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Franco-Fuquen P, Figueroa-Aguirre J, Martínez DA, Moreno-Cortes EF, Garcia-Robledo JE, Vargas-Cely F, Castro-Martínez DA, Almaini M, Castro JE. Cellular therapies in rheumatic and musculoskeletal diseases. J Transl Autoimmun 2025; 10:100264. [PMID: 39931050 PMCID: PMC11808717 DOI: 10.1016/j.jtauto.2024.100264] [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: 10/29/2024] [Revised: 12/12/2024] [Accepted: 12/13/2024] [Indexed: 02/13/2025] Open
Abstract
A substantial proportion of patients diagnosed with rheumatologic and musculoskeletal diseases (RMDs) exhibit resistance to conventional therapies or experience recurrent symptoms. These diseases, which include autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus, are marked by the presence of autoreactive B cells that play a critical role in their pathogenesis. The persistence of these autoreactive B cells within lymphatic organs and inflamed tissues impairs the effectiveness of B-cell-depleting monoclonal antibodies like rituximab. A promising therapeutic approach involves using T cells genetically engineered to express chimeric antigen receptors (CARs) that target specific antigens. This strategy has demonstrated efficacy in treating B-cell malignancies by achieving long-term depletion of malignant and normal B cells. Preliminary data from patients with RMDs, particularly those with lupus erythematosus and dermatomyositis, suggest that CAR T-cells targeting CD19 can induce rapid and sustained depletion of circulating B cells, leading to complete clinical and serological responses in cases that were previously unresponsive to conventional therapies. This review will provide an overview of the current state of preclinical and clinical studies on the use of CAR T-cells and other cellular therapies for RMDs. Additionally, it will explore potential future applications of these innovative treatment modalities for managing patients with refractory and recurrent manifestations of these diseases.
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Affiliation(s)
- Pedro Franco-Fuquen
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | - Juana Figueroa-Aguirre
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | - David A. Martínez
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | - Eider F. Moreno-Cortes
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | - Juan E. Garcia-Robledo
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | - Fabio Vargas-Cely
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
| | | | - Mustafa Almaini
- Rheumatology, Allergy & Clinical Immunology Division, Mafraq Hospital, United Arab Emirates
| | - Januario E. Castro
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
- Cancer Research and Cellular Therapies Laboratory, Mayo Clinic, Phoenix, AZ, USA
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Wolski M, Ciesielski T, Buczma K, Fus Ł, Girstun A, Trzcińska-Danielewicz J, Cudnoch-Jędrzejewska A. Administration of Adipose-Derived Stem Cells After the Onset of the Disease Does Not Lower the Levels of Inflammatory Cytokines IL1 and IL6 in a Rat Model of Necrotizing Enterocolitis. Biomedicines 2024; 12:2897. [PMID: 39767803 PMCID: PMC11727438 DOI: 10.3390/biomedicines12122897] [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: 11/12/2024] [Revised: 12/15/2024] [Accepted: 12/16/2024] [Indexed: 01/16/2025] Open
Abstract
Background/Objectives: Research on the roles of stem cells in necrotizing enterocolitis (NEC) has primarily focused on the effects of bone marrow- and amniotic fluid-derived stem cells in mitigating the clinical manifestations of the disease. However, the potential of adipose tissue-derived stem cells (ADSCs) remains unexplored in this context. The aim of this study was to evaluate the therapeutic potential of ADSC administration during the active inflammatory phase of NEC, with a specific focus on reducing the levels of the inflammatory cytokines IL-1 and IL-6. Methods: A self-modified hypoxia-hypothermia-formula feeding rat NEC model was employed. A total of 117 rat pups were divided into two groups: a treatment group (NEC-ADSC, n = 55) and a control group (NEC-PLCB (placebo), n = 62). In the NEC-ADSC group, ADSCs were administered intraperitoneally 24 h into the NEC protocol. After 72 h, bowel and fluid samples were collected for analysis. Results: The analysis revealed no significant effect on NEC histopathology (p = 0.347) or on the levels of IL-1 and IL-6 (p = 0.119 and p = 0.414, respectively). Conclusions: The administration of adipose tissue-derived stem cells after the onset of necrotizing enterocolitis does not reduce the levels of inflammatory cytokines IL-1 and IL-6, nor does it influence the histopathological outcomes of the disease in the rat model. Further research is needed to explore the potential therapeutic role of adipose tissue-derived stem cells in the treatment of necrotizing enterocolitis.
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Affiliation(s)
- Marek Wolski
- Department of Pediatric Surgery, Medical University of Warsaw, Zwirki i Wigury 63a, 02-091 Warsaw, Poland
| | - Tomasz Ciesielski
- Laboratory of Centre for Preclinical Research, Chair and Department of Experimental and Clinical Physiology, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland; (T.C.); (K.B.); (A.C.-J.)
| | - Kasper Buczma
- Laboratory of Centre for Preclinical Research, Chair and Department of Experimental and Clinical Physiology, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland; (T.C.); (K.B.); (A.C.-J.)
| | - Łukasz Fus
- Department of Pathology, Medical University of Warsaw, Pawinskiego 7, 02-106 Warsaw, Poland;
| | - Agnieszka Girstun
- Department of Molecular Biology, Institute of Biochemistry, Faculty of Biology, University of Warsaw, Ilji Miecznikowa 1, 02-096 Warsaw, Poland; (A.G.); (J.T.-D.)
| | - Joanna Trzcińska-Danielewicz
- Department of Molecular Biology, Institute of Biochemistry, Faculty of Biology, University of Warsaw, Ilji Miecznikowa 1, 02-096 Warsaw, Poland; (A.G.); (J.T.-D.)
| | - Agnieszka Cudnoch-Jędrzejewska
- Laboratory of Centre for Preclinical Research, Chair and Department of Experimental and Clinical Physiology, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland; (T.C.); (K.B.); (A.C.-J.)
