system. Mesenchymal stem cells (MSCs) have also been tried for the treatment of refractory skin ulcers in SSc using the ability of MSCs to differentiate into vascular endothelial cells and for the treatment of systemic lupus erythematosus SLE using the immunosuppressive effect of MSCs. CD34-positive endothelial progenitor cells (EPCs), which are found in the mononuclear cell fraction of bone marrow and peripheral blood, can differentiate into vascular endothelial cells at the site of ischemia. Therefore, EPCs have been used in research on vascular regeneration therapy for patients with severe lower limb ischemia caused by rheumatic diseases such as SSc. Since the first report of induced pluripotent stem cells (iPSCs) in 2007, research on regenerative medicine using iPSCs has been actively conducted, and their application to rheumatic diseases is expected. However, there are many safety issues and bioethical issues involved in regenerative medicine research, and it is essential to resolve these issues for practical application and spread of regenerative medicine in the future. The environment surrounding regenerative medicine research is changing drastically, and the required expertise is becoming higher. This paper outlines the current status and challenges of regenerative medicine in rheumatic diseases.
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Mesenchymal Stem Cell-Based Therapy as a New Approach for the Treatment of Systemic Sclerosis. Clin Rev Allergy Immunol 2022; 64:284-320. [PMID: 35031958 DOI: 10.1007/s12016-021-08892-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/24/2021] [Indexed: 12/13/2022]
Abstract
Systemic sclerosis (SSc) is an intractable autoimmune disease with unmet medical needs. Conventional immunosuppressive therapies have modest efficacy and obvious side effects. Targeted therapies with small molecules and antibodies remain under investigation in small pilot studies. The major breakthrough was the development of autologous haematopoietic stem cell transplantation (AHSCT) to treat refractory SSc with rapidly progressive internal organ involvement. However, AHSCT is contraindicated in patients with advanced visceral involvement. Mesenchymal stem cells (MSCs) which are characterized by immunosuppressive, antifibrotic and proangiogenic capabilities may be a promising alternative option for the treatment of SSc. Multiple preclinical and clinical studies on the use of MSCs to treat SSc are underway. However, there are several unresolved limitations and safety concerns of MSC transplantation, such as immune rejections and risks of tumour formation, respectively. Since the major therapeutic potential of MSCs has been ascribed to their paracrine signalling, the use of MSC-derived extracellular vesicles (EVs)/secretomes/exosomes as a "cell-free" therapy might be an alternative option to circumvent the limitations of MSC-based therapies. In the present review, we overview the current knowledge regarding the therapeutic efficacy of MSCs in SSc, focusing on progresses reported in preclinical and clinical studies using MSCs, as well as challenges and future directions of MSC transplantation as a treatment option for patients with SSc.
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Galderisi U, Peluso G, Di Bernardo G. Clinical Trials Based on Mesenchymal Stromal Cells are Exponentially Increasing: Where are We in Recent Years? Stem Cell Rev Rep 2022; 18:23-36. [PMID: 34398443 PMCID: PMC8365566 DOI: 10.1007/s12015-021-10231-w] [Citation(s) in RCA: 120] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/29/2021] [Indexed: 12/16/2022]
Abstract
Mesenchymal stromal cells (MSCs), present in the stromal component of several tissues, include multipotent stem cells, progenitors, and differentiated cells. MSCs have quickly attracted considerable attention in the clinical field for their regenerative properties and their ability to promote tissue homeostasis following injury. In recent years, MSCs mainly isolated from bone marrow, adipose tissue, and umbilical cord-have been utilized in hundreds of clinical trials for the treatment of various diseases. However, in addition to some successes, MSC-based therapies have experienced several failures. The number of new trials with MSCs is exponentially growing; still, complete results are only available for a limited number of trials. This dearth does not help prevent potentially inefficacious and unnecessary clinical trials. Results from unsuccessful studies may be useful in planning new therapeutic approaches to improve clinical outcomes. In order to bolster critical analysis of trial results, we reviewed the state of art of MSC clinical trials that have been published in the last six years. Most of the 416 published trials evaluated MSCs' effectiveness in treating cardiovascular diseases, GvHD, and brain and neurological disorders, although some trials sought to treat immune system diseases and wounds and to restore tissue. We also report some unorthodox clinical trials that include unusual studies.
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Affiliation(s)
- Umberto Galderisi
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy
- Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, USA
- Genome and Stem Cell Center (GENKÖK), Erciyes University, Kayseri, Turkey
| | | | - Giovanni Di Bernardo
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy.
- Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, USA.
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Zheng S, Gao Y, Chen K, Liu Y, Xia N, Fang F. A Robust and Highly Efficient Approach for Isolation of Mesenchymal Stem Cells From Wharton's Jelly for Tissue Repair. Cell Transplant 2022; 31:9636897221084354. [PMID: 35313748 PMCID: PMC8943591 DOI: 10.1177/09636897221084354] [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] [Indexed: 11/15/2022] Open
Abstract
Mesenchymal stem cells derived from umbilical cord Wharton's Jelly (WJ-MSCs) are emerging as promising therapeutics for a variety of diseases due to their ability of regeneration and immunomodulation, and their non-tumorigenic and non-immunogenic properties. Although multiple protocols have been developed for WJ-MSC isolation, insufficient cell numbers, heterogeneous cell population, and variations in procedures between different laboratories impede further clinical applications. Here, we compared six widely used WJ-MSC isolation methods regarding cell morphology, yield, purity, proliferation rate, and differentiation potential. Based on these analyses, we identified that the inefficiency of the extracellular matrix digestion results in low cell yield. Thus, we developed a new method called "Mince-Soak-Digest (MSD)" to isolate MSCs from WJ by incorporating a soaking step to facilitate the digestion of the extracellular matrix and release of the cells. Our newly developed method generates significantly higher cell yield (4- to 10-fold higher) than six widely used methods that we tested with high purity and consistency. Importantly, by transplantation of WJ-MSCs to the rat uterus, we repair the endometrial injury and restore the fertility of the rats. In conclusion, our results provide a robust and highly efficient approach for the isolation of WJ-MSCs to restore injured tissue. The higher efficiency of MSD assures the abundance of WJ-MSCs for clinical applications. Furthermore, the reliability of MSD contributes to the standardization of WJ-MSC isolation, which eliminates the discrepancies due to isolation procedures, thus facilitating the evaluation of the efficacy of WJ-MSCs across various human clinical applications.
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Affiliation(s)
- Shengxia Zheng
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yanyan Gao
- Anhui Tianlun Infertility Specialist Hospital, Hefei, China
| | - Kai Chen
- Wannan Medical College, Wuhu, China
| | - Yusheng Liu
- Anhui Tianlun Infertility Specialist Hospital, Hefei, China
| | - Ninuo Xia
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Fang Fang
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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