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Hsiao PJ, Kao WY, Sung LC, Lin CY, Tsou LLA, Kao YH, Chou CL, Lee KT. The Role of Mesenchymal Stem Cells in Treating Diabetic Kidney Disease: Immunomodulatory Effects and Kidney Regeneration. Int J Med Sci 2025; 22:1720-1735. [PMID: 40093796 PMCID: PMC11905258 DOI: 10.7150/ijms.103806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 02/21/2025] [Indexed: 03/19/2025] Open
Abstract
Background: Diabetic kidney disease (DKD), also known as diabetic nephropathy (DN), is characterized by progressive glomerulosclerosis and chronic inflammation. The potential of mesenchymal stem cells (MSCs) in treating DKD could be explored. Methods: In this study, a streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) DKD mouse model was utilized to investigate the renoprotective potential of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) through immunohistochemical, histopathological, and biochemical analyses. Two separate experiments were conducted to assess the therapeutic efficacy of hUC-MSCs in a DN mouse model. The first experiment determined the optimal dose by assigning the body weight and food intake alterations, serum cytokines and kidney function changes post hUC-MSCs treatment. STZ-induced DKD mice were divided to four groups: DKD control and other three hUC-MSCs treatment groups (low-dose: 3x106, intermediate (middle)-dose: 1x107, and high-dose: 3x107 cells/kg), with intravenous administration at weeks 8, 10, and 12 over 14 weeks. The second experiment evaluated treatment frequency, with mice assigned to hUC-MSCs x1, x2, and x3 groups (3x107 cells/kg) administered at weeks 5, 6, and 7 across 12 weeks, assessing the kidney histology and morphometry changes. Results: In the first experiment, the body weight and food intake showed no significant alterations among the DN and other 3 hUC-MSCs treatment groups. Compared to the DKD control group, only high-dose hUC-MSCs (3x107 cells/kg) treatment group significantly reduced the levels of inflammatory cytokines (IL-1β, and TNF-α) (p <0.05). Additionally, the urine albumin-to-creatinine ratio (UACR) levels in the high-dose hUC-MSCs (3×10⁷ cells/kg) treatment group showed a decreasing trend compared to those in the DN control group (p = 0.06). In the second experiment, the hUC-MSCs x3 treatment group (3×10⁷ cells/kg) significantly alleviated kidney histopathology compared to the DKD group (p <0.05). Conclusion: hUC-MSCs treatment may present a potential avenue for reversing glomerulosclerosis and mitigating inflammation in DKD mice. The long-term therapeutic benefits of MSCs-based treatments in patients with DKD and other kidney diseases could be further investigated.
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Affiliation(s)
- Po-Jen Hsiao
- Division of Nephrology, Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defence Medical Centre, Taipei, Taiwan
- Department of Life Sciences, National Central University, Taoyuan, Taiwan
| | - Wen-Yi Kao
- Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Li-Chin Sung
- Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Taipei Medical University-Research Centre of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
| | - Chia-Yi Lin
- Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Liam Li-An Tsou
- Nephrology Division, Department of Medicine, Mount Sinai Hospital, New York, NY, USA
- Biochemistry, Department of Chemistry, Hofstra University, Hempstead, New York, USA
| | - Yung-Hsi Kao
- Department of Life Sciences, National Central University, Taoyuan, Taiwan
| | - Chu-Lin Chou
- Taipei Medical University-Research Centre of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- Division of Nephrology, Department of Internal Medicine, Hsin Kuo Min Hospital, Taipei Medical University, Taoyuan City, Taiwan
| | - Kung-Ta Lee
- Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
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Ruan MF, Yin YH, Shao XD, Qi XS. Bone marrow mesenchymal stem cell transplantation for treatment of liver cirrhosis: Recent advances. Shijie Huaren Xiaohua Zazhi 2025; 33:106-113. [DOI: 10.11569/wcjd.v33.i2.106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 01/20/2025] [Accepted: 02/20/2025] [Indexed: 02/28/2025] Open
Affiliation(s)
- Meng-Fan Ruan
- Department of Gastroenterology, General Hospital of Northern Theater Command (Teaching Hospital of Jinzhou Medical University), Shenyang 110840, Liaoning Province, China
- Postgraduate College, Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Yu-Hang Yin
- Department of Gastroenterology, General Hospital of Northern Theater Command (Teaching Hospital of Jinzhou Medical University), Shenyang 110840, Liaoning Province, China
- Postgraduate College, China Medical University, Shenyang 110122, Liaoning Province, China
| | - Xiao-Dong Shao
- Department of Gastroenterology, General Hospital of Northern Theater Command (Teaching Hospital of Jinzhou Medical University), Shenyang 110840, Liaoning Province, China
| | - Xing-Shun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command (Teaching Hospital of Jinzhou Medical University), Shenyang 110840, Liaoning Province, China
- Postgraduate College, Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
- Postgraduate College, China Medical University, Shenyang 110122, Liaoning Province, China
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Cerveró-Varona A, Prencipe G, Peserico A, Canciello A, House AH, Santos HA, Perugini M, Sulcanese L, Takano C, Miki T, Iannetta A, Russo V, Mattioli M, Barboni B. Amniotic epithelial Cell microvesicles uptake inhibits PBMCs and Jurkat cells activation by inducing mitochondria-dependent apoptosis. iScience 2025; 28:111830. [PMID: 39967871 PMCID: PMC11834128 DOI: 10.1016/j.isci.2025.111830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 10/15/2024] [Accepted: 01/15/2025] [Indexed: 02/20/2025] Open
Abstract
Amniotic epithelial cells (AECs) exhibit significant immunomodulatory and pro-regenerative properties, largely due to their intrinsic paracrine functions that are currently harnessed through the collection of their secretomes. While there is increasing evidence of the role of bioactive components freely secreted or carried by exosomes, the bioactive cargo of AEC microvesicles (MVs) and their crosstalk with the immune cells remains to be fully explored. We showed that under intrinsic conditions or in response to LPS, AEC-derived MV carries components such as lipid-mediated signaling molecules, ER, and mitochondria. They foster the intra/interspecific mitochondrial transfer into immune cells (PBMCs and Jurkat cells) in vitro and in vivo on the zebrafish larvae model of injury. The internalization of MV cargoes through macropinocytosis induces hyperpolarization of PBMC mitochondrial membranes and triggers MV-mediated apoptosis. This powerful immune suppressive mechanism triggered by AEC-MV cargo delivery paves the way for controlled and targeted cell-free therapeutic approaches.
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Affiliation(s)
- Adrián Cerveró-Varona
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Giuseppe Prencipe
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Alessia Peserico
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Angelo Canciello
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Andrew H. House
- Helsinki University Lipidomics Unit, Helsinki Institute for Life Science (HiLIFE), Biocenter 3, Viikinkaari 1, 00790 Helsinki, Finland
| | - Hélder A. Santos
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland
- Department of Biomaterials and Biomedical Technology, The Personalized Medicine Research Institute (PRECISION), University Medical Center Groningen (UMCG), University of Groningen, 9713 AV Groningen, the Netherlands
| | - Monia Perugini
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Ludovica Sulcanese
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Chika Takano
- Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan
| | - Toshio Miki
- Department of Physiology, Nihon University School of Medicine, Tokyo, Japan
| | - Annamaria Iannetta
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Valentina Russo
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Mauro Mattioli
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Barbara Barboni
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
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Teng FS, de Faria Lainetti P, Simão Franzoni M, Fernando Leis Filho A, de Oliveira Massoco Salles Gomes C, Laufer-Amorim R, Martins Amorim R, Fonseca-Alves CE. Canine Adipose-Derived Mesenchymal Stromal Cells Reduce Cell Viability and Migration of Metastatic Canine Oral Melanoma Cell Lines In Vitro. Vet Sci 2024; 11:636. [PMID: 39728976 PMCID: PMC11680336 DOI: 10.3390/vetsci11120636] [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: 11/11/2024] [Revised: 11/28/2024] [Accepted: 12/06/2024] [Indexed: 12/28/2024] Open
Abstract
Canine oral melanoma (COM) is a promising target for immunomodulatory therapies aimed at enhancing the immune system's antitumor response. Given that adipose-derived mesenchymal stem cells (Ad-MSCs) possess immunomodulatory properties through cytokine release, we hypothesized that co-culturing Ad-MSCs and canine peripheral blood mononuclear cells (PBMCs) could stimulate interleukin (IL) production against melanoma cell lines (MCCLs) and help identify therapeutic targets. This study evaluated IL-2, IL-8, and IL-12 expressions in co-culture with MCCL, Ad-MSCs, and PBMCs and assessed the relationship between gene expression, cell viability, and migration. Using four experimental groups in a Transwell insert system to separate cell types, we found that Ad-MSCs can reduce MCCL migration and viability, though the effect may vary depending on each cell line's susceptibility. Furthermore, Ad-MSCs modified IL expression profiles in co-cultured cells. Our findings suggest that Ad-MSCs could have therapeutic potential for COM by inhibiting cell migration and reducing viability. However, deeper insights into Ad-MSC interactions with the tumor microenvironment and melanoma-specific factors will be essential to optimize therapeutic efficacy.
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Affiliation(s)
- Fwu Shing Teng
- Department of Veterinary Surgery and Animal Reproduction, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu 18618-681, Brazil; (F.S.T.); (P.d.F.L.); (M.S.F.); (A.F.L.F.)
| | - Patricia de Faria Lainetti
- Department of Veterinary Surgery and Animal Reproduction, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu 18618-681, Brazil; (F.S.T.); (P.d.F.L.); (M.S.F.); (A.F.L.F.)
| | - Mayara Simão Franzoni
- Department of Veterinary Surgery and Animal Reproduction, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu 18618-681, Brazil; (F.S.T.); (P.d.F.L.); (M.S.F.); (A.F.L.F.)
| | - Antonio Fernando Leis Filho
- Department of Veterinary Surgery and Animal Reproduction, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu 18618-681, Brazil; (F.S.T.); (P.d.F.L.); (M.S.F.); (A.F.L.F.)
| | | | - Renée Laufer-Amorim
- Department of Veterinary Clinic, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu 18618-681, Brazil; (R.L.-A.); (R.M.A.)
| | - Rogério Martins Amorim
- Department of Veterinary Clinic, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu 18618-681, Brazil; (R.L.-A.); (R.M.A.)
| | - Carlos Eduardo Fonseca-Alves
- Department of Veterinary Surgery and Animal Reproduction, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu 18618-681, Brazil; (F.S.T.); (P.d.F.L.); (M.S.F.); (A.F.L.F.)
- Institute of Veterinary Oncology (IOVET), Sao Paulo 05027-020, Brazil
- Vet Precision Laboratory, Botucatu 18610-034, Brazil
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Yuan Y, Liu T. Influence of mesenchymal stem cells from different origins on the therapeutic effectiveness of systemic lupus erythematosus. Exp Cell Res 2024; 442:114263. [PMID: 39307406 DOI: 10.1016/j.yexcr.2024.114263] [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: 06/17/2024] [Revised: 08/09/2024] [Accepted: 09/19/2024] [Indexed: 11/01/2024]
Abstract
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune inflammatory disorder characterized by alterations in the balance between inflammatory and regulatory cytokines. Mesenchymal stem cells (MSCs), which are non-hematopoietic stem cells with multipotent differentiation potential, due to their immunomodulatory, tissue repair, low immunogenicity, and chemotactic properties, have garnered increasing interest in SLE treatment. Studies increasingly reveal the heterogeneous nature of MSC populations. With sources including dental pulp, adipose tissue, bone marrow, and umbilical cord, the therapeutic effects of MSCs on SLE vary depending on their origin. This review consolidates clinical research on MSCs from different sources in treating SLE and analyzes the possible causes underlying these variable outcomes. Additionally, it elucidates five potential factors impacting the outcomes of MSC therapy in SLE: the influence of the microenvironment on MSCs, the complexity and paradoxical aspects of MSC mechanisms in SLE treatment, the heterogeneity of MSCs, the in vivo differentiation potential and post-transplant survival rates of MSCs, and disparities in MSC preparation conditions.
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Affiliation(s)
- Yuan Yuan
- Hengyang Medical College, University of South China, Hengyang, 421001, Hunan Province, China.
| | - Tong Liu
- Hengyang Medical College, University of South China, Hengyang, 421001, Hunan Province, China
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Rattanapinyopituk K, Chaweewannakorn C, Tangjit N, Dechkunakorn S, Anuwongnukroh N, Sritanaudomchai H. Osteogenic potency of dental stem cell-composite scaffolds in an animal cleft palate model. Heliyon 2024; 10:e36036. [PMID: 39224373 PMCID: PMC11367540 DOI: 10.1016/j.heliyon.2024.e36036] [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: 01/04/2024] [Revised: 08/07/2024] [Accepted: 08/08/2024] [Indexed: 09/04/2024] Open
Abstract
Objective To evaluate the osteogenic potency of stem cells isolated from human exfoliated deciduous teeth (SHED) in polycaprolactone with gelatin surface modification (PCL-GE) and poly (lactic-co-glycolic acid)-bioactive glass composite (PLGA-bioactive glass (BG)) scaffolds after implantation in a rat cleft model. Methods Cleft palate-like lesions were induced in Sprague-Dawley rats by extracting the right maxillary first molars and drilling the intact alveolar bone. Rats were then divided into five groups: Control, PCL-GE, PCL-GE-SHED, PLGA-BG, and PLGA-BG-SHED, and received corresponding composite scaffolds with/without SHED at the extraction site. Tissue samples were collected at 2, 3, and 6 months post-implantation (4 rats per group). Gross and histological analyses were conducted to assess osteoid or bone formation. Immunohistochemistry for osteocalcin and human mitochondria was performed to evaluate bone components and human stem cell viability in the tissue. Results Bone tissue formation was observed in the PCL-GE and PLGA-BG groups compared to the control, where no bone formation occurred. PLGA-BG scaffolds demonstrated greater bone regeneration potential than PCL-GE over 2-6 months. Additionally, scaffolds with SHED accelerated bone formation compared to scaffolds alone. Osteocalcin expression was detected in all rats, and positive immunoreactivity for human mitochondria was observed in the regenerated bone tissue with PCL-GE-SHED and PLGA-BG-SHED. Conclusion PCL-GE and PLGA-BG composite scaffolds effectively repaired and regenerated bone tissue in rat cleft palate defects. Moreover, scaffolds supplemented with SHED exhibited enhanced osteogenic potency. Clinical significance PCL-GE and PLGA-BG scaffolds, augmented with SHED, emerge as promising biomaterial candidates for addressing cleft repair and advancing bone tissue engineering endeavors.