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Niu Q, Hao J, Li Z, Zhang H. Helper T cells: A potential target for sex hormones to ameliorate rheumatoid arthritis? (Review). Mol Med Rep 2024; 30:215. [PMID: 39370806 PMCID: PMC11450432 DOI: 10.3892/mmr.2024.13339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 09/06/2024] [Indexed: 10/08/2024] Open
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease whose etiology is not fully understood. Defective peripheral immune tolerance and subsequent mis‑differentiation and aberrant infiltration of synovium by various immune cells, especially helper T (Th) cells, play an important role in the development of RA. There are significant sex differences in RA, but the results of studies on the effects of sex hormones on RA have been difficult to standardize and hormone replacement therapy has been limited by the potential for serious side effects. Existing research has amply demonstrated that cellular immune responses are largely determined by sex and that sex hormones play a key role in Th cell responses. Based on the aforementioned background and the plasticity of Th cells, it is reasonable to hypothesize that the action of sex hormones on Th cells will hopefully become a therapeutic target for RA. The present review discussed the role of various Th cell subsets in the pathogenesis of RA and also explored the role of sex hormones on the phenotype and function of these aberrantly regulated immune cells in RA as well as other pathologic effects on RA.
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Affiliation(s)
- Quanjun Niu
- Department of Orthopedics IV, Handan Hospital of Traditional Chinese Medicine, Handan, Hebei 056001, P.R. China
| | - Junhang Hao
- Department of Orthopedics IV, Handan Hospital of Traditional Chinese Medicine, Handan, Hebei 056001, P.R. China
| | - Zhen Li
- Department of Orthopedics IV, Handan Hospital of Traditional Chinese Medicine, Handan, Hebei 056001, P.R. China
| | - Huiping Zhang
- Department of Orthopedics IV, Handan Hospital of Traditional Chinese Medicine, Handan, Hebei 056001, P.R. China
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Wolski M, Ciesielski T, Buczma K, Fus Ł, Girstun A, Trzcińska-Danielewicz J, Cudnoch-Jędrzejewska A. Administration of Adipose Tissue Derived Stem Cells before the Onset of the Disease Lowers the Levels of Inflammatory Cytokines IL-1 and IL-6 in the Rat Model of Necrotizing Enterocolitis. Int J Mol Sci 2024; 25:11052. [PMID: 39456833 PMCID: PMC11507542 DOI: 10.3390/ijms252011052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 10/10/2024] [Accepted: 10/11/2024] [Indexed: 10/28/2024] Open
Abstract
There is little research concerning the role of stem cells in necrotizing enterocolitis (NEC). Bone marrow-derived mesenchymal stem cells (BMDSC) and amniotic fluid-derived stem cells significantly reduced the amount and severity of NEC in the animal models. ADSCs share similar surface markers and differentiation potential with BMDSCs. Their potential role in the setting of NEC has not been researched before. The hypothesis of the study was that prophylactic intraperitoneal administration of ADSCs before the onset of the disease will result in limiting the inflammatory response, effecting a lower incidence of NEC. On a molecular level, this should result in lowering the levels of inflammatory cytokines IL-1 and IL-6. The local ethical committee for animal experiments approval was acquired (WAW2/093/2021). We utilized a self-modified rat NEC model based on single exposure to hypothermia, hypoxia, and formula feeding. One hundred and twenty-eight rat puppies were divided into two groups-prophylaxis (ADSC-NEC, n = 66) and control group (NEC-PLCB, n = 62)-to measure the influence of ADSCs administration on the inflammatory changes in NEC, the level of cell engraftment, and the histopathology of the disease. The analysis did not show a significant effect on histopathology between groups, H(2) = 2.12; p = 0.347; η²H = 0.00. The intensity of the NEC variable results was similar across the analyzed groups (NEC-PLCB and ADSC-NEC). For IL-1 and IL-6, the difference between the NEC-PLCB group and the ADSC-NEC group was statistically significant, p = 0.002 and p < 0.001, respectively. To conclude, administration of adipose tissue-derived stem cells before the onset of the disease lowers the levels of inflammatory cytokines IL-1 and IL-6 but does not affect the histopathological results in the rat model of NEC.
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Affiliation(s)
- Marek Wolski
- Department of Pediatric Surgery, Medical University of Warsaw, Zwirki i Wigury 63a, 02-091 Warsaw, Poland
| | - Tomasz Ciesielski
- Chair and Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland; (T.C.); (K.B.); (A.C.-J.)
| | - Kasper Buczma
- Chair and Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland; (T.C.); (K.B.); (A.C.-J.)
| | - Łukasz Fus
- Department of Pathology, Medical University of Warsaw, Pawinskiego 7, 02-106 Warsaw, Poland;
| | - Agnieszka Girstun
- Department of Molecular Biology, Institute of Biochemistry, Faculty of Biology, University of Warsaw, Ilji Miecznikowa 1, 02-096 Warsaw, Poland; (A.G.); (J.T.-D.)
| | - Joanna Trzcińska-Danielewicz
- Department of Molecular Biology, Institute of Biochemistry, Faculty of Biology, University of Warsaw, Ilji Miecznikowa 1, 02-096 Warsaw, Poland; (A.G.); (J.T.-D.)
| | - Agnieszka Cudnoch-Jędrzejewska
- Chair and Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland; (T.C.); (K.B.); (A.C.-J.)