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Affiliation(s)
- Kasem Rattanapinyopituk
- Department of Pathology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
| | | | - Nathaphon Tangjit
- Department of Orthodontics, Faculty of Dentistry, Mahidol University, Bangkok, Thailand
| | - Surachai Dechkunakorn
- Department of Orthodontics, Faculty of Dentistry, Mahidol University, Bangkok, Thailand
| | - Niwat Anuwongnukroh
- Department of Orthodontics, Faculty of Dentistry, Mahidol University, Bangkok, Thailand
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Prencipe G, Cerveró-Varona A, Perugini M, Sulcanese L, Iannetta A, Haidar-Montes AA, Stöckl J, Canciello A, Berardinelli P, Russo V, Barboni B. Amphiregulin orchestrates the paracrine immune-suppressive function of amniotic-derived cells through its interplay with COX-2/PGE 2/EP4 axis. iScience 2024; 27:110508. [PMID: 39156643 PMCID: PMC11326934 DOI: 10.1016/j.isci.2024.110508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 06/10/2024] [Accepted: 07/11/2024] [Indexed: 08/20/2024] Open
Abstract
The paracrine crosstalk between amniotic-derived membranes (AMs)/epithelial cells (AECs) and immune cells is pivotal in tissue healing following inflammation. Despite evidence collected to date, gaps in understanding the underlying molecular mechanisms have hindered clinical applications. The present study represents a significant step forward demonstrating that amphiregulin (AREG) orchestrates the native immunomodulatory functions of amniotic derivatives via the COX-2/PGE2/EP4 axis. The results highlight the immunosuppressive efficacy of PGE2-dependent AREG release, dampening PBMCs' activation, and NFAT pathway in Jurkat reporter cells via TGF-β signaling. Moreover, AREG emerges as a key protein mediator by attenuating acute inflammatory response in Tg(lysC:DsRed2) zebrafish larvae. Notably, the interplay of diverse COX-2/PGE2 pathway activators enables AM/AEC to adapt rapidly to external stimuli (LPS and/or stretching) through a responsive positive feedback loop on the AREG/EGFR axis. These findings offer valuable insights for developing innovative cell-free therapies leveraging the potential of amniotic derivatives in immune-mediated diseases and regenerative medicine.
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Affiliation(s)
- Giuseppe Prencipe
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Adrián Cerveró-Varona
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Monia Perugini
- Department of Bioscience and Agro-Food and Environmental Technology, University of Teramo, Teramo, Italy
| | - Ludovica Sulcanese
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Annamaria Iannetta
- Department of Bioscience and Agro-Food and Environmental Technology, University of Teramo, Teramo, Italy
| | - Arlette Alina Haidar-Montes
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Johannes Stöckl
- Centre for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Medical University of Vienna, Vienna 1090, Austria
| | - Angelo Canciello
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Paolo Berardinelli
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Valentina Russo
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
| | - Barbara Barboni
- Unit of Basic and Applied Sciences, Department of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy
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Kim JR, Hong BK, Pham THN, Kim WU, Kim HA. Interferon-gamma signaling promotes cartilage regeneration after injury. Sci Rep 2024; 14:8046. [PMID: 38580748 PMCID: PMC10997668 DOI: 10.1038/s41598-024-58779-0] [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: 12/05/2023] [Accepted: 04/03/2024] [Indexed: 04/07/2024] Open
Abstract
Osteoarthritis is a common chronic disease and major cause of disability and chronic pain in ageing populations. In this pathology, the entire joint is involved, and the regeneration of articular cartilage still remains one of the main challenges. Here, we investigated the molecular mechanisms underlying cartilage regeneration in young mice using a full-thickness cartilage injury (FTCI) model. FTCI-induced cartilage defects were created in the femoral trochlea of young and adult C57BL/6 mice. To identify key molecules and pathways involved in the early response to cartilage injury, we performed RNA sequencing (RNA-seq) analysis of cartilage RNA at 3 days after injury. Young mice showed superior cartilage regeneration compared to adult mice after cartilage injury. RNA-seq analysis revealed significant upregulation of genes associated with the immune response, particularly in the IFN-γ signaling pathway and qRT-PCR analysis showed macrophage polarization in the early phase of cartilage regeneration (3 days) in young mice after injury, which might promote the removal of damaged or necrotic cells and initiate cartilage regeneration in response to injury. IFN-γR1- and IFN-γ-deficient mice exhibited impaired cartilage regeneration following cartilage injury. DMM-induced and spontaneous OA phenotypes were exacerbated in IFN-γR1-/- mice than in wild-type mice. Our data support the hypothesis that IFN-γ signaling is necessary for cartilage regeneration, as well as for the amelioration of post-traumatic and age-induced OA.
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Affiliation(s)
- Ju-Ryoung Kim
- Division of Rheumatology, Department of Internal Medicine, Hallym University Sacred Heart Hospital, 896, Pyungchon, Anyang, Kyunggi, 14068, Korea
- Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
- Center for Intergrative Rheumatoid Transcriptomics and Dynamics, School of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
| | - Bong-Ki Hong
- Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
- Center for Intergrative Rheumatoid Transcriptomics and Dynamics, School of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
| | - Thi Hong Nhung Pham
- Division of Rheumatology, Department of Internal Medicine, Hallym University Sacred Heart Hospital, 896, Pyungchon, Anyang, Kyunggi, 14068, Korea
- Institute for Skeletal Aging, Hallym University, Chuncheon, Gangwon-do, 24252, Korea
| | - Wan-Uk Kim
- Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
- Center for Intergrative Rheumatoid Transcriptomics and Dynamics, School of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
| | - Hyun Ah Kim
- Division of Rheumatology, Department of Internal Medicine, Hallym University Sacred Heart Hospital, 896, Pyungchon, Anyang, Kyunggi, 14068, Korea.
- Institute for Skeletal Aging, Hallym University, Chuncheon, Gangwon-do, 24252, Korea.
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Gao M, Guo H, Dong X, Wang Z, Yang Z, Shang Q, Wang Q. Regulation of inflammation during wound healing: the function of mesenchymal stem cells and strategies for therapeutic enhancement. Front Pharmacol 2024; 15:1345779. [PMID: 38425646 PMCID: PMC10901993 DOI: 10.3389/fphar.2024.1345779] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 02/05/2024] [Indexed: 03/02/2024] Open
Abstract
A wound takes a long time to heal and involves several steps. Following tissue injury, inflammation is the primary cause of tissue regeneration and repair processes. As a result, the pathophysiological processes involving skin damage, healing, and remodeling depend critically on the control of inflammation. The fact that it is a feasible target for improving the prognosis of wound healing has lately become clear. Mesenchymal stem cells (MSCs) are an innovative and effective therapeutic option for wound healing due to their immunomodulatory and paracrine properties. By controlling the inflammatory milieu of wounds through immunomodulation, transplanted MSCs have been shown to speed up the healing process. In addition to other immunomodulatory mechanisms, including handling neutrophil activity and modifying macrophage polarization, there may be modifications to the activation of T cells, natural killer (NK) cells, and dendritic cells (DCs). Furthermore, several studies have shown that pretreating MSCs improves their ability to modulate immunity. In this review, we summarize the existing knowledge about how MSCs influence local inflammation in wounds by influencing immunity to facilitate the healing process. We also provide an overview of MSCs optimizing techniques when used to treat wounds.
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Affiliation(s)
| | | | | | | | | | | | - Qiying Wang
- Department of Plastic Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Najar M, Bouhtit F, Rahmani S, Bouali A, Melki R, Najimi M, Lewalle P, Merimi M. The immunogenic profile and immunomodulatory function of mesenchymal stromal / stem cells in the presence of Ptychotis verticillata. Heliyon 2024; 10:e24822. [PMID: 38317994 PMCID: PMC10838760 DOI: 10.1016/j.heliyon.2024.e24822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 01/15/2024] [Accepted: 01/15/2024] [Indexed: 02/07/2024] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) are considered to be a promising immunotherapeutic tool due to their easy accessibility, culture expansion possibilities, safety profile, and immunomodulatory properties. Although several studies have demonstrated the therapeutic effects of MSCs, their efficacy needs to be improved while also preserving their safety. It has been suggested that cell homeostasis may be particularly sensitive to plant extracts. The impact of natural compounds on immunity is thus a fascinating and growing field. Ptychotis verticillata and its bioactive molecules, carvacrol and thymol, are potential candidates for improving MSC therapeutic effects. They can be used as immunotherapeutic agents to regulate MSC functions and behavior during immunomodulation. Depending on their concentrations and incubation time, these compounds strengthened the immunomodulatory functions of MSCs while maintaining their immune-evasive profile. Incubating MSCs with carvacrol and thymol does not alter their hypoimmunogenicity, as no induction of the allogeneic immune response was observed. MSCs also showed enhanced abilities to reduce the proliferation of activated T cells. Thus, MSCs are immunologically responsive to bioactive molecules derived from PV. The bioactivity may depend on the whole phyto-complex of the oil. These findings may contribute to the development of safe and efficient immunotherapeutic MSCs by using medicinal plant-derived active molecules.
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Affiliation(s)
- Mehdi Najar
- Faculty of Medicine, ULB721, Université Libre de Bruxelles, 1070 Brussels, Belgium
- Osteoarthritis Research Unit, Department of Medicine, University of Montreal Hospital Research Center (CRCHUM), University of Montreal, Montreal H2X 0A9, QC, Canada
| | - Fatima Bouhtit
- Laboratory of Experimental Hematology, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Brussels, Belgium
- LBBES Laboratory, Genetics and Immune Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda 60000, Morocco
| | - Saida Rahmani
- Laboratory of Experimental Hematology, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Brussels, Belgium
| | - Abderrahim Bouali
- LBBES Laboratory, Genetics and Immune Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda 60000, Morocco
| | - Rahma Melki
- LBBES Laboratory, Genetics and Immune Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda 60000, Morocco
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, 1200 Brussels, Belgium
| | - Philippe Lewalle
- Laboratory of Experimental Hematology, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Brussels, Belgium
| | - Makram Merimi
- LBBES Laboratory, Genetics and Immune Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda 60000, Morocco
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Karimi F, Nejati B, Rahimi F, Alivirdiloo V, Alipourfard I, Aghighi A, Raji-Amirhasani A, Eslami M, Babaeizad A, Ghazi F, Firouzi Amandi A, Dadashpour M. A State-of-the-Art Review on the Recent Advances of Mesenchymal Stem Cell Therapeutic Application in Systematic Lupus Erythematosus. Immunol Invest 2024; 53:160-184. [PMID: 38031988 DOI: 10.1080/08820139.2023.2289066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2023]
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease with an unknown etiology that has widespread clinical and immunological manifestations. Despite the increase in knowledge about the pathogenesis process and the increase in treatment options, however, the treatments fail in half of the cases. Therefore, there is still a need for research on new therapies. Mesenchymal stem cells (MSCs) are powerful regulators of the immune system and can reduce the symptoms of systemic lupus erythematosus. This study aimed to review the mechanisms of immune system modulation by MSCs and the role of these cells in the treatment of SLE. MSCs suppress T lymphocytes through various mechanisms, including the production of transforming growth factor-beta (TGF-B), prostaglandin E2 (PGE2), nitric oxide (NO), and indolamine 2 and 3-oxygenase (IDO). In addition, MSCs inhibit the production of their autoantibodies by inhibiting the differentiation of lymphocytes. The production of autoantibodies against nuclear antigens is an important feature of SLE. On the other hand, MSCs inhibit antigen delivery by antigen-presenting cells (APCs) to T lymphocytes. Studies in animal models have shown the effectiveness of these cells in treating SLE. However, few studies have been performed on the effectiveness of this treatment in humans. It can be expected that new treatment strategies for SLE will be introduced in the future, given the promising results of MSCs application.
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Affiliation(s)
- Farshid Karimi
- Department of Optometry, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Babak Nejati
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Rahimi
- Division of Clinical Laboratory, Zahra Mardani Azar Children Training Research and Treatment Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Alivirdiloo
- Medical Doctor Ramsar Campus, Mazandaran University of Medical Sciences, Ramsar, Iran
| | - Iraj Alipourfard
- Institute of Physical Chemistry, Polish Academy of Science, Warsaw, Poland
| | - Ali Aghighi
- Department of Clinical Biochemistry, Zahedan University of Medical Science, Zahedan, Iran
| | - Alireza Raji-Amirhasani
- Department of Physiology and Pharmacology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Endocrinology and Metabolism Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Majid Eslami
- Department of Bacteriology and Virology, Semnan University of Medical Sciences, Semnan, Iran
| | - Ali Babaeizad
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Farhood Ghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mehdi Dadashpour
- Department of Medical Biotechnology, Semnan University of Medical Sciences, Semnan, Iran
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12
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Li F, Wang X, Shi J, Wu S, Xing W, He Y. Anti-inflammatory effect of dental pulp stem cells. Front Immunol 2023; 14:1284868. [PMID: 38077342 PMCID: PMC10701738 DOI: 10.3389/fimmu.2023.1284868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 11/06/2023] [Indexed: 12/18/2023] Open
Abstract
Dental pulp stem cells (DPSCs) have received a lot of attention as a regenerative medicine tool with strong immunomodulatory capabilities. The excessive inflammatory response involves a variety of immune cells, cytokines, and has a considerable impact on tissue regeneration. The use of DPSCs for controlling inflammation for the purpose of treating inflammation-related diseases and autoimmune disorders such as supraspinal nerve inflammation, inflammation of the pulmonary airways, systemic lupus erythematosus, and diabetes mellitus is likely to be safer and more regenerative than traditional medicines. The mechanism of the anti-inflammatory and immunomodulatory effects of DPSCs is relatively complex, and it may be that they themselves or some of the substances they secrete regulate a variety of immune cells through inflammatory immune-related signaling pathways. Most of the current studies are still at the laboratory cellular level and animal model level, and it is believed that through the efforts of more researchers, DPSCs/SHED are expected to be transformed into excellent drugs for the clinical treatment of related diseases.