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Claessens AAE, Vriend L, Ovadja ZN, Harmsen MC, van Dongen JA, Coert JH. Therapeutic Efficacy of Adipose Tissue-Derived Components in Neuropathic Pain: A Systematic Review. Bioengineering (Basel) 2024; 11:992. [PMID: 39451368 PMCID: PMC11504850 DOI: 10.3390/bioengineering11100992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/02/2024] [Accepted: 09/24/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND Neuropathic pain results from a defect in the somatosensory nervous system caused by a diversity of etiologies. The effect of current treat-ment with analgesics and surgery is limited. Studies report the therapeutic use of adipose tissue-derived components to treat neuropathic pain as a new treatment modality. OBJECTIVE The aim of this systematic review was to investigate the therapeutic clinical efficacy of adipose tissue-derived components on neuro-pathic pain. METHODS PubMed, Medline, Cochrane and Embase databases were searched until August 2023. Clinical studies assessing neuropathic pain after autologous fat grafting or the therapeutic use of adipose tissue-derived com-ponents were included. The outcomes of interest were neuropathic pain and quality of life. RESULTS In total, 433 studies were identified, of which 109 dupli-cates were removed, 324 abstracts were screened and 314 articles were excluded. In total, ten studies were included for comparison. Fat grafting and cellular stromal vascular fraction were used as treatments. Fat grafting indications were post-mastectomy pain syndrome, neuromas, post-herpetic neuropathy, neuro-pathic scar pain and trigeminal neuropathic pain. In seven studies, neuropathic pain levels decreased, and overall, quality of life did not improve. CONCLUSIONS The therapeutic efficacy of adipose tissue-derived components in the treatment of neuropathic pain remains unclear due to the few performed clinical trials with small sample sizes for various indications. Larger and properly designed (randomized) controlled trials are required.
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Affiliation(s)
- Anouk A. E. Claessens
- Department of Plastic, Reconstructive and Hand Surgery, Medisch Centrum Leeuwarden, 8934 AD Leeuwarden, The Netherlands;
| | - Linda Vriend
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht (UMC Utrecht), 3584 CX Utrecht, The Netherlands; (L.V.); (J.A.v.D.); (J.H.C.)
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands;
| | - Zachri N. Ovadja
- Department of Plastic, Reconstructive and Hand Surgery, Medisch Centrum Leeuwarden, 8934 AD Leeuwarden, The Netherlands;
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht (UMC Utrecht), 3584 CX Utrecht, The Netherlands; (L.V.); (J.A.v.D.); (J.H.C.)
| | - Martin C. Harmsen
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands;
| | - Joris. A. van Dongen
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht (UMC Utrecht), 3584 CX Utrecht, The Netherlands; (L.V.); (J.A.v.D.); (J.H.C.)
| | - J. Henk Coert
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht (UMC Utrecht), 3584 CX Utrecht, The Netherlands; (L.V.); (J.A.v.D.); (J.H.C.)
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Jouybari MT, Mojtahedi F, Babaahmadi M, Faeed M, Eslaminejad MB, Taghiyar L. Advancements in extracellular vesicle targeted therapies for rheumatoid arthritis: insights into cellular origins, current perspectives, and emerging challenges. Stem Cell Res Ther 2024; 15:276. [PMID: 39227964 PMCID: PMC11373471 DOI: 10.1186/s13287-024-03887-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 08/16/2024] [Indexed: 09/05/2024] Open
Abstract
Rheumatoid arthritis (RA) remains a challenging chronic autoimmune disorder characterized by persistent joint inflammation and damage. While modern regenerative strategies, encompassing cell/stem cell-based therapies, gene therapy, and tissue engineering, have advanced tissue repair efforts, a definitive cure for RA remains elusive. Consequently, there is growing interest in developing targeted therapies that directly address the underlying mechanisms driving RA pathogenesis, such as extracellular vesicles (EVs). These small membrane-bound particles can modulate immune responses within the inflammatory microenvironment of damaged cartilage. To launch the clinical potential of EVs, they can be isolated from various cell types through several techniques. EVs can carry various bioactive molecules and anti-inflammatory or pro-regenerative drugs, deliver them directly to the affected joints, and affect the behavior of injured cells, making them a compelling choice for targeted therapy and drug delivery in RA patients. However, there are still several challenges and limitations associated with EV-based therapy, including the absence of standardized protocols for EV isolation, characterization, and delivery. This review provides a comprehensive overview of the cellular sources of EVs in RA and delves into their therapeutic potential and the hurdles they must overcome.
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Affiliation(s)
- Maryam Talebi Jouybari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Banihashem Square, Banihashem St., Resalat Highway, PO Box: 16635-148, Tehran, 1665659911, Iran
- Department of Developmental Biology, University of Science and Culture, Tehran, Iran
| | - Fatemeh Mojtahedi
- Department of Immunology, Shahid Sadoughi University of Medical Science, Yazd, Iran
| | - Mahnaz Babaahmadi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Banihashem Square, Banihashem St., Resalat Highway, PO Box: 16635-148, Tehran, 1665659911, Iran
| | - Maryam Faeed
- School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Mohammadreza Baghaban Eslaminejad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Banihashem Square, Banihashem St., Resalat Highway, PO Box: 16635-148, Tehran, 1665659911, Iran.
| | - Leila Taghiyar
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Banihashem Square, Banihashem St., Resalat Highway, PO Box: 16635-148, Tehran, 1665659911, Iran.
- Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
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McSweeney JE, Yong LY, Goddard NV, Wong JK. Does Secondary Mechanical Manipulation of Lipoaspirate Enhance the Vasculogenic Potential of Fat Grafts? A Systematic Review. Ann Plast Surg 2024; 93:389-396. [PMID: 39150855 DOI: 10.1097/sap.0000000000004048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/18/2024]
Abstract
BACKGROUND Fat grafting is a highly versatile option in the reconstructive armamentarium but with unpredictable retention rates and outcomes. The primary outcome of this systematic review was to assess whether secondary mechanically processed lipoaspirate favorably enhances the vasculogenic potential of fat grafts when compared to unprocessed lipoaspirate or fat grafts prepared using centrifugation alone. The secondary outcome was to assess the evidence around graft retention and improved outcomes when comparing the aforementioned groups. METHODS A search on MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials was conducted up to February 2022. All human and animal research, which provided a cross-comparison between unprocessed, centrifuged, secondary mechanically fragmented (SMF) or secondary mechanically disrupted (SMD) fat grafts, was included. RESULTS Thirty-one full texts were included. Vasculogenic potential was assessed by quantification of angiogenic growth factors and cellular composition. Cellular composition of mesenchymal stem cells, perivascular stem cells, and endothelial progenitor cells was quantified by fluorescence activated cell sorting (FACS) analysis. Fat graft volume retention rates and fat grafting to aid wound healing were assessed. Although the presence of industry-funded studies and inadequate reporting of methodological data in some studies were sources of bias, data showed SMF grafts contain an enriched pericyte population with increased vascular endothelial growth factor (VEGF) secretion. Animal studies indicate that SMD grafts may increase rates of fat graft retention and wound closure compared to centrifuged grafts; however, clinical studies are yet to show similar results. CONCLUSIONS In this systematic review, we were able to conclude that the existing literature suggests mechanically processing fat, whether it be through fragmentation or disruption, improves vasculogenic potential by enhancing angiogenic growth factor and relevant vascular progenitor cell levels. Whilst in vivo animal studies are scarce, the review findings suggest that secondary mechanically processed fat enhances fat graft retention and can aid with wound healing. Further clinical studies are required to assess potential differences in human studies.
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Affiliation(s)
- Jared Ethan McSweeney
- From the Blond McIndoe Laboratories, Division of Cell Matrix Biology and Regenerative Medicine, University of Manchester, Manchester, M13 9PL, UK
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Park SH, Song SW, Lee YJ, Kang H, Kim JE. Mesenchymal Stem Cell Therapy in Alopecia Areata: Visual and Molecular Evidence from a Mouse Model. Int J Mol Sci 2024; 25:9236. [PMID: 39273184 PMCID: PMC11394813 DOI: 10.3390/ijms25179236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 08/22/2024] [Accepted: 08/23/2024] [Indexed: 09/15/2024] Open
Abstract
Recent studies have highlighted the potential of Mesenchymal Stem Cells (MSCs) as an alternative treatment for Alopecia Areata (AA) due to their immunosuppressive properties. While MSCs have shown promise in cell experiments, their effectiveness in vivo remains uncertain. This study aims to validate local administration of MSC therapy's efficacy in AA treatment through animal experiments. AA was induced through Interferon-gamma (IFN-γ) administration in mice, and MSC treatment (MSCT)'s effects were assessed visually and through tissue analysis. The MSC-treated group showed more hair regrowth compared to the control (CTL) group. MSCT notably reduced local inflammatory cytokines (JAK1, JAK2, STAT1, STAT3, IFN-γR, IL-1β, IL-16, IL-17α, and IL-18) in AA-induced mice's skin, but systemic cytokine levels remained unchanged. Furthermore, MSC treatment normalized the expression of Wnt/β-catenin signaling pathway genes (LEF1 and β-catenin) and growth factors (FGF7 and FGF2), which are crucial for hair cycle regulation. This study lays the groundwork for further exploring MSCs as a potential treatment for AA, but more research is needed to fully understand their therapeutic potential.
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Affiliation(s)
- Song-Hee Park
- Department of Dermatology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Republic of Korea
| | - Seo-Won Song
- Department of Dermatology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Republic of Korea
| | - Yu-Jin Lee
- Department of Dermatology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Republic of Korea
| | - Hoon Kang
- Department of Dermatology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Republic of Korea
| | - Jung-Eun Kim
- Department of Dermatology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Republic of Korea
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Liu YR, Wang JQ, Fang L, Xia Q. Diagnostic and Therapeutic Roles of Extracellular Vesicles and Their Enwrapped ncRNAs in Rheumatoid Arthritis. J Inflamm Res 2024; 17:5475-5494. [PMID: 39165320 PMCID: PMC11334919 DOI: 10.2147/jir.s469032] [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: 04/11/2024] [Accepted: 08/02/2024] [Indexed: 08/22/2024] Open
Abstract
Rheumatoid arthritis (RA) is a systemic inflammatory disease whose precise pathogenesis remains mysterious. The involvement of epigenetic regulation in the pathogenesis of RA is one of the most anticipated findings, among which non-coding RNAs (ncRNAs) hold great application promise as diagnostic and therapeutic biomarkers for RA. Extracellular vesicles (EVs) are a heterogeneous group of nano-sized, membrane-enclosed vesicles that mediate intercellular communication and substance exchange, especially the transfer of ncRNAs from donor cells, thereby regulating the functional activities and biological processes of recipient cells. In light of the significant correlation between EVs, ncRNAs, and RA, we first documented expression levels of EVs and their-encapsulated ncRNAs in RA individuals, and methodically discussed their-implicated signaling pathways and phenotypic changes. The last but not least, we paied special attention to the therapeutic benefits of gene therapy reagents specifically imitating or silencing candidate ncRNAs with exosomes as carriers on RA animal models, and briefly highlighted their clinical application advantage and foreground. In conclusion, the present review may be conducive to a deeper comprehension of the diagnostic and therapeutic roles of EVs-enwrapped ncRNAs in RA, with special emphasis on exosomal ncRNAs, which may offer hints for the monitoring and treatment of RA.