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Affiliation(s)
- FenYao Li
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - XinXin Wang
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - Jin Shi
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - ShuTing Wu
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - WenBo Xing
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - Yan He
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
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13
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Rawiwet V, Vijitruth R, Thonabulsombat C, Vongsavan K, Sritanaudomchai H. Evaluation of the Efficacy of Human Dental Pulp Stem Cell Transplantation in Sprague-Dawley Rats with Sensorial Neural Hearing Loss. Eur J Dent 2023; 17:1207-1214. [PMID: 36716786 PMCID: PMC10756831 DOI: 10.1055/s-0043-1761190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
OBJECTIVES The purpose of the present study was to evaluate the efficacy of spiral ganglion neuron (SGN) regeneration after dental pulp stem cell (DPSC) transplantation in a rat sensorineural hearing loss (HL) model. MATERIALS AND METHODS Sham or experimental HL was induced in adult Sprague-Dawley rats by cochlear round window surgery. An HL rat model was established with a single 10 mM ouabain intratympanic injection. After 7 days, the rats received DPSCs, stem cells from human exfoliated deciduous teeth (SHED), or culture medium in the sutural area to establish four groups: sham, HL-DPSC, HL-SHED, and HL-medium. Histological analyses were performed at 4, 7, and 10 weeks after transplantation, and the number of SGNs, specific SGN protein expression, and the function of SGNs were evaluated. STATISTICAL ANALYSIS Data were statistically by MS Excel and SPSS v.15.0. Intergroup level of significance was determined via a one-way analysis of variance and Duncan's multiple range test with 95% confidence intervals. RESULTS New SGN formation was observed in the HL-DPSC and HL-SHED rat groups. The number of SGNs was significantly higher in the HL-DPSC and HL-SHED groups than in the HL-medium group over 4 to 10-week survival period. HL-DPSC rats exhibited higher SGN density compared with that in HL-SHED group, which was statistically significant at week 10. The regenerated SGNs expressed cochlear wiring regulator GATA-binding-protein 3. Moreover, the SGNs from the HL-DPSC group also exhibited a higher expression of synaptic vesicle protein and regulated action potential-dependent neurotransmitter release compared with SGNs from the HL-SHED group. CONCLUSIONS Our findings suggest that DPSCs and SHED repair and regenerate SGNs in rat HL model. Dental pulp stem cells represent a promising treatment strategy for restoring damage to the sensory circuits associated with deafness.
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Affiliation(s)
- Visut Rawiwet
- Central Animal Facility, Faculty of Science, Mahidol University (MUSC-CAF), Bangkok, Thailand
| | | | | | - Kutkao Vongsavan
- Department of Pediatric Dentistry, Faculty of Dentistry, Mahidol University, Bangkok, Thailand
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14
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Lian XF, Lu DH, Liu HL, Liu YJ, Yang Y, Lin Y, Xie F, Huang CH, Wu HM, Long AM, Hui CJ, Shi Y, Chen Y, Gao YF, Zhang F. Safety evaluation of human umbilical cord-mesenchymal stem cells in type 2 diabetes mellitus treatment: A phase 2 clinical trial. World J Clin Cases 2023; 11:5083-5096. [PMID: 37583846 PMCID: PMC10424020 DOI: 10.12998/wjcc.v11.i21.5083] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 05/23/2023] [Accepted: 06/16/2023] [Indexed: 07/26/2023] Open
Abstract
BACKGROUND Progressive pancreatic β cell dysfunction is a fundamental aspect of the pathology underlying type 2 diabetes mellitus (T2DM). Recently, mesenchymal stem cell (MSC) transplantation has emerged as a new therapeutic method due to its ability to promote the regeneration of pancreatic β cells. However, current studies have focused on its efficacy, and there are few clinical studies on its safety. AIM To evaluate the safety of human umbilical cord (hUC)-MSC infusion in T2DM treatment. METHODS An open-label and randomized phase 2 clinical trial was designed to evaluate the safety of hUC-MSC transplantation in T2DM in a Class A hospital. Ten patients in the placebo group received acellular saline intravenously once per week for 3 wk. Twenty-four patients in the hUC-MSC group received hUC-MSCs (1 × 106 cells/kg) intravenously once per week for 3 wk. Diabetic clinical symptoms and signs, laboratory findings, and imaging findings were evaluated weekly for the 1st mo and then at weeks 12 and 24 post-treatment. RESULTS No serious adverse events were observed during the 24-wk follow-up. Four patients (16.7%) in the hUC-MSC group experienced transient fever, which occurred within 24 h after the second or third infusion; this did not occur in any patients in the placebo group. One patient from the hUC-MSC group experienced hypoglycemic attacks within 1 mo after transplantation. Significantly lower lymphocyte levels (weeks 2 and 3) and thrombin coagulation time (week 2) were observed in the hUC-MSC group compared to those in the placebo group (all P < 0.05). Significantly higher platelet levels (week 3), immunoglobulin levels (weeks 1, 2, 3, and 4), fibrinogen levels (weeks 2 and 3), D-dimer levels (weeks 1, 2, 3, 4, 12, and 24), and neutrophil-to-lymphocyte ratios (weeks 2 and 3) were observed in the hUC-MSC group compared to those in the placebo group (all P < 0.05). There were no significant differences between the two groups for tumor markers (alpha-fetoprotein, carcinoembryonic antigen, and carbohydrate antigen 199) or blood fat. No liver damage or other side effects were observed on chest X-ray. CONCLUSION Our study suggested that hUC-MSC transplantation has good tolerance and high safety in the treatment of T2DM. It can improve human immunity and inhibit lymphocytes. Coagulation function should be monitored vigilantly for abnormalities.
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Affiliation(s)
- Xiao-Fen Lian
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Dong-Hui Lu
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Hong-Li Liu
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Yan-Jing Liu
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Yang Yang
- Department of Endocrinology, Huizhou Central People’s Hospital, Huizhou 516000, Guangdong Province, China
| | - Yuan Lin
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Feng Xie
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Cai-Hao Huang
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Hong-Mei Wu
- Department of Endocrinology, Longgang District Central Hospital of Shenzhen, Shenzhen 518000, Guangdong Province, China
| | - Ai-Mei Long
- Department of Endocrinology, Longgang District Central Hospital of Shenzhen, Shenzhen 518000, Guangdong Province, China
| | - Chen-Jun Hui
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Yu Shi
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Yun Chen
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Yun-Feng Gao
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Fan Zhang
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
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15
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Jiang H, Ni J, Hu L, Xiang Z, Zeng J, Shi J, Chen Q, Li W. Resveratrol May Reduce the Degree of Periodontitis by Regulating ERK Pathway in Gingival-Derived MSCs. Int J Mol Sci 2023; 24:11294. [PMID: 37511053 PMCID: PMC10378998 DOI: 10.3390/ijms241411294] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 07/04/2023] [Accepted: 07/04/2023] [Indexed: 07/30/2023] Open
Abstract
Gingival-derived mesenchymal stem cells (GMSCs) have strong self-renewal, multilineage differentiation, and immunomodulatory properties and are expected to be applied in anti-inflammatory and tissue regeneration. However, achieving the goal of using endogenous stem cells to treat diseases and even regenerate tissues remains a challenge. Resveratrol is a natural compound with multiple biological activities that can regulate stem cell immunomodulation when acting on them. This study found that resveratrol can reduce inflammation in human gingival tissue and upregulate the stemness of GMSCs in human gingiva. In cell experiments, it was found that resveratrol can reduce the expression of TLR4, TNFα, and NFκB and activate ERK/Wnt crosstalk, thereby alleviating inflammation, promoting the proliferation and osteogenic differentiation ability of GMSCs, and enhancing their immunomodulation. These results provide a new theoretical basis for the application of resveratrol to activate endogenous stem cells in the treatment of diseases in the future.
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Affiliation(s)
- Han Jiang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Hangzhou 310000, China
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
- Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, China
| | - Jia Ni
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, China
| | - Longshuang Hu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Hangzhou 310000, China
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
- Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, China
| | - Zichao Xiang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Hangzhou 310000, China
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
- Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, China
| | - Jincheng Zeng
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, China
| | - Jiejun Shi
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Hangzhou 310000, China
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
- Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, China
| | - Qianming Chen
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Hangzhou 310000, China
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
- Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, China
| | - Wen Li
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Hangzhou 310000, China
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
- Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, China
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16
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Hoseinzadeh A, Rezaieyazdi Z, Afshari JT, Mahmoudi A, Heydari S, Moradi R, Esmaeili SA, Mahmoudi M. Modulation of Mesenchymal Stem Cells-Mediated Adaptive Immune Effectors' Repertoire in the Recovery of Systemic Lupus Erythematosus. Stem Cell Rev Rep 2023; 19:322-344. [PMID: 36272020 DOI: 10.1007/s12015-022-10452-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2022] [Indexed: 02/07/2023]
Abstract
The breakdown of self-tolerance of the immune response can lead to autoimmune conditions in which chronic inflammation induces tissue damage. Systemic lupus erythematosus (SLE) is a debilitating multisystemic autoimmune disorder with a high prevalence in women of childbearing age; however, SLE incidence, prevalence, and severity are strongly influenced by ethnicity. Although the mystery of autoimmune diseases remains unsolved, disturbance in the proportion and function of B cell subsets has a major role in SLE's pathogenesis. Additionally, colocalizing hyperactive T helper cell subgroups within inflammatory niches are indispensable. Despite significant advances in standard treatments, nonspecific immunosuppression, the risk of serious infections, and resistance to conventional therapies in some cases have raised the urgent need for new treatment strategies. Without the need to suppress the immune system, mesenchymal stem cells (MSCs), as ''smart" immune modulators, are able to control cellular and humoral auto-aggression responses by participating in precursor cell development. In lupus, due to autologous MSCs disorder, the ability of allogenic engrafted MSCs in tissue regeneration and resetting immune homeostasis with the provision of a new immunocyte repertoire has been considered simultaneously. In Brief The bone marrow mesenchymal stem cells (BM-MSCs) lineage plays a critical role in maintaining the hematopoietic stem-cell microstructure and modulating immunocytes. The impairment of BM-MSCs and their niche partially contribute to the pathogenesis of SLE-like diseases. Allogenic MSC transplantation can reconstruct BM microstructure, possibly contributing to the recovery of immunocyte phenotype restoration of immune homeostasis. In terms of future prospects of MSCs, artificially gained by ex vivo isolation and culture adaptation, the wide variety of potential mediators and mechanisms might be linked to the promotion of the immunomodulatory function of MSCs.
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Affiliation(s)
- Akram Hoseinzadeh
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Rezaieyazdi
- Department of Rheumatology, Ghaem Hospital, Mashhad University of Medical Science, Mashhad, Iran.,Rheumatic Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Jalil Tavakol Afshari
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Mahmoudi
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sahar Heydari
- Department of Physiology and Pharmacology, Faculty of Medicine, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Reza Moradi
- Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed-Alireza Esmaeili
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Mahmoudi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. .,Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. .,Department of Immunology, Mashhad University of Medical Sciences, Azadi Square, Kalantari Blvd, Pardi's campusMashhad, Iran.
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Caiati C, Jirillo E. Transplantation of Mesenchymal Stem Cells as a New Approach for Cardiovascular Diseases: From Bench to Bedside: A Perspective. Endocr Metab Immune Disord Drug Targets 2023; 23:1359-1364. [PMID: 37055907 DOI: 10.2174/1871530323666230411142308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 03/01/2023] [Indexed: 04/15/2023]
Affiliation(s)
- Carlo Caiati
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Emilio Jirillo
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
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18
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Inflammation in myocardial infarction: roles of mesenchymal stem cells and their secretome. Cell Death Dis 2022; 8:452. [DOI: 10.1038/s41420-022-01235-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 09/25/2022] [Accepted: 10/21/2022] [Indexed: 11/11/2022]
Abstract
AbstractInflammation plays crucial roles in the regulation of pathophysiological processes involved in injury, repair and remodeling of the infarcted heart; hence, it has become a promising target to improve the prognosis of myocardial infarction (MI). Mesenchymal stem cells (MSCs) serve as an effective and innovative treatment option for cardiac repair owing to their paracrine effects and immunomodulatory functions. In fact, transplanted MSCs have been shown to accumulate at injury sites of heart, exerting multiple effects including immunomodulation, regulating macrophages polarization, modulating the activation of T cells, NK cells and dendritic cells and alleviating pyroptosis of non-immune cells. Many studies also proved that preconditioning of MSCs can enhance their inflammation-regulatory effects. In this review, we provide an overview on the current understanding of the mechanisms on MSCs and their secretome regulating inflammation and immune cells after myocardial infarction and shed light on the applications of MSCs in the treatment of cardiac infarction.