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Affiliation(s)
- Ya-ru Liu
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of China
- The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, 230022, People’s Republic of China
| | - Jie-Quan Wang
- Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, 230000, People’s Republic of China
- Department of Pharmacy, Hefei Fourth People’s Hospital, Hefei, 230000, People’s Republic of China
- Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, 230000, People’s Republic of China
| | - Ling Fang
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of China
- The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, 230022, People’s Republic of China
| | - Quan Xia
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of China
- The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, 230022, People’s Republic of China
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Berry CE, Abbas DB, Lintel HA, Churukian AA, Griffin M, Guo JL, Cotterell AC, Parker JBL, Downer MA, Longaker MT, Wan DC. Adipose-Derived Stromal Cell-Based Therapies for Radiation-Induced Fibrosis. Adv Wound Care (New Rochelle) 2024; 13:235-252. [PMID: 36345216 PMCID: PMC11304913 DOI: 10.1089/wound.2022.0103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 10/25/2022] [Indexed: 11/11/2022] Open
Abstract
Significance: Half of all cancer patients receive radiation therapy as a component of their treatment regimen, and the most common resulting complication is radiation-induced fibrosis (RIF) of the skin and soft tissue. This thickening of the dermis paired with decreased vascularity results in functional limitations and esthetic concerns and poses unique challenges when considering surgical exploration or reconstruction. Existing therapeutic options for RIF of the skin are limited both in scope and efficacy. Cell-based therapies have emerged as a promising means of utilizing regenerative cell populations to improve both functional and esthetic outcomes, and even as prophylaxis for RIF. Recent Advances: As one of the leading areas of cell-based therapy research, adipose-derived stromal cells (ADSCs) demonstrate significant therapeutic potential in the treatment of RIF. The introduction of the ADSC-augmented fat graft has shown clinical utility. Recent research dedicated to characterizing specific ADSC subpopulations points toward further granularity in understanding of the mechanisms driving the well-established clinical outcomes seen with fat grafting therapy. Critical Issues: Various animal models of RIF demonstrated improved clinical outcomes following treatment with cell-based therapies, but the cellular and molecular basis underlying these effects remains poorly understood. Future Directions: Recent literature has focused on improving the efficacy of cell-based therapies, most notably through (1) augmentation of fat grafts with platelet-rich plasma and (2) the modification of expressed RNA through epitranscriptomics. For the latter, new and promising gene targets continue to be identified which have the potential to reverse the effects of fibrosis by increasing angiogenesis, decreasing inflammation, and promoting adipogenesis.
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Affiliation(s)
- Charlotte E. Berry
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Darren B. Abbas
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Hendrik A. Lintel
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Andrew A. Churukian
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Michelle Griffin
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Jason L. Guo
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Asha C. Cotterell
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Jennifer B. Laufey Parker
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Mauricio A. Downer
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Michael T. Longaker
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Derrick C. Wan
- Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
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11
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Alavi-Dana SMM, Gholami Y, Meghdadi M, Fadaei MS, Askari VR. Mesenchymal stem cell therapy for COVID-19 infection. Inflammopharmacology 2024; 32:319-334. [PMID: 38117433 DOI: 10.1007/s10787-023-01394-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 11/14/2023] [Indexed: 12/21/2023]
Abstract
COVID-19 emerged in December 2019 in Wuhan, China, spread worldwide rapidly, and caused millions of deaths in a short time. Many preclinical and clinical studies were performed to discover the most efficient therapy to reduce the mortality of COVID-19 patients. Among various approaches for preventing and treating COVID-19, mesenchymal stem cell (MSC) therapy can be regarded as a novel and efficient treatment for managing COVID-19 patients. In this review, we explain the pathogenesis of COVID-19 infection in humans and discuss the role of MSCs in suppressing the inflammation and cytokine storm produced by COVID-19. Then, we reviewed the clinical trial and systematic review studies that investigated the safety and efficacy of MSC therapy in the treatment of COVID-19 infection.
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Affiliation(s)
| | - Yazdan Gholami
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammadreza Meghdadi
- Department of Hematology and Blood Banking, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Saleh Fadaei
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Azadi Sq, Vakil Abad Highway, Mashhad, 9177948564, Iran
| | - Vahid Reza Askari
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Azadi Sq, Vakil Abad Highway, Mashhad, 9177948564, Iran.
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran.
- International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran.