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19
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Wang D, Cao H, Hua W, Gao L, Yuan Y, Zhou X, Zeng Z. Mesenchymal Stem Cell-Derived Extracellular Vesicles for Bone Defect Repair. MEMBRANES 2022; 12:716. [PMID: 35877919 PMCID: PMC9315966 DOI: 10.3390/membranes12070716] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/17/2022] [Accepted: 07/18/2022] [Indexed: 12/12/2022]
Abstract
The repair of critical bone defects is a hotspot of orthopedic research. With the development of bone tissue engineering (BTE), there is increasing evidence showing that the combined application of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) (MSC-EVs), especially exosomes, with hydrogels, scaffolds, and other bioactive materials has made great progress, exhibiting a good potential for bone regeneration. Recent studies have found that miRNAs, proteins, and other cargo loaded in EVs are key factors in promoting osteogenesis and angiogenesis. In BTE, the expression profile of the intrinsic cargo of EVs can be changed by modifying the gene expression of MSCs to obtain EVs with enhanced osteogenic activity and ultimately enhance the osteoinductive ability of bone graft materials. However, the current research on MSC-EVs for repairing bone defects is still in its infancy, and the underlying mechanism remains unclear. Therefore, in this review, the effect of bioactive materials such as hydrogels and scaffolds combined with MSC-EVs in repairing bone defects is summarized, and the mechanism of MSC-EVs promoting bone defect repair by delivering active molecules such as internal miRNAs is further elucidated, which provides a theoretical basis and reference for the clinical application of MSC-EVs in repairing bone defects.
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Affiliation(s)
- Dongxue Wang
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
| | - Hong Cao
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China; (H.C.); (Y.Y.)
| | - Weizhong Hua
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
| | - Lu Gao
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
| | - Yu Yuan
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China; (H.C.); (Y.Y.)
| | - Xuchang Zhou
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China; (H.C.); (Y.Y.)
| | - Zhipeng Zeng
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
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20
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Effect of MicroRNA-138 on Tumor Necrosis Factor-Alpha-Induced Suppression of Osteogenic Differentiation of Dental Pulp Stem Cells and Underlying Mechanism. BIOMED RESEARCH INTERNATIONAL 2022; 2022:7230167. [PMID: 35845957 PMCID: PMC9286885 DOI: 10.1155/2022/7230167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 06/18/2022] [Accepted: 06/22/2022] [Indexed: 11/25/2022]
Abstract
High doses of tumor necrosis factor-α (TNF-α) suppress osteogenic differentiation of human dental pulp stem cells (hDPSCs). In the present study, we aimed to explore the role and potential regulatory mechanism of microRNA-138 (miR-138) in the osteogenic differentiation of hDPSCs after treatment with a high dose of TNF-α. The hDPSCs were cultured in osteogenic medium with or without 50 ng/ml TNF-α. The miR-138 levels were upregulated during osteogenic differentiation of the hDPSCs following TNF-α treatment. The miR-138 overexpression accelerated but miR-138 knockdown alleviated the TNF-α-induced suppression of the alkaline phosphatase activity, calcium deposition, and protein abundance of dentin sialophosphoprotein, dentin matrix protein 1, bone sialoprotein, and osteopontin during osteogenic differentiation induction of hDPSCs. Additionally, miR-138 overexpression accelerated but miR-138 knockdown alleviated the suppression of the focal adhesion kinase- (FAK-) extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway during osteogenic differentiation induction of hDPSCs under TNF-α treatment. In conclusion, miR-138 accelerates TNF-α-induced suppression of osteogenic differentiation of hDPSCs. Inactivation of the FAK-ERK1/2 signaling pathway may be one of the mechanisms underlying the effect of miR-138. Inhibition of miR-138 expression may be a strategy to weaken the inhibitory effect of high-dose TNF-α on the osteogenic differentiation of hDPSCs.
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21
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Liu H, Lu J, Jiang Q, Haapasalo M, Qian J, Tay FR, Shen Y. Biomaterial scaffolds for clinical procedures in endodontic regeneration. Bioact Mater 2022; 12:257-277. [PMID: 35310382 PMCID: PMC8897058 DOI: 10.1016/j.bioactmat.2021.10.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 10/04/2021] [Accepted: 10/04/2021] [Indexed: 12/14/2022] Open
Abstract
Regenerative endodontic procedures have been rapidly evolving over the past two decades and are employed extensively in clinical endodontics. These procedures have been perceived as valuable adjuvants to conventional strategies in the treatment of necrotic immature permanent teeth that were deemed to have poor prognosis. As a component biological triad of tissue engineering (i.e., stem cells, growth factors and scaffolds), biomaterial scaffolds have demonstrated clinical potential as an armamentarium in regenerative endodontic procedures and achieved remarkable advancements. The aim of the present review is to provide a broad overview of biomaterials employed for scaffolding in regenerative endodontics. The favorable properties and limitations of biomaterials organized in naturally derived, host-derived and synthetic material categories were discussed. Preclinical and clinical studies published over the past five years on the performance of biomaterial scaffolds, as well as current challenges and future perspectives for the application of biomaterials for scaffolding and clinical evaluation of biomaterial scaffolds in regenerative endodontic procedures were addressed in depth.
Overview of biomaterials for scaffolding in regenerative endodontics are presented. Findings of preclinical and clinical studies on the performance of biomaterial scaffolds are summarized. Challenges and future prospects in biomaterial scaffolds are discussed.
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22
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Genç D, Bulut O, Günaydin B, Göksu M, Düzgün M, Dere Y, Sezgin S, Aladağ A, Bülbül A. Dental follicle mesenchymal stem cells ameliorated glandular dysfunction in Sjögren's syndrome murine model. PLoS One 2022; 17:e0266137. [PMID: 35511824 PMCID: PMC9070867 DOI: 10.1371/journal.pone.0266137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 03/14/2022] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVE Dental mesenchymal stem cells (MSCs) are potential for use in tissue regeneration in inflammatory diseases due to their rapid proliferating, multilineage differentiation, and strong anti-inflammatory features. In the present study, immunoregulatory and glandular tissue regeneration effects of the dental follicle (DF)MSCs in Sjögren's Syndrome (SS) were investigated. METHODS Dental follicle (DF) tissues were obtained from healthy individuals during tooth extraction, tissues were digested enzymatically and DFMSCs were cultured until the third passage. DFMSCs were labeled with Quantum dot 655 for cell tracking analysis. The induction of the SS mouse model was performed by the injection of Ro60-273-289 peptide intraperitoneally. DFMSCs were injected intraperitoneally, or into submandibular, or lacrimal glands. Splenocytes were analyzed for intracellular cytokine (IFN-γ, IL-17, IL-10) secretion in T helper cells, lymphocyte proliferation, and B lymphocyte subsets. Histologic analysis was done for submandibular and lacrimal glands with hematoxylin-eosin staining for morphologic examination. RESULTS The systemic injection of DFMSCs significantly reduced intracellular IFN-γ and IL-17 secreting CD4+ T cells in splenocytes (p<0.05), and decreased inflammatory cell deposits and fibrosis in the glandular tissues. DFMSCs differentiated to glandular epithelial cells in submandibular and lacrimal injections with a significant reduction in lymphocytic foci. The results showed that few amounts of DFMSCs were deposited in glandular tissues when applied intraperitoneally, while high amounts of DFMSCs were located in glandular tissues and differentiated to glandular epithelial cells when applied locally in SS murine model. CONCLUSION DFMSCs have the potential for the regulation of Th1, Th17, and Treg balance in SS, and ameliorate glandular dysfunction. DFMSCs can be a beneficial therapeutic application for SS.
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Affiliation(s)
- Deniz Genç
- Faculty of Health Sciences, Muğla Sıtkı Koçman University, Muğla, Turkey
- Research Laboratories Center, Muğla Sıtkı Koçman University, Muğla, Turkey
| | - Osman Bulut
- Milas Veterinary Medicine Faculty, Muğla Sıtkı Koçman University, Muğla, Turkey
| | - Burcu Günaydin
- Department of Histology and Embryology, Institute of Health Sciences, Muğla Sıtkı Koçman University, Muğla, Turkey
| | - Mizgin Göksu
- Faculty of Science, Department of Molecular Biology and Genetics, Muğla Sıtkı Koçman University, Muğla, Turkey
| | - Mert Düzgün
- Faculty of Science, Department of Molecular Biology and Genetics, Muğla Sıtkı Koçman University, Muğla, Turkey
| | - Yelda Dere
- Faculty of Medicine, Department of Pathology, Muğla Sıtkı Koçman University, Muğla, Turkey
| | - Serhat Sezgin
- Faculty of Dentistry, Muğla Sıtkı Koçman Üniversity, Muğla, Turkey
| | - Akın Aladağ
- Faculty of Dentistry, Muğla Sıtkı Koçman Üniversity, Muğla, Turkey
| | - Aziz Bülbül
- Milas Veterinary Medicine Faculty, Muğla Sıtkı Koçman University, Muğla, Turkey
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23
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Li P, Zhang Y, Li Q, Zhang Y. Effect of HO-1-modified BMMSCs on immune function in liver transplantation. Sci Rep 2022; 12:3046. [PMID: 35197503 PMCID: PMC8866406 DOI: 10.1038/s41598-022-06141-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 01/25/2022] [Indexed: 11/10/2022] Open
Abstract
We examined whether haem oxygenase-1 (HO-1) could enhance the immunosuppressive effects of bone marrow mesenchymal stem cells (BMMSCs) on the rejection of transplanted liver allografts in rats. The animals were divided into three groups: the normal saline (NS) group, BMMSC group and HO-1/BMMSCs group. In vitro, the extraction, culture and HO-1 transfection of BMMSCs were performed. Mixed lymphocyte response (MLR) analysis of HO-1/BMMSCs efficacy was performed. The rejection model of orthotopic liver transplantation in rats was established when BMMSCs and HO-1/BMMSCs were transfused via the portal vein. To reduce research bias, we established an isogenic Liver transplantation model of (LEW → LEW) and (BN → BN), which can achieve tolerance. Changes in histopathology and liver function in the transplanted liver and changes in regulatory T cell (Tregs), natural killer (NK) cells and cytokines after transplantation were observed in the different groups. The severe acute rejection after liver transplantation on postoperative Day 10 was observed in the NS group. The BMMSC group showed strong protective effects against rejection within the first 10 days after transplantation, while HO-1/BMMSCs showed stronger effects on rejection than BMMSCs alone. In addition, the activity of natural killer (NK) cells decreased significantly, the levels of regulatory T cells (Tregs), interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) increased significantly and the levels of interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-17 (IL-17), interleukin-23 (IL-23), tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) decreased significantly in the HO-1/BMMSC group compared with the BMMSC group. HO-1/BMMSCs showed better immunosuppressive effects after liver transplantation than the other treatments. Our findings reveal that HO-1 can enhance the effects of BMMSCs on inhibiting acute rejection in orthotopic liver transplantation in rats.
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Affiliation(s)
- Peng Li
- Department of Hepatobiliary Surgery, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, 441000, China
| | - Yuyi Zhang
- Department of Obstetrics and Gynaecology, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, 441000, China.
| | - Qiongxia Li
- Department of Digestive Endoscopy Centre, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, 441000, China
| | - Yubo Zhang
- Department of Stomatology, Xinchang Hospital Affiliated with Wenzhou Medical University, Shaoxing, 312500, China.
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24
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Alvites R, Branquinho M, Sousa AC, Lopes B, Sousa P, Maurício AC. Mesenchymal Stem/Stromal Cells and Their Paracrine Activity-Immunomodulation Mechanisms and How to Influence the Therapeutic Potential. Pharmaceutics 2022; 14:381. [PMID: 35214113 PMCID: PMC8875256 DOI: 10.3390/pharmaceutics14020381] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 01/31/2022] [Accepted: 02/04/2022] [Indexed: 02/07/2023] Open
Abstract
With high clinical interest to be applied in regenerative medicine, Mesenchymal Stem/Stromal Cells have been widely studied due to their multipotency, wide distribution, and relative ease of isolation and expansion in vitro. Their remarkable biological characteristics and high immunomodulatory influence have opened doors to the application of MSCs in many clinical settings. The therapeutic influence of these cells and the interaction with the immune system seems to occur both directly and through a paracrine route, with the production and secretion of soluble factors and extracellular vesicles. The complex mechanisms through which this influence takes place is not fully understood, but several functional manipulation techniques, such as cell engineering, priming, and preconditioning, have been developed. In this review, the knowledge about the immunoregulatory and immunomodulatory capacity of MSCs and their secretion products is revisited, with a special focus on the phenomena of migration and homing, direct cell action and paracrine activity. The techniques for homing improvement, cell modulation and conditioning prior to the application of paracrine factors were also explored. Finally, multiple assays where different approaches were applied with varying success were used as examples to justify their exploration.
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Affiliation(s)
- Rui Alvites
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Mariana Branquinho
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Ana C. Sousa
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Bruna Lopes
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Patrícia Sousa
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Ana Colette Maurício
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
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25
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Genç D, Günaydın B, Sezgin S, Aladağ A, Tarhan EF. Immunoregulatory effects of dental mesenchymal stem cells on T and B lymphocyte responses in primary Sjögren's syndrome. Immunotherapy 2022; 14:225-247. [PMID: 35012368 DOI: 10.2217/imt-2021-0174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Background: In this article, the authors investigate the modulatory effects of dental mesenchymal stem cells (MSCs) on lymphocyte responses in primary Sjögren's syndrome (pSS), which is an autoimmune disease resulting from keratoconjunctivitis sicca and xerostomia. Methods: Mononuclear cells isolated from pSS patients cultured with or without dental MSCs and analyzed for lymphocyte responses via flow cytometry. Results: Dental-follicle (DF)- and dental-pulp (DP)-MSCs downregulated CD4+ T lymphocyte proliferation by increasing Fas-ligand expression on T lymphocytes and FoxP3 expressing Tregs, and decreasing intracellular IFN-γ and IL-17 secretion in pSS patients. DF-MSCs decreased the plasma B cell ratio in the favor of naive B cell population in pSS patients' mononuclear cells. Conclusion: DF- and DP-MSCs can be the new cellular therapeutic candidates for the regulation of immune responses in pSS.