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12
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Mahmoud M, Abdel-Rasheed M, Galal ER, El-Awady RR. Factors Defining Human Adipose Stem/Stromal Cell Immunomodulation in Vitro. Stem Cell Rev Rep 2024; 20:175-205. [PMID: 37962697 PMCID: PMC10799834 DOI: 10.1007/s12015-023-10654-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/06/2023] [Indexed: 11/15/2023]
Abstract
Human adipose tissue-derived stem/stromal cells (hASCs) are adult multipotent mesenchymal stem/stromal cells with immunomodulatory capacities. Here, we present up-to-date knowledge on the impact of different experimental and donor-related factors on hASC immunoregulatory functions in vitro. The experimental determinants include the immunological status of hASCs relative to target immune cells, contact vs. contactless interaction, and oxygen tension. Factors such as the ratio of hASCs to immune cells, the cellular context, the immune cell activation status, and coculture duration are also discussed. Conditioning of hASCs with different approaches before interaction with immune cells, hASC culture in xenogenic or xenofree culture medium, hASC culture in two-dimension vs. three-dimension with biomaterials, and the hASC passage number are among the experimental parameters that greatly may impact the hASC immunosuppressive potential in vitro, thus, they are also considered. Moreover, the influence of donor-related characteristics such as age, sex, and health status on hASC immunomodulation in vitro is reviewed. By analysis of the literature studies, most of the indicated determinants have been investigated in broad non-standardized ranges, so the results are not univocal. Clear conclusions cannot be drawn for the fine-tuned scenarios of many important factors to set a standard hASC immunopotency assay. Such variability needs to be carefully considered in further standardized research. Importantly, field experts' opinions may help to make it clearer.
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Affiliation(s)
- Marwa Mahmoud
- Stem Cell Research Group, Medical Research Centre of Excellence, National Research Centre, 33 El Buhouth St, Ad Doqi, Dokki, 12622, Cairo Governorate, Egypt.
- Department of Medical Molecular Genetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
| | - Mazen Abdel-Rasheed
- Stem Cell Research Group, Medical Research Centre of Excellence, National Research Centre, 33 El Buhouth St, Ad Doqi, Dokki, 12622, Cairo Governorate, Egypt
- Department of Reproductive Health Research, National Research Centre, Cairo, Egypt
| | - Eman Reda Galal
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| | - Rehab R El-Awady
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
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13
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Keese M, Zheng J, Yan K, Bieback K, Yard BA, Pallavi P, Reissfelder C, Kluth MA, Sigl M, Yugublu V. Adipose-Derived Mesenchymal Stem Cells Protect Endothelial Cells from Hypoxic Injury by Suppressing Terminal UPR In Vivo and In Vitro. Int J Mol Sci 2023; 24:17197. [PMID: 38139026 PMCID: PMC10742997 DOI: 10.3390/ijms242417197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 11/29/2023] [Accepted: 11/29/2023] [Indexed: 12/24/2023] Open
Abstract
Adipose-derived stem cells (ASCs) have been used as a therapeutic intervention for peripheral artery disease (PAD) in clinical trials. To further explore the therapeutic mechanism of these mesenchymal multipotent stromal/stem cells in PAD, this study was designed to test the effect of xenogeneic ASCs extracted from human adipose tissue on hypoxic endothelial cells (ECs) and terminal unfolded protein response (UPR) in vitro and in an atherosclerosis-prone apolipoprotein E-deficient mice (ApoE-/- mice) hindlimb ischemia model in vivo. ASCs were added to Cobalt (II) chloride-treated ECs; then, metabolic activity, cell migration, and tube formation were evaluated. Fluorescence-based sensors were used to assess dynamic changes in Ca2+ levels in the cytosolic- and endoplasmic reticulum (ER) as well as changes in reactive oxygen species. Western blotting was used to observe the UPR pathway. To simulate an acute-on-chronic model of PAD, ApoE-/- mice were subjected to a double ligation of the femoral artery (DLFA). An assessment of functional recovery after DFLA was conducted, as well as histology of gastrocnemius. Hypoxia caused ER stress in ECs, but ASCs reduced it, thereby promoting cell survival. Treatment with ASCs ameliorated the effects of ischemia on muscle tissue in the ApoE-/- mice hindlimb ischemia model. Animals showed less muscle necrosis, less inflammation, and lower levels of muscle enzymes after ASC injection. In vitro and in vivo results revealed that all ER stress sensors (BIP, ATF6, CHOP, and XBP1) were activated. We also observed that the expression of these proteins was reduced in the ASCs treatment group. ASCs effectively alleviated endothelial dysfunction under hypoxic conditions by strengthening ATF6 and initiating a transcriptional program to restore ER homeostasis. In general, our data suggest that ASCs may be a meaningful treatment option for patients with PAD who do not have traditional revascularization options.
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Affiliation(s)
- Michael Keese
- Department of Surgery, Medical Centre Mannheim, Medical Faculty Manheim, Heidelberg University, 68167 Mannheim, Germany; (M.K.); (J.Z.); (K.Y.); (P.P.); (C.R.)
- European Center of Angioscience (ECAS), Medical Faculty Manheim, Heidelberg University, 68167 Mannheim, Germany
- Department for Vascular Surgery, Theresienkrankenhaus Mannheim, 68165 Mannheim, Germany
| | - Jiaxing Zheng
- Department of Surgery, Medical Centre Mannheim, Medical Faculty Manheim, Heidelberg University, 68167 Mannheim, Germany; (M.K.); (J.Z.); (K.Y.); (P.P.); (C.R.)
- European Center of Angioscience (ECAS), Medical Faculty Manheim, Heidelberg University, 68167 Mannheim, Germany
| | - Kaixuan Yan
- Department of Surgery, Medical Centre Mannheim, Medical Faculty Manheim, Heidelberg University, 68167 Mannheim, Germany; (M.K.); (J.Z.); (K.Y.); (P.P.); (C.R.)
| | - Karen Bieback
- Institute of Transfusion Medicine and Immunology, Medical Faculty Manheim, Heidelberg University, 68167 Mannheim, Germany;
| | - Benito A. Yard
- V Department of Medicine, Medical Faculty Manheim, Heidelberg University, 68167 Mannheim, Germany;
| | - Prama Pallavi
- Department of Surgery, Medical Centre Mannheim, Medical Faculty Manheim, Heidelberg University, 68167 Mannheim, Germany; (M.K.); (J.Z.); (K.Y.); (P.P.); (C.R.)