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Affiliation(s)
- Deniz Genç
- Muğla Sıtkı Koçman University, Faculty of Health Sciences, Muğla, 48000, Turkey.,Muğla Sıtkı Koçman University, Research Laboratories Center, Muğla, 48000, Turkey
| | - Burcu Günaydın
- Department of Histology & Embryology, Muğla Sıtkı Koçman University, Institute of Health Sciences, Muğla, 48000, Turkey
| | - Serhat Sezgin
- Muğla Sıtkı Koçman University, Faculty of Dentistry, Muğla, 48000, Turkey
| | - Akın Aladağ
- Muğla Sıtkı Koçman University, Faculty of Dentistry, Muğla, 48000, Turkey
| | - Emine Figen Tarhan
- Department of Rheumatology, Muğla Sıtkı Koçman University, Faculty of Medicine, Muğla, 48000, Turkey
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26
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Lara-Barba E, Araya MJ, Hill CN, Bustamante-Barrientos FA, Ortloff A, García C, Galvez-Jiron F, Pradenas C, Luque-Campos N, Maita G, Elizondo-Vega R, Djouad F, Vega-Letter AM, Luz-Crawford P. Role of microRNA Shuttled in Small Extracellular Vesicles Derived From Mesenchymal Stem/Stromal Cells for Osteoarticular Disease Treatment. Front Immunol 2021; 12:768771. [PMID: 34790203 PMCID: PMC8591173 DOI: 10.3389/fimmu.2021.768771] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 10/14/2021] [Indexed: 12/18/2022] Open
Abstract
Osteoarticular diseases (OD), such as rheumatoid arthritis (RA) and osteoarthritis (OA) are chronic autoimmune/inflammatory and age-related diseases that affect the joints and other organs for which the current therapies are not effective. Cell therapy using mesenchymal stem/stromal cells (MSCs) is an alternative treatment due to their immunomodulatory and tissue differentiation capacity. Several experimental studies in numerous diseases have demonstrated the MSCs’ therapeutic effects. However, MSCs have shown heterogeneity, instability of stemness and differentiation capacities, limited homing ability, and various adverse responses such as abnormal differentiation and tumor formation. Recently, acellular therapy based on MSC secreted factors has raised the attention of several studies. It has been shown that molecules embedded in extracellular vesicles (EVs) derived from MSCs, particularly those from the small fraction enriched in exosomes (sEVs), effectively mimic their impact in target cells. The biological effects of sEVs critically depend on their cargo, where sEVs-embedded microRNAs (miRNAs) are particularly relevant due to their crucial role in gene expression regulation. Therefore, in this review, we will focus on the effect of sEVs derived from MSCs and their miRNA cargo on target cells associated with the pathology of RA and OA and their potential therapeutic impact.
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Affiliation(s)
- Eliana Lara-Barba
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile
| | - María Jesús Araya
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile
| | - Charlotte Nicole Hill
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile.,Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile.,Facultad de Ciencias Biológicas, Millennium Institute for Immunology and Immunotherapy, Santiago, Chile
| | - Felipe A Bustamante-Barrientos
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile
| | - Alexander Ortloff
- Departamento de Ciencias Veterinarias y Salud Pública, Facultad de Recursos Naturales, Universidad Católica de Temuco, Temuco, Chile
| | - Cynthia García
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile
| | - Felipe Galvez-Jiron
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile
| | - Carolina Pradenas
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile
| | - Noymar Luque-Campos
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile
| | - Gabriela Maita
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile.,Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Roberto Elizondo-Vega
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Farida Djouad
- Institute for Regenerative Medicine and Biotherapy (IRMB), Univ Montpellier, Institut national de la santé et de la recherche médicale (INSERM), Montpellier, France
| | - Ana María Vega-Letter
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile
| | - Patricia Luz-Crawford
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile.,IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
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27
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Yu J, Chen S, Lei S, Li F, Wang Y, Shu X, Xu W, Tang X. The Effects of Porphyromonas gingivalis on Inflammatory and Immune Responses and Osteogenesis of Mesenchymal Stem Cells. Stem Cells Dev 2021; 30:1191-1201. [PMID: 34628938 DOI: 10.1089/scd.2021.0068] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are increasingly used in tissue regeneration, not only because of their multilineage differentiation ability, but also because of their immunomodulatory function, which allows them to play a role in the inflammatory milieu, especially in periodontitis. Porphyromonas gingivalis (P. gingivalis) is an important pathogen associated with the progression of periodontitis. Heterogeneous MSC sources show differences in their inflammatory-immune responsiveness and osteogenesis capabilities when exposed to P. gingivalis and its virulence factors. This article reviews the promoted inflammatory and immune responses of periodontal ligament stem cells, which are potential pitfalls in bone regeneration. MSCs from other sources showed contradictory inflammatory and immune reactions in the few studies on this topic. We also summarize the mechanisms involved in the inflammatory, immune responses and osteogenic potential of MSCs exposed to P. gingivalis and its virulence factors to inform an improved utilization of MSCs in regenerative therapies for periodontitis.
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Affiliation(s)
- Jingjun Yu
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Shuangshuang Chen
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Shuang Lei
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Fulong Li
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Yan Wang
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Xiufang Shu
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Wanlin Xu
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Xiaolin Tang
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
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28
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Yang N, Liu X, Chen X, Yu S, Yang W, Liu Y. Stem cells from exfoliated deciduous teeth transplantation ameliorates Sjögren's syndrome by secreting soluble PD-L1. J Leukoc Biol 2021; 111:1043-1055. [PMID: 34622984 DOI: 10.1002/jlb.6ma0921-752rr] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cell transplantation (MSCT) regulates immune cells, and is a promising therapeutic approach for treating autoimmune diseases. Stem cells from human exfoliated deciduous teeth (SHED) are a unique postnatal stem cell population from the cranial neural crest with high self-renewal, multipotent differentiation, and superior immunomodulatory properties. However, the mechanisms by which SHED can treat autoimmune diseases remain unclear. Sjögren's syndrome (SS) is an autoimmune disease histologically characterized by high lymphocytic infiltration in the salivary and lacrimal glands that results in dryness symptoms. This study explores the potential of systemic transplantation of SHED to ameliorate SS-induced dryness symptoms in mice. Overall, SHED could rescue the balance of regulatory T cell (Treg)/T helper cell 17 (Th17) in the recipient SS mice. Mechanistically, SHED promoted Treg conversion and inhibited Th17 function via paracrine effects, which were related to the secretion of soluble programmed cell death ligand 1 (sPD-L1). Moreover, it directly induced Th17 apoptosis via cell-cell contact, leading to the up-regulation of Treg and down-regulation of Th17 cells. In summary, SHED-mediated rescue of Treg/Th17 balance via the sPD-L1/PD-1 pathway ameliorates the gland inflammation and dryness symptoms in SS mice. These findings suggest that SHED are a promising stem cell source for the treatment of autoimmune diseases in the clinical setting.
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Affiliation(s)
- Ning Yang
- Department of Pediatric Dentistry, School and Hospital of Stomatology, China Medical University, Shenyang, China.,Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Xuemei Liu
- Department of Pediatric Dentistry, School and Hospital of Stomatology, China Medical University, Shenyang, China.,Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Xu Chen
- Department of Pediatric Dentistry, School and Hospital of Stomatology, China Medical University, Shenyang, China.,Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Si Yu
- Department of Pediatric Dentistry, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Wenxiao Yang
- Department of Pediatric Dentistry, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Yao Liu
- Department of Pediatric Dentistry, School and Hospital of Stomatology, China Medical University, Shenyang, China.,Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
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29
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Zheng K, Niu W, Lei B, Boccaccini AR. Immunomodulatory bioactive glasses for tissue regeneration. Acta Biomater 2021; 133:168-186. [PMID: 34418539 DOI: 10.1016/j.actbio.2021.08.023] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 08/06/2021] [Accepted: 08/16/2021] [Indexed: 02/07/2023]
Abstract
The regulatory functions of the immune response in tissue healing, repair, and regeneration have been evidenced in the last decade. Immune cells play central roles in immune responses toward inducing favorable tissue regenerative processes. Modulating and controlling the immune cell responses (particularly macrophages) is an emerging approach to enhance tissue regeneration. Bioactive glasses (BGs) are multifunctional materials exhibiting osteogenic, angiogenic, and antibacterial properties, being increasingly investigated for various tissue regeneration scenarios, including bone regeneration and wound healing. On the other hand, the immunomodulatory effects of BGs in relation to regenerating tissues have started to be understood, and key knowledge is emerging. This is the first review article summarizing the immunomodulatory effects of BGs for tissue repair and regeneration. The immune response to BGs is firstly introduced, discussing potential mechanisms regarding the immunomodulation effects induced by BGs. Moreover, the interactions between the immune cells involved in the immunomodulation process and BGs (dissolution products) are summarized in detail. Particularly, a well-regulated and timely switch of macrophage phenotype from pro-inflammatory to anti-inflammatory is crucial to constructive tissue regeneration through modulating osteogenesis, osteoclastogenesis, and angiogenesis. The influence of BG characteristics on macrophage responses is discussed. We highlight the strategies employed to harness macrophage responses for enhanced tissue regeneration, including the incorporation of active ions, surface functionalization, and controlled release of immunomodulatory molecules. Finally, we conclude with our perspectives on future research challenges and directions in the emerging field of immunomodulatory BGs for tissue regeneration. STATEMENT OF SIGNIFICANCE: Immunomodulatory effects of bioactive glasses (BGs) in relation to bone regeneration and wound healing have started to be understood. We summarize those studies which have focused on immunomodulatory BGs for tissue regeneration. We first introduce the potential mechanisms of the immunomodulation effects induced by BGs. Interactions between the cells involved in immunomodulation processes and BGs (and their dissolution products, biologically active ions) are elaborated. We highlight the strategies employed to modulate macrophage responses for enhancing tissue regeneration, including incorporation of active ions, surface functionalization, and controlled release of immunomodulatory agents. This is the first review article summarizing and outlining the immunomodulatory effects of BGs for tissue regeneration. We anticipate that increasing research efforts will start to emerge in the area of immunomodulatory BGs.
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Affiliation(s)
- Kai Zheng
- Institute of Biomaterials, University of Erlangen-Nuremberg, 91058 Erlangen, Germany.
| | - Wen Niu
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, 710000 Xi'an, China
| | - Bo Lei
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, 710000 Xi'an, China.
| | - Aldo R Boccaccini
- Institute of Biomaterials, University of Erlangen-Nuremberg, 91058 Erlangen, Germany.
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Zhang Q, Yu J, Chen Q, Yan H, Du H, Luo W. Regulation of pathophysiological and tissue regenerative functions of MSCs mediated via the WNT signaling pathway (Review). Mol Med Rep 2021; 24:648. [PMID: 34278470 PMCID: PMC8299209 DOI: 10.3892/mmr.2021.12287] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 06/22/2021] [Indexed: 12/18/2022] Open
Abstract
Tissues have remarkable natural capabilities to regenerate for the purpose of physiological turnover and repair of damage. Adult mesenchymal stem cells (MSCs) are well known for their unique self-renewal ability, pluripotency, homing potential, paracrine effects and immunomodulation. Advanced research of the unique properties of MSCs have opened up new horizons for tissue regenerative therapies. However, certain drawbacks of the application of MSCs, such as the low survival rate of transplanted MSCs, unsatisfactory efficiency and even failure to regenerate under an unbalanced microenvironment, are concerning with regards to their wider therapeutic applications. The activity of stem cells is mainly regulated by the anatomical niche; where they are placed during their clinical and therapeutic applications. Crosstalk between various niche signals maintains MSCs in homeostasis, in which the WNT signaling pathway plays vital roles. Several external or internal stimuli have been reported to interrupt the normal bioactivity of stem cells. The irreversible tissue loss that occurs during infection at the site of tissue grafting suggests an inhibitory effect mediated by microbial infections within MSC niches. In addition, MSC-seeded tissue engineering success is difficult in various tissues, when sites of injury are under the effects of a severe infection despite the immunomodulatory properties of MSCs. In the present review, the current understanding of the way in which WNT signaling regulates MSC activity modification under physiological and pathological conditions was summarized. An effort was also made to illustrate parts of the underlying mechanism, including the inflammatory factors and their interactions with the regulatory WNT signaling pathway, aiming to promote the clinical translation of MSC-based therapy.
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Affiliation(s)
- Qingtao Zhang
- Department of Stomatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310085, P.R. China
| | - Jian Yu
- Department of Stomatology, Zhejiang Hospital, Hangzhou, Zhejiang 310030, P.R. China
| | - Qiuqiu Chen
- Department of Stomatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310085, P.R. China
| | - Honghai Yan
- Department of Stomatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310085, P.R. China
| | - Hongjiang Du
- Department of Stomatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310085, P.R. China
| | - Wenjing Luo
- Department of General Dentistry, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118, USA
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Mallis P, Michalopoulos E, Chatzistamatiou T, Giokas CS. Interplay between mesenchymal stromal cells and immune system: clinical applications in immune-related diseases. EXPLORATION OF IMMUNOLOGY 2021. [DOI: 10.37349/ei.2021.00010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/07/2021] [Indexed: 11/08/2024]
Abstract
Mesenchymal stromal cells (MSCs) are a mesodermal stem cell population, with known self-renewal and multilineage differentiation properties. In the last century, MSCs have been widely used in regenerative medicine and tissue engineering approaches. MSCs initially were isolated from bone marrow aspirates, but currently have been identified in a great number of tissues of the human body. Besides their utilization in regenerative medicine, MSCs possess significant immunoregulatory/immunosuppressive properties, through interaction with the cells of innate and adaptive immunity. MSCs can exert their immunomodulatory properties with either cell-cell contact or via paracrine secretion of molecules, such as cytokines, growth factors and chemokines. Of particular importance, the MSCs’ immunomodulatory properties are explored as promising therapeutic strategies in immune-related disorders, such as autoimmune diseases, graft versus host disease, cancer. MSCs may also have an additional impact on coronavirus disease-19 (COVID-19), by attenuating the severe symptoms of this disorder. Nowadays, a great number of clinical trials, of MSC-mediated therapies are evaluated for their therapeutic potential. In this review, the current knowledge on cellular and molecular mechanisms involved in MSC-mediated immunomodulation were highlighted. Also, the most important aspects, regarding their potential application in immune-related diseases, will be highlighted. The broad application of MSCs has emerged their role as key immunomodulatory players, therefore their utilization in many disease situations is full of possibilities for future clinical treatment.
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Affiliation(s)
- Panagiotis Mallis
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece
| | - Efstathios Michalopoulos
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece
| | - Theofanis Chatzistamatiou
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece 2Histocompatibility & Immunogenetics Lab, Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece
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Sanchez-Diaz M, Quiñones-Vico MI, Sanabria de la Torre R, Montero-Vílchez T, Sierra-Sánchez A, Molina-Leyva A, Arias-Santiago S. Biodistribution of Mesenchymal Stromal Cells after Administration in Animal Models and Humans: A Systematic Review. J Clin Med 2021; 10:jcm10132925. [PMID: 34210026 PMCID: PMC8268414 DOI: 10.3390/jcm10132925] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal Stromal Cells (MSCs) are of great interest in cellular therapy. Different routes of administration of MSCs have been described both in pre-clinical and clinical reports. Knowledge about the fate of the administered cells is critical for developing MSC-based therapies. The aim of this review is to describe how MSCs are distributed after injection, using different administration routes in animal models and humans. A literature search was performed in order to consider how MSCs distribute after intravenous, intraarterial, intramuscular, intraarticular and intralesional injection into both animal models and humans. Studies addressing the biodistribution of MSCs in “in vivo” animal models and humans were included. After the search, 109 articles were included in the review. Intravenous administration of MSCs is widely used; it leads to an initial accumulation of cells in the lungs with later redistribution to the liver, spleen and kidneys. Intraarterial infusion bypasses the lungs, so MSCs distribute widely throughout the rest of the body. Intramuscular, intraarticular and intradermal administration lack systemic biodistribution. Injection into various specific organs is also described. Biodistribution of MSCs in animal models and humans appears to be similar and depends on the route of administration. More studies with standardized protocols of MSC administration could be useful in order to make results homogeneous and more comparable.
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Affiliation(s)
- Manuel Sanchez-Diaz
- Dermatology Department, Hospital Universitario Virgen de las Nieves, IBS Granada, 18014 Granada, Spain; (M.S.-D.); (T.M.-V.); (A.M.-L.); (S.A.-S.)
| | - Maria I. Quiñones-Vico
- Cellular Production Unit, Hospital Universitario Virgen de las Nieves, IBS Granada, 18014 Granada, Spain; (R.S.d.l.T.); (A.S.-S.)
- Correspondence:
| | - Raquel Sanabria de la Torre
- Cellular Production Unit, Hospital Universitario Virgen de las Nieves, IBS Granada, 18014 Granada, Spain; (R.S.d.l.T.); (A.S.-S.)
| | - Trinidad Montero-Vílchez
- Dermatology Department, Hospital Universitario Virgen de las Nieves, IBS Granada, 18014 Granada, Spain; (M.S.-D.); (T.M.-V.); (A.M.-L.); (S.A.-S.)
| | - Alvaro Sierra-Sánchez
- Cellular Production Unit, Hospital Universitario Virgen de las Nieves, IBS Granada, 18014 Granada, Spain; (R.S.d.l.T.); (A.S.-S.)
| | - Alejandro Molina-Leyva
- Dermatology Department, Hospital Universitario Virgen de las Nieves, IBS Granada, 18014 Granada, Spain; (M.S.-D.); (T.M.-V.); (A.M.-L.); (S.A.-S.)
| | - Salvador Arias-Santiago
- Dermatology Department, Hospital Universitario Virgen de las Nieves, IBS Granada, 18014 Granada, Spain; (M.S.-D.); (T.M.-V.); (A.M.-L.); (S.A.-S.)
- Cellular Production Unit, Hospital Universitario Virgen de las Nieves, IBS Granada, 18014 Granada, Spain; (R.S.d.l.T.); (A.S.-S.)
- School of Medicine, University of Granada, 18014 Granada, Spain
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He L, Xiao J, Song L, Zhou R, Rong Z, He W, Dai F. HVEM Promotes the Osteogenesis of allo-MSCs by Inhibiting the Secretion of IL-17 and IFN-γ in Vγ4T Cells. Front Immunol 2021; 12:689269. [PMID: 34248977 PMCID: PMC8261146 DOI: 10.3389/fimmu.2021.689269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 06/02/2021] [Indexed: 12/29/2022] Open
Abstract
Bone defects are a common orthopaedic concern, and an increasing number of tissue-engineered bones (TEBs) are used to repair bone defects. Allogeneic mesenchymal stem cells (allo-MSCs) are used as seed cells in many approaches to develop TEB constructs, but the immune response caused by allogeneic transplantation may lead to transplant failure. V gamma 4 T (Vγ4T) cells play an important role in mediating the immune response in the early stage after transplantation; therefore, we wanted to verify whether suppressing Vγ4T cells by herpesvirus entry mediator (HVEM)/B and T lymphocyte attenuator (BTLA) signalling can promote MSCs osteogenesis in the transplanted area. In vitro experiments showed that the osteogenic differentiation of MSCs and Vγ4T cells was weakened after co-culture, and an increase in interleukin-17 (IL-17) and interferon-γ (IFN-γ) levels was detected in the culture supernatant. HVEM-transfected MSCs (MSCs-HVEM) still exhibited osteogenic differentiation activity after co-culture with Vγ4T cells, and the levels of IL-17 and IFN-γ in the co-culture supernatant were significantly reduced. In vivo experiments revealed that inflammation in the transplanted area was reduced and osteogenic repair was enhanced after Vγ4T cells were removed. MSCs-HVEM can also consistently contribute to reduced inflammation in the transplanted area and enhanced bone repair in wild-type (WT) mice. Therefore, our experiments verified that HVEM can promote the osteogenesis of allo-MSCs by inhibiting IL-17 and IFN-γ secretion from Vγ4T cells.
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Affiliation(s)
- Lei He
- Department of Orthopaedics, First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Jun Xiao
- Special Service Recuperation Center of Rocket Army, Guangzhou, China
| | - Lei Song
- Department of Orthopaedics, First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Rui Zhou
- Department of Orthopaedics, First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Zhigang Rong
- Department of Orthopaedics, First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Weifeng He
- State Key Laboratory of Trauma, Institute of Burn Research, Southwest Hospital, Army Medical University, Chongqing, China
| | - Fei Dai
- Department of Orthopaedics, First Affiliated Hospital, Army Medical University, Chongqing, China
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Das UN. Bioactive lipid-based therapeutic approach to COVID-19 and other similar infections. Arch Med Sci 2021; 19:1327-1359. [PMID: 37732033 PMCID: PMC10507771 DOI: 10.5114/aoms/135703] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 04/11/2021] [Indexed: 09/22/2023] Open
Abstract
COVID-19 is caused by SARS-CoV-2 infection. Epithelial and T, NK, and other immunocytes release bioactive lipids especially arachidonic acid (AA) in response to microbial infections to inactivate them and upregulate the immune system. COVID-19 (coronavirus) and other enveloped viruses including severe acute respiratory syndrome (SARS-CoV-1 of 2002-2003) and Middle East respiratory syndrome (MERS; 2012-ongoing) and hepatitis B and C (HBV and HCV) can be inactivated by AA, γ-linolenic acid (GLA, dihomo-GLA (DGLA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), which are precursors to several eicosanoids. Prostaglandin E1, lipoxin A4, resolvins, protectins and maresins enhance phagocytosis of macrophages and leukocytes to clear debris from the site(s) of infection and injury, enhance microbial clearance and wound healing to restore homeostasis. Bioactive lipids modulate the generation of M1 and M2 macrophages and the activity of other immunocytes. Mesenchymal and adipose tissue-derived stem cells secrete LXA4 and other bioactive lipids to bring about their beneficial actions in COVID-19. Bioactive lipids regulate vasomotor tone, inflammation, thrombosis, immune response, inactivate enveloped viruses, regulate T cell proliferation and secretion of cytokines, stem cell survival, proliferation and differentiation, and leukocyte and macrophage functions, JAK kinase activity and neutrophil extracellular traps and thus, have a critical role in COVID-19.
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Affiliation(s)
- Undurti N. Das
- UND Life Sciences, Battle Ground, WA, USA
- Department of Medicine, Omega Hospitals, Gachibowli, Hyderabad, India
- International Research Centre, Biotechnologies of the third Millennium, ITMO University, Saint-Petersburg, Russia
- Department of Biotechnology, Indian Institute of Technology-Hyderabad, Telangana, India
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Autophagy-Mediated Activation of Mucosal-Associated Invariant T Cells Driven by Mesenchymal Stem Cell-Derived IL-15. Stem Cell Reports 2021; 16:926-939. [PMID: 33798448 PMCID: PMC8072065 DOI: 10.1016/j.stemcr.2021.03.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 12/30/2022] Open
Abstract
Mucosal-associated invariant T (MAIT) cells are innate-like unconventional T cells that are abundant in humans and have attracted increasing attention in recent years. Mesenchymal stem cells (MSCs) are crucial regulators of immune cells. However, whether MAIT cells are regulated by MSCs is unclear. Here, we explored the effect of MSCs on MAIT cells and revealed the underlying mechanism. We found that MSCs did not influence the proliferation of MAIT cells but strikingly induced an activated phenotype with an increased expression of CD69, TNF-α, IFN-γ, and granzyme B. Moreover, MSCs activated MAIT cells in a TCR-MR1-independent mechanism through MSC-secreted IL-15. We revealed that MSC-derived IL-15 activated MAIT cells by enhancing autophagy activity, which was abolished by the autophagy inhibitor 3-methyladenine. Based on our findings, MAIT cells are activated by MSCs through IL-15-induced autophagy, which may help elucidate the mechanisms underlying some immune responses and diseases and provide guidance for future research.
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Kunwong N, Tangjit N, Rattanapinyopituk K, Dechkunakorn S, Anuwongnukroh N, Arayapisit T, Sritanaudomchai H. Optimization of poly (lactic-co-glycolic acid)-bioactive glass composite scaffold for bone tissue engineering using stem cells from human exfoliated deciduous teeth. Arch Oral Biol 2021; 123:105041. [PMID: 33454420 DOI: 10.1016/j.archoralbio.2021.105041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 12/30/2020] [Accepted: 12/31/2020] [Indexed: 11/26/2022]
Abstract
OBJECTIVE The aim of this study was to develop a composite scaffold with the optimal poly(lactic-co-glycolic acid) (PLGA) and bioactive glass proportions to provide an environment for bone tissue regeneration and repair. DESIGN PLGA-bioactive glass composite scaffolds were prepared using a salt-leaching technique with different percentages of bioactive glass (0%, 10 %, and 15 % [w/w]) with PLGA. The resulting scaffolds were characterized using scanning electron microscopy and energy dispersive X-ray spectroscopy (SEM-EDS), and water contact angle, dynamic mechanical, and pH analysis. The scaffold biocompatibility was investigated using stem cells from human exfoliated deciduous teeth (SHED) and rat experiments. RESULTS SEM-EDS confirmed the successful fabrication of three-dimensional PLGA-bioactive glass scaffolds. The results showed that 10 % bioactive glass with PLGA exhibited favorable properties including increased pore size, hydrophilicity, and mechanical properties. The growth medium pH was increased for scaffolds containing bioactive glass. All scaffolds were biocompatible, and 10 % bioactive glass composite scaffolding showed better attachment, growth, and proliferation of SHED compared to the other scaffolds. Moreover, it enhanced osteogenic differentiation of SHED in vitro and in vivo. CONCLUSIONS Salt-leaching-derived PLGA-bioactive glass composite scaffolds were successfully established. PLGA with 10 % bioactive glass had adequate physical properties and bioactivity, and it could be considered as a composite for bone tissue engineering applications.
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Affiliation(s)
- Natsuda Kunwong
- Department of Materials Science and Engineering, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand
| | - Nathaphon Tangjit
- Department of Orthodontics, Faculty of Dentistry, Mahidol University, Bangkok, 10400, Thailand
| | - Kasem Rattanapinyopituk
- Department of Pathology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Surachai Dechkunakorn
- Department of Orthodontics, Faculty of Dentistry, Mahidol University, Bangkok, 10400, Thailand
| | - Niwat Anuwongnukroh
- Department of Orthodontics, Faculty of Dentistry, Mahidol University, Bangkok, 10400, Thailand
| | - Taweepong Arayapisit
- Department of Anatomy, Faculty of Dentistry, Mahidol University, Bangkok, 10400, Thailand
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Analysis of Same Selected Immunomodulatory Properties of Chorionic Mesenchymal Stem Cells. APPLIED SCIENCES-BASEL 2020. [DOI: 10.3390/app10249040] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Mesenchymal stem cells (MSCs) represent a population of adherent cells that can be isolated from multiple adult tissues. MSCs have immunomodulatory capacity and the ability to differentiate into many cell lines. Research study examines the immunomodulatory properties of MSCs isolated from chorion (CMSCs). Following the stimulation process, it was found that MSCs are capable of immunomodulatory action via the release of bioactive molecules as well as through direct contact with the immune cells. Immunomodulatory potential of the CMSCs was analyzed by modifying proliferative capacity of mitogen-activated lymphocytes. CMSCs and lymphocytes were tested in cell-to-cell contact. Lymphocytes were stained with carboxyfluorescein diacetate succinimidyl ester. Inhibition of the proliferation of activated lymphocytes was observed. Following the co-cultivation, the expression of markers involved in the immune response modulation was assessed. Afterwards, an increase in CMSCs expression of IL-10 was detected. Following the co-cultivation with activated lymphocyte, adhesion molecules CD54 and CD44 in the CMSCs increased. An increase of CD54 expression was observed. The properties of CMSCs, adherence and differentiation ability, were confirmed. The phenotype of CMSCs CD105+, CD90+, CD73+, CD44+, CD29+, CD45−, CD34−, CD54+ was characterized. It was demonstrated that chorion-derived MSCs have important immunomodulatory effects.