- European Center of Angioscience (ECAS), Medical Faculty Manheim, Heidelberg University, 68167 Mannheim, Germany
| | - Christoph Reissfelder
- Department of Surgery, Medical Centre Mannheim, Medical Faculty Manheim, Heidelberg University, 68167 Mannheim, Germany; (M.K.); (J.Z.); (K.Y.); (P.P.); (C.R.)
- DKFZ-Hector Cancer Institute, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Mark Andreas Kluth
- RHEACELL GmbH & Co. KG, Im Neuenheimer Feld 517, 69120 Heidelberg, Germany;
| | - Martin Sigl
- Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany;
| | - Vugar Yugublu
- Department of Surgery, Medical Centre Mannheim, Medical Faculty Manheim, Heidelberg University, 68167 Mannheim, Germany; (M.K.); (J.Z.); (K.Y.); (P.P.); (C.R.)
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14
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Moghaddam MZ, Mousavi MJ, Ghotloo S. Cell-based therapies for the treatment of rheumatoid arthritis. Immun Inflamm Dis 2023; 11:e1091. [PMID: 38018576 PMCID: PMC10664399 DOI: 10.1002/iid3.1091] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 11/01/2023] [Accepted: 11/03/2023] [Indexed: 11/30/2023] Open
Abstract
Autoimmune diseases, including rheumatoid arthritis that is the most prevalent rheumatic autoimmune disorder, affect autologous connective tissues caused by the breakdown of the self-tolerance mechanisms of the immune system. During the last two decades, cell-based therapy, including stem cells and none-stem cells has been increasingly considered as a therapeutic option in various diseases. This is partly due to the unique properties of stem cells that divide and differentiate from the specialized cells in the damaged tissue. Moreover, stem cells and none-stem cells, impose immunomodulatory properties affecting the diseases caused by immunological abnormalities such as rheumatic autoimmune disorders. In the present review, the efficacy of cell-based therapy with four main types of stem cells, including mesenchymal stem cells, hematopoietic stem cells, embryonic stem cells, and human amniotic membrane cells, as well as none-stem cells, including regulatory T cells, chimeric antigen receptor T cells, and tolerogenic dendritic cells will be evaluated. Moreover, other related issues, including safety, changes in immunological parameters, suitable choice of stem cell and none-stem cell origin, conditioning regimen, limitations, and complications will be discussed.
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Affiliation(s)
| | - Mohammad Javad Mousavi
- Department of HematologyFaculty of Allied Medicine, Bushehr University of Medical SciencesBushehrIran
| | - Somayeh Ghotloo
- Autoimmune Diseases Research CenterKashan University of Medical SciencesKashanIran
- Department of Clinical Laboratory SciencesKashan University of Medical SciencesKashanIran
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15
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He L, Zheng Y, Liu M, Dong X, Shen L, He Y, An J, Zhang Y. Nd:YAG-photobiomodulation enhanced ADSCs multilineage differentiation and immunomodulation potentials. Lasers Med Sci 2023; 38:190. [PMID: 37608016 PMCID: PMC10444653 DOI: 10.1007/s10103-023-03818-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 06/17/2023] [Indexed: 08/24/2023]
Abstract
To investigate the effects of Nd: YAG (1064 nm) photobiomodulation on multilineage differentiation and immunomodulation potentials of adipose tissue-derived stem cells (ADSCs) in vitro and in vivo. For in vitro experiments, cells were divided into the control group (non-irradiated control ADSCs) and photobiomodulation groups. 0.5 J/cm2, 1 J/cm2, 2 J/cm2, and 4 J/cm2 were used for proliferation assays; for ADSCs adipogenic differentiation assays, 0.5 J/cm2, 1 J/cm2 were applied; 1 J/cm2 was used for migration and immunomodulation assays. The differentiation abilities were assessed by qPCR, Oil Red O staining, and Alizarin Red staining. The immunomodulation potential was assessed by qPCR and human cytokine array. DSS-induced colitis model. was used to test the effect of photobiomodulation on ADSCs immunomodulation potentials in vivo. Nd:YAG-based photobiomodulation dose-dependently promoted ADSCs proliferation and migration; 1 J/cm2 showed the best promotion effect on proliferation. Moreover, Nd:YAG photobiomodulation promoted ADSCs osteogenic differentiation and brown adipose adipogenic differentiation. The potential immunomodulation assays showed Nd:YAG photobiomodulation improved Anti-inflammation capacity of ADSCs and photobiomodulation irradiated ADSCs effectively alleviated DSS-induced colitis severity in vivo. Our study suggests Nd:YAG photobiomodulation might enhance the ADSCs multilineage differentiation and immunomodulation potentials. These results might help to enhance ADSCs therapeutic effects for clinical application. However, further studies are needed to explore the mechanisms of Nd:YAG photobiomodulation promoting multilineage differentiation and immunomodulation potentials of ADSCs.