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Regenerating the Pulp-Dentine Complex Using Autologous Platelet Concentrates: A Critical Appraisal of the Current Histological Evidence. Tissue Eng Regen Med 2020; 18:37-48. [PMID: 33150561 PMCID: PMC7862478 DOI: 10.1007/s13770-020-00291-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/06/2020] [Accepted: 07/27/2020] [Indexed: 12/13/2022] Open
Abstract
Background: Autologous platelet concentrates such as platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) have gained overwhelming popularity in regenerative endodontics. Clinical evidence reveals the lack of a particular advantage of using PRP or PRF over an evoked blood clot in promoting canal wall thickening and/or continued root development in immature necrotic teeth. Moreover, despite stimulating tissue repair and repopulating the root canals of immature and mature permanent teeth, the new vital tissue may not possess the functional activity of the native pulp tissue. Methods: To better understand the origin, nature, and long-term fate of the tissue types found within the pulp space, we critically examine all available histo-/morphological evidence for pulp–dentine complex regeneration using PRP and/or PRF, alone or together with an evoked blood clot, specialised or unspecialised primary cells, and other biomaterials. Results: Histological data from clinical studies is scant. Reportedly, the inner dentinal surface supports cementum-like tissue formation, but this interface likely deviates in structure and function from the native cementodentinal junction. Presence of bone-like tissue within the pulp space is intriguing since de novo osteogenesis requires closely coordinated recruitment and differentiation of osteoprogenitor cells. Compared to untreated necrotic teeth, an evoked blood clot (with/without PRF) improves fracture resistance. Tooth regeneration using PRF and dental bud cells is unreliable and the constituent neoformed tissues are poorly organised. Conclusion: PRP/PRF fail to demonstrate a significant advantage over an induced blood clot, alone. The true nature of neoformed tissues remains poorly characterised while their response to subsequent insult/injury is unexplored.
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Radmanesh F, Mahmoudi M, Yazdanpanah E, Keyvani V, Kia N, Nikpoor AR, Zafari P, Esmaeili SA. The immunomodulatory effects of mesenchymal stromal cell-based therapy in human and animal models of systemic lupus erythematosus. IUBMB Life 2020; 72:2366-2381. [PMID: 33006813 DOI: 10.1002/iub.2387] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 09/11/2020] [Accepted: 09/12/2020] [Indexed: 12/17/2022]
Abstract
Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune inflammatory disease with no absolute cure. Although the exact etiopathogenesis of SLE is still enigmatic, it has been well demonstrated that a combination of genetic predisposition and environmental factors trigger a disturbance in immune responses and thereby participate in the development of this condition. Almost all available therapeutic strategies in SLE are primarily based on the administration of immunosuppressive drugs and are not curative. Mesenchymal stromal cells (MSCs) are a subset of non-hematopoietic adult stem cells that can be isolated from many adult tissues and are increasingly recognized as immune response modulating agents. MSC-mediated inhibition of immune responses is a complex mechanism that involves almost every aspect of the immune response. MSCs suppress the maturation of antigen-presenting cells (DC and MQ), proliferation of T cells (Th1, T17, and Th2), proliferation and immunoglobulin production of B cells, the cytotoxic activity of CTL and NK cells in addition to increasing regulatory cytokines (TGF-β and IL10), and decreasing inflammatory cytokines (IL17, INF-ϒ, TNF-α, and IL12) levels. MSCs have shown encouraging results in the treatment of several autoimmune diseases, in particular SLE. This report aims to review the beneficial and therapeutic properties of MSCs; it also focuses on the results of animal model studies, preclinical studies, and clinical trials of MSC therapy in SLE from the immunoregulatory aspect.
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Affiliation(s)
| | - Mahmoud Mahmoudi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Esmaeil Yazdanpanah
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vahideh Keyvani
- Molecular Genetics, Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Nadia Kia
- Skin Cancer Prevention Research Center, Torvergata University of Medical Sciences, Rome, Italy
| | - Amin Reza Nikpoor
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Parisa Zafari
- Department of Immunology, School of Medicine, Mazandaran University of Medical Science, Sari, Iran.,Student Research Committee, Mazandaran University of Medical Science, Sari, Iran
| | - Seyed-Alireza Esmaeili
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Mallis P, Michalopoulos E, Chatzistamatiou T, Stavropoulos-Giokas C. Mesenchymal stromal cells as potential immunomodulatory players in severe acute respiratory distress syndrome induced by SARS-CoV-2 infection. World J Stem Cells 2020; 12:731-751. [PMID: 32952855 PMCID: PMC7477656 DOI: 10.4252/wjsc.v12.i8.731] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/10/2020] [Accepted: 07/19/2020] [Indexed: 02/06/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus-2 and the related coronavirus disease-19 (COVID-19) is a worldwide emerging situation, which was initially reported in December 2019 in Wuhan, China. Currently, more than 7258842 new cases, and more than 411879 deaths have been reported globally. This new highly transmitted coronavirus is responsible for the development of severe acute respiratory distress syndrome. Due to this disorder, a great number of patients are hospitalized in the intensive care unit followed by connection to extracorporeal membrane oxygenation for breath supporting and survival. Severe acute respiratory distress syndrome is mostly accompanied by the secretion of proinflammatory cytokines, including interleukin (IL)-2, IL-6, IL-7, granulocyte colony-stimulating factor (GSCF), interferon-inducible protein 10 (IP10), monocyte chemotactic protein-1 (MCP1), macrophage inflammatory protein 1A (MIP1A), and tumor necrosis factor alpha (TNF-α), an event which is known as "cytokine storm". Further disease pathology involves a generalized modulation of immune responses, leading to fatal multiorgan failure. Currently, no specific treatment or vaccination against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been developed. Mesenchymal stromal cells (MSCs), which are known for their immunosuppressive actions, could be applied as an alternative co-therapy in critically-ill COVID-19 patients. Specifically, MSCs can regulate the immune responses through the conversion of Th1 to Th2, activation of M2 macrophages, and modulation of dendritic cells maturation. These key immunoregulatory properties of MSCs may be exerted either by produced soluble factors or by cell-cell contact interactions. To date, several clinical trials have been registered to assess the safety, efficacy, and therapeutic potential of MSCs in COVID-19. Moreover, MSC treatment may be effective for the reversion of ground-glass opacity of damaged lungs and reduce the tissue fibrosis. Taking into account the multifunctional properties of MSCs, the proposed stem-cell-based therapy may be proven significantly effective in critically-ill COVID-19 patients. The current therapeutic strategy may improve the patient's overall condition and in parallel may decrease the mortality rate of the current disease.
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Affiliation(s)
- Panagiotis Mallis
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece.
| | - Efstathios Michalopoulos
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
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Das UN. Bioactive Lipids as Mediators of the Beneficial Action(s) of Mesenchymal Stem Cells in COVID-19. Aging Dis 2020; 11:746-755. [PMID: 32765941 PMCID: PMC7390526 DOI: 10.14336/ad.2020.0521] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 05/21/2020] [Indexed: 12/15/2022] Open
Abstract
It is proposed that the beneficial action of mesenchymal stem cells (MSCs) in COVID-19 and other inflammatory diseases could be attributed to their ability to secrete bioactive lipids (BALs) such as prostaglandin E2 (PGE2) and lipoxin A4 (LXA4) and other similar BALs. This implies that MSCs that have limited or low capacity to secrete BALs may be unable to bring about their beneficial actions. This proposal implies that pretreatment of MSCs with BALs enhance their physiological action or improve their (MSCs) anti-inflammatory and disease resolution capacity to a significant degree. Thus, the beneficial action of MSCs reported in the management of COVID-19 could be attributed to their ability to secrete BALs, especially PGE2 and LXA4. Since PGE2, LXA4 and their precursors AA (arachidonic acid), dihomo-gamma-linolenic acid (DGLA) and gamma-linolenic acid (GLA) inhibit the production of pro-inflammatory IL-6 and TNF-α, they could be employed to treat cytokine storm seen in COVID-19, immune check point inhibitory (ICI) therapy, sepsis and ARDS (acute respiratory disease). This is further supported by the observation that GLA, DGLA and AA inactivate enveloped viruses including COVID-19. Thus, infusions of appropriate amounts of GLA, DGLA, AA, PGE2 and LXA4 are of significant therapeutic benefit in COVID-19, ICI therapy and other inflammatory conditions including but not limited to sepsis. AA is the precursor of both PGE2 and LXA4 suggesting that AA is most suited for such preventive and therapeutic approach.
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Affiliation(s)
- Undurti N Das
- 1UND Life Sciences, Battle Ground, WA 98604, USA.,2BioScience Research Centre and Department of Medicine, Gayatri Vidya Parishad Medical College and Hospital, Visakhapatnam-530048, India
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Wang XD, Li SY, Zhang SJ, Gupta A, Zhang CP, Wang L. The neural system regulates bone homeostasis via mesenchymal stem cells: a translational approach. Am J Cancer Res 2020; 10:4839-4850. [PMID: 32308753 PMCID: PMC7163440 DOI: 10.7150/thno.43771] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 03/12/2020] [Indexed: 12/11/2022] Open
Abstract
Large bone reconstruction is a major clinical issue associated with several challenges, and autograft is the main method for reconstructing large defects of maxillofacial bone. However, postoperative osteoporosis of the bone graft, even with sufficient vascularization, remains a primary problem. Therefore, better understanding of the mechanisms and clinical translation of bone homeostasis is required. Neuronal innervation of the bone is an emerging research topic, especially with regards to the role of peripheral nerves in regulating bone homeostasis. Moreover, sensory and autonomic nerves regulate this process via different types of neurotransmitters, but the specific mechanism is still elusive. In this review article, the current understanding of the interaction between the peripheral nerve and the skeleton system is summarized, with a particular focus on bone marrow mesenchymal stem cells (BMMSCs), except for osteoblasts and osteoclasts. The novel application of nerve-based bone regeneration via BMMSCs may provide a new strategy in tissue engineering and clinical treatment of osteoporosis and bone disorders.
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Hadryś A, Sochanik A, McFadden G, Jazowiecka-Rakus J. Mesenchymal stem cells as carriers for systemic delivery of oncolytic viruses. Eur J Pharmacol 2020; 874:172991. [PMID: 32044323 DOI: 10.1016/j.ejphar.2020.172991] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 01/09/2020] [Accepted: 02/04/2020] [Indexed: 12/13/2022]
Abstract
Progress in genetic engineering led to the emergence of some viruses as potent anticancer therapeutics. These oncolytic viruses combine self-amplification with dual antitumor action: oncolytic (destruction of cancer cells) and immunostimulatory (eliciting acquired antitumor response against cancer epitopes). As any other viruses, they trigger antiviral response upon systemic administration. Mesenchymal stem cells are immature cells capable of self-renewing and differentiating into many cell types that belong to three germinal layers. Due to their inherent tumor tropism mesenchymal stem cells loaded with oncolytic virus can improve delivery of the therapeutic cargo to cancer sites. Shielding of oncolytic viral construct from antiviral host immune response makes these cells prospective delivery vehicles to even hard-to-reach metastatic neoplastic foci. Use of mesenchymal stem cells has been criticized by some investigators as limiting proliferative abilities of primary cells and increasing the risk of malignant transformation, as well as attenuating therapeutic responses. However, majority of preclinical studies indicate safety and efficacy of mesenchymal stem cells used as carriers of oncolytic viruses. In view of contradictory postulates, the debate continues. The review discusses mesenchymal stem cells as carriers for delivery of genetically engineered oncolytic constructs and focuses on systemic approach to oncoviral treatment of some deadly neoplasms.
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Affiliation(s)
- Agata Hadryś
- Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland; Institute of Chemistry, University of Silesia, Poland.
| | - Aleksander Sochanik
- Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland.
| | - Grant McFadden
- Biodesign Institute, Arizona State University, Tempe, AZ, USA.
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Wang W, Wu RD, Chen P, Xu XJ, Shi XZ, Huang LH, Shao ZL, Guo W. Liraglutide combined with human umbilical cord mesenchymal stem cell transplantation inhibits beta-cell apoptosis via mediating the ASK1/JNK/BAX pathway in rats with type 2 diabetes. Diabetes Metab Res Rev 2020; 36:e3212. [PMID: 31411368 DOI: 10.1002/dmrr.3212] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Revised: 06/15/2019] [Accepted: 08/09/2019] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Accumulating evidence suggests an association between beta-cell apoptosis and the ASK1/JNK/BAX pathway. The aim of this study was to investigate the effects of a combined therapy of liraglutide and human umbilical cord mesenchymal stem cells (hUC-MSCs) on the glucose metabolism and islet beta-cell apoptosis, and further explore its relationship to the ASK1/JNK/BAX pathway. METHOD Type 2 diabetes mellitus (T2DM) rat model was induced by a high-sugar and high-fat diet and intraperitoneal injection of low-dose streptozotocin (STZ) (30 mg/kg). Three days after STZ injection, diabetic rats were randomly treated with subcutaneous injection of liraglutide (200 μg/kg/12 h) for 8 weeks and or hUC-MSCs (1 × 106 /rat) at the first and fifth weeks. Diabetes-related physical and biochemical parameters, pancreatic histopathological changes, immunohistochemical staining, quantitative real-time polymerase chain reaction, and western blot were used to measure the expression of apoptosis signal-regulating kinase 1 (ASK1), Jun N-terminal kinase (JNK), Bcl-2 associated X protein (BAX), and B-cell lymphoma-2 (Bcl-2). RESULTS Eight weeks after liraglutide or human umbilical cord mesenchymal stem cell administration, FPG, HbA1c , glucagon, body weight, and pancreatic ASK1, JNK, and BAX mRNA and proteins were significantly decreased, and the levels of serum C-p, INS and GLP-1, ratio of insulin positive area, and Bcl-2 expression were significantly increased in three treatment groups compared with T2DM group (P<.05). CONCLUSION Liraglutide combined with hUC-MSCs improve glucose metabolism and inhibit islet beta-cell apoptosis in a ASK1/JNK/BAX pathway-dependent manner.
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Affiliation(s)
- Wei Wang
- Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Endocrinology, Fuzhou General Hospital, Fuzhou, China
| | - Rong Dan Wu
- Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Endocrinology, Fuzhou General Hospital, Fuzhou, China
| | - Pin Chen
- Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Endocrinology, Fuzhou General Hospital, Fuzhou, China
| | - Xiang Jin Xu
- Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Endocrinology, Fuzhou General Hospital, Fuzhou, China
| | - Xiao Zhi Shi
- Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Endocrinology, Fuzhou General Hospital, Fuzhou, China
| | - Li Hong Huang
- Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Endocrinology, Fuzhou General Hospital, Fuzhou, China
| | - Zhu Lin Shao
- Department of Endocrinology, Fuzhou General Hospital, Fuzhou, China
| | - Wen Guo
- Department of Endocrinology, Fuzhou General Hospital, Fuzhou, China
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Chung JW, Chun SY, Lee EH, Ha YS, Lee JN, Song PH, Yoo ES, Kwon TG, Chung SK, Kim BS. Verification of mesenchymal stem cell injection therapy for interstitial cystitis in a rat model. PLoS One 2019; 14:e0226390. [PMID: 31830131 PMCID: PMC6907861 DOI: 10.1371/journal.pone.0226390] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 11/25/2019] [Indexed: 12/31/2022] Open
Abstract
Objective Interstitial cystitis (IC) is a chronic intractable disease. Recently, the potential application of stem cell (SC) therapy was suggested for IC management. This study aimed to establish an optimal SC source and verify the efficacy and safety of SC injection therapy in an IC rat model. Design After IC animal model induction, urine-derived stem cells (USCs), adipose tissue-derived stem cells (ADSCs), bone marrow-derived stem cells (BMSCs) and amniotic fluid-derived stem cells (AFSCs) were injected into the bladder submucosa. The following parameters were analysed: 1) functional improvement of bladder via cystometry, 2) histological changes and 3) inflammatory gene expression and regenerative potential of damaged bladder tissues. Additionally, an optimal method for SC introduction in terms of effective bladder regeneration was analysed. Results Intercontraction interval was significantly increased and inflammatory reactions and fibrotic changes were decreased in all of the SC-injected groups than in the control group. PCR analysis revealed that inflammatory gene expression significantly decreased in the USC-treated group than in the other groups. To confirm the optimal SC injection route in the IC rat model, group was divided according to the following criteria: 1) direction of SC injection into the bladder submucosa, 2) injection via tail vein, 3) transurethral instillation. In each analysis, the groups in which SCs were injected into the bladder submucosa showed significantly longer intercontraction interval, better morphologic regeneration and inhibition of bladder inflammatory reaction compared with the other groups. Conclusion Regardless of the cell source, human tissue-derived mesenchymal SCs regenerated damaged bladder tissue, promoted functional recovery and inhibited inflammatory cell accumulation in an IC rat model; particularly, USC had the highest inhibitory effect on inflammation. Additionally, direct USC injection into the bladder submucosa was expected to have the best therapeutic effect, which will be an important factor for clinical applications in the future.
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Affiliation(s)
- Jae-Wook Chung
- Department of Urology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea
| | - So Young Chun
- BioMedical Research Institute, Joint Institute for Regenerative Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Eun Hye Lee
- Department of Pathology, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Yun-Sok Ha
- Department of Urology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea
- Joint Institute for Regenerative Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Jun Nyung Lee
- Department of Urology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea
- Joint Institute for Regenerative Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Phil Hyun Song
- Department of Urology, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Eun Sang Yoo
- Department of Urology, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Tae Gyun Kwon
- Department of Urology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea
- Joint Institute for Regenerative Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Sung Kwang Chung
- Department of Urology, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Bum Soo Kim
- Joint Institute for Regenerative Medicine, Kyungpook National University, Daegu, Republic of Korea
- Department of Urology, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
- * E-mail:
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Rahmatizadeh F, Gholizadeh-Ghaleh Aziz S, Khodadadi K, Lale Ataei M, Ebrahimie E, Soleimani Rad J, Pashaiasl M. Bidirectional and Opposite Effects of Naïve Mesenchymal Stem Cells on Tumor Growth and Progression. Adv Pharm Bull 2019; 9:539-558. [PMID: 31857958 PMCID: PMC6912184 DOI: 10.15171/apb.2019.063] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 07/31/2019] [Accepted: 08/13/2019] [Indexed: 12/16/2022] Open
Abstract
Cancer has long been considered as a heterogeneous population of uncontrolled proliferation of
different transformed cell types. The recent findings concerning tumorigeneses have highlighted
the fact that tumors can progress through tight relationships among tumor cells, cellular, and
non-cellular components which are present within tumor tissues. In recent years, studies have
shown that mesenchymal stem cells (MSCs) are essential components of non-tumor cells within
the tumor tissues that can strongly affect tumor development. Several forms of MSCs have been
identified within tumor stroma. Naïve (innate) mesenchymal stem cells (N-MSCs) derived from
different sources are mostly recruited into the tumor stroma. N-MSCs exert dual and divergent
effects on tumor growth through different conditions and factors such as toll-like receptor
priming (TLR-priming), which is the primary underlying causes of opposite effects. Moreover,
MSCs also have the contrary effects by various molecular mechanisms relying on direct cellto-
cell connections and indirect communications through the autocrine, paracrine routes, and
tumor microenvironment (TME).
Overall, cell-based therapies will hold great promise to provide novel anticancer treatments.
However, the application of intact MSCs in cancer treatment can theoretically cause adverse
clinical outcomes. It is essential that to extensively analysis the effective factors and conditions
in which underlying mechanisms are adopted by MSCs when encounter with cancer.
The aim is to review the cellular and molecular mechanisms underlying the dual effects of
MSCs followed by the importance of polarization of MSCs through priming of TLRs.
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Affiliation(s)
- Faramarz Rahmatizadeh
- Department of Molecular Medicine, Faculty of Advanced Medical Science, Tabriz University of Medical Science, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Khodadad Khodadadi
- Murdoch Children's Research Institute, Royal Children's Hospital, The University of Melbourne, Melbourne, Australia
| | - Maryam Lale Ataei
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Esmaeil Ebrahimie
- Adelaide Medical School, University of Adelaide, Adelaide, Australia.,School of Animal and Veterinary Sciences, University of Adelaide, Adelaide, Australia
| | - Jafar Soleimani Rad
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Reproductive Biology, Faculty of Advanced Medical Science, Tabriz University of Medical Science, Tabriz, Iran
| | - Maryam Pashaiasl
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Reproductive Biology, Faculty of Advanced Medical Science, Tabriz University of Medical Science, Tabriz, Iran.,Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Alvarez C, Monasterio G, Cavalla F, Córdova LA, Hernández M, Heymann D, Garlet GP, Sorsa T, Pärnänen P, Lee HM, Golub LM, Vernal R, Kantarci A. Osteoimmunology of Oral and Maxillofacial Diseases: Translational Applications Based on Biological Mechanisms. Front Immunol 2019; 10:1664. [PMID: 31379856 PMCID: PMC6657671 DOI: 10.3389/fimmu.2019.01664] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 07/03/2019] [Indexed: 12/23/2022] Open
Abstract
The maxillofacial skeleton is highly dynamic and requires a constant equilibrium between the bone resorption and bone formation. The field of osteoimmunology explores the interactions between bone metabolism and the immune response, providing a context to study the complex cellular and molecular networks involved in oro-maxillofacial osteolytic diseases. In this review, we present a framework for understanding the potential mechanisms underlying the immuno-pathobiology in etiologically-diverse diseases that affect the oral and maxillofacial region and share bone destruction as their common clinical outcome. These otherwise different pathologies share similar inflammatory pathways mediated by central cellular players, such as macrophages, T and B cells, that promote the differentiation and activation of osteoclasts, ineffective or insufficient bone apposition by osteoblasts, and the continuous production of osteoclastogenic signals by immune and local stromal cells. We also present the potential translational applications of this knowledge based on the biological mechanisms involved in the inflammation-induced bone destruction. Such applications can be the development of immune-based therapies that promote bone healing/regeneration, the identification of host-derived inflammatory/collagenolytic biomarkers as diagnostics tools, the assessment of links between oral and systemic diseases; and the characterization of genetic polymorphisms in immune or bone-related genes that will help diagnosis of susceptible individuals.
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Affiliation(s)
- Carla Alvarez
- Forsyth Institute, Cambridge, MA, United States
- Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
| | - Gustavo Monasterio
- Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
| | - Franco Cavalla
- Department of Conservative Dentistry, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
| | - Luis A. Córdova
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, San Jose's Hospital and Clínica Las Condes, Universidad de Chile, Santiago, Chile
| | - Marcela Hernández
- Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
| | - Dominique Heymann
- INSERM, UMR 1232, LabCT, CRCINA, Institut de Cancérologie de l'Ouest, Université de Nantes, Université d'Angers, Saint-Herblain, France
| | - Gustavo P. Garlet
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, Brazil
| | - Timo Sorsa
- Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
- Department of Oral Diseases, Karolinska Institutet, Stockholm, Sweden
| | - Pirjo Pärnänen
- Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
| | - Hsi-Ming Lee
- Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, United States
| | - Lorne M. Golub
- Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, United States
| | - Rolando Vernal
- Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
- Dentistry Unit, Faculty of Health Sciences, Universidad Autónoma de Chile, Santiago, Chile
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Wu J, Chen L, Wang R, Song Z, Shen Z, Zhao Y, Huang S, Lin Z. Exosomes Secreted by Stem Cells from Human Exfoliated Deciduous Teeth Promote Alveolar Bone Defect Repair through the Regulation of Angiogenesis and Osteogenesis. ACS Biomater Sci Eng 2019; 5:3561-3571. [PMID: 33405738 DOI: 10.1021/acsbiomaterials.9b00607] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Jinyan Wu
- Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, No. 56, Lingyuan West Road, Guangzhou 510055, China
| | - Lingling Chen
- Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, No. 56, Lingyuan West Road, Guangzhou 510055, China
| | - Runfu Wang
- Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, No. 56, Lingyuan West Road, Guangzhou 510055, China
| | - Zhi Song
- Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, No. 56, Lingyuan West Road, Guangzhou 510055, China
| | - Zongshan Shen
- Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, No. 56, Lingyuan West Road, Guangzhou 510055, China
| | - Yiming Zhao
- Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, No. 56, Lingyuan West Road, Guangzhou 510055, China
| | - Shuheng Huang
- Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, No. 56, Lingyuan West Road, Guangzhou 510055, China
| | - Zhengmei Lin
- Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, No. 56, Lingyuan West Road, Guangzhou 510055, China
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Tanaka Y, Sonoda S, Yamaza H, Murata S, Nishida K, Kyumoto-Nakamura Y, Uehara N, Nonaka K, Kukita T, Yamaza T. Acetylsalicylic Acid Treatment and Suppressive Regulation of AKT Accelerate Odontogenic Differentiation of Stem Cells from the Apical Papilla. J Endod 2019; 45:591-598.e6. [DOI: 10.1016/j.joen.2019.01.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 01/07/2019] [Accepted: 01/17/2019] [Indexed: 01/26/2023]
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50
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Mosanya CH, Isaacs JD. Tolerising cellular therapies: what is their promise for autoimmune disease? Ann Rheum Dis 2019; 78:297-310. [PMID: 30389690 PMCID: PMC6390030 DOI: 10.1136/annrheumdis-2018-214024] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 09/22/2018] [Accepted: 10/06/2018] [Indexed: 12/11/2022]
Abstract
The current management of autoimmunity involves the administration of immunosuppressive drugs coupled to symptomatic and functional interventions such as anti-inflammatory therapies and hormone replacement. Given the chronic nature of autoimmunity, however, the ideal therapeutic strategy would be to reinduce self-tolerance before significant tissue damage has accrued. Defects in, or defective regulation of, key immune cells such as regulatory T cells have been documented in several types of human autoimmunity. Consequently, it has been suggested that the administration of ex vivo generated, tolerogenic immune cell populations could provide a tractable therapeutic strategy. Several potentially tolerogenic cellular therapies have been developed in recent years; concurrent advances in cell manufacturing technologies promise scalable, affordable interventions if safety and efficacy can be demonstrated. These therapies include mesenchymal stromal cells, tolerogenic dendritic cells and regulatory T cells. Each has advantages and disadvantages, particularly in terms of the requirement for a bespoke versus an 'off-the-shelf' treatment but also their suitability in particular clinical scenarios. In this review, we examine the current evidence for these three types of cellular therapy, in the context of a broader discussion around potential development pathway(s) and their likely future role. A brief overview of preclinical data is followed by a comprehensive discussion of human data.
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Affiliation(s)
- Chijioke H Mosanya
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - John D Isaacs
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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