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Affiliation(s)
- Linhai He
- First Clinical Division, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, People's Republic of China
| | - Yi Zheng
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22 Zhongguancun Nandajie, Haidian District, Beijing, 100081, People's Republic of China
| | - Meng Liu
- Laser and Cosmetic Surgery Division, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, People's Republic of China
| | - Xian Dong
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22 Zhongguancun Nandajie, Haidian District, Beijing, 100081, People's Republic of China
| | - Lihang Shen
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22 Zhongguancun Nandajie, Haidian District, Beijing, 100081, People's Republic of China
| | - Yang He
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22 Zhongguancun Nandajie, Haidian District, Beijing, 100081, People's Republic of China
| | - Jingang An
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22 Zhongguancun Nandajie, Haidian District, Beijing, 100081, People's Republic of China
| | - Yi Zhang
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22 Zhongguancun Nandajie, Haidian District, Beijing, 100081, People's Republic of China.
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16
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Riekert M, Almanzar G, Schmalzing M, Schütze N, Jakob F, Prelog M. Mesenchymal stem cells modulate IL-17 and IL-9 production induced by Th17-inducing cytokine conditions in autoimmune arthritis: an explorative analysis. Adv Rheumatol 2023; 63:37. [PMID: 37525265 DOI: 10.1186/s42358-023-00317-z] [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: 12/08/2022] [Accepted: 07/19/2023] [Indexed: 08/02/2023] Open
Abstract
BACKGROUND The importance of proinflammatory T-cells and their cytokine production in patients with autoimmune arthritis has been widely described. Due to their immunomodulatory properties, mesenchymal stem cells (MSCs) have come into focus as a potential therapeutic concept. The aim of this study was to investigate the influence of MSCs on the phenotype, cytokine profile, and functionality of naive and non-naive CD4+ T-cells from healthy donors (HD) and patients with autoimmune arthritis under Th17-cytokine polarizing conditions in an explorative way using a transwell system prohibiting any cell-cell-contact. METHODS Magnetically isolated naive and non-naive CD4+ T-cells were stimulated under Th17-polarizing proinflammatory cytokine conditions in presence and absence of bone marrow derived mesenchymal stromal cells (MSCs). After an incubation period of 6 days, the proportions of the T-cell subpopulations TEMRA (CD45RA+CD27-), memory (CD45RA-CD27+), effector (CD45RA-CD27-) and naive cells (CD45RA+CD27+) were determined. Quantitative immunofluorescence intensity was used as a measure for IL-9, IL-17 and IFN-γ production in each subpopulation. RESULTS In isolated naive CD4+ T-cells from HD and patients, MSCs suppressed the differentiation of naive towards an effector phenotype while memory and naive cells showed higher percentages in culture with MSCs. In patients, MSCs significantly decreased the proportion of IL-9 and IL-17 producing effector T-cells. MSCs also reduced IFN-γ production in the naive and memory phenotype from HD. CONCLUSION The results of the study indicate significant immunomodulatory properties of MSCs, as under Th17-polarizing conditions MSCs are still able to control T-cell differentiation and proinflammatory cytokine production in both HD and patients with autoimmune arthritis.
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Affiliation(s)
- Maximilian Riekert
- Department of Pediatrics, University Hospital Wuerzburg, Wuerzburg, Germany.
- Department of Oral and Craniomaxillofacial and Plastic Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Straße 62, 50924, Cologne, Germany.
| | - Giovanni Almanzar
- Department of Pediatrics, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Marc Schmalzing
- Department of Internal Medicine II, University Hospital of Wuerzburg, Wuerzburg, Germany
| | - Norbert Schütze
- Orthopedic Clinic, Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Wuerzburg, Germany
| | - Franz Jakob
- Orthopedic Clinic, Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Wuerzburg, Germany
| | - Martina Prelog
- Department of Pediatrics, University Hospital Wuerzburg, Wuerzburg, Germany
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17
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Carballo-Pedrares N, Ponti F, Lopez-Seijas J, Miranda-Balbuena D, Bono N, Candiani G, Rey-Rico A. Non-viral gene delivery to human mesenchymal stem cells: a practical guide towards cell engineering. J Biol Eng 2023; 17:49. [PMID: 37491322 PMCID: PMC10369726 DOI: 10.1186/s13036-023-00363-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 06/27/2023] [Indexed: 07/27/2023] Open
Abstract
In recent decades, human mesenchymal stem cells (hMSCs) have gained momentum in the field of cell therapy for treating cartilage and bone injuries. Despite the tri-lineage multipotency, proliferative properties, and potent immunomodulatory effects of hMSCs, their clinical potential is hindered by donor variations, limiting their use in medical settings. To address this challenge, gene delivery technologies have emerged as a promising approach to modulate the phenotype and commitment of hMSCs towards specific cell lineages, thereby enhancing osteochondral repair strategies. This review provides a comprehensive overview of current non-viral gene delivery approaches used to engineer MSCs, highlighting key factors such as the choice of nucleic acid or delivery vector, transfection strategies, and experimental parameters. Additionally, it outlines various protocols and methods for qualitative and quantitative evaluation of their therapeutic potential as a delivery system in osteochondral regenerative applications. In summary, this technical review offers a practical guide for optimizing non-viral systems in osteochondral regenerative approaches. hMSCs constitute a key target population for gene therapy techniques. Nevertheless, there is a long way to go for their translation into clinical treatments. In this review, we remind the most relevant transfection conditions to be optimized, such as the type of nucleic acid or delivery vector, the transfection strategy, and the experimental parameters to accurately evaluate a delivery system. This survey provides a practical guide to optimizing non-viral systems for osteochondral regenerative approaches.
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Affiliation(s)
- Natalia Carballo-Pedrares
- Gene & Cell Therapy Research Group (G-CEL). Centro Interdisciplinar de Química y Biología - CICA, Universidade da Coruña, As Carballeiras, S/N. Campus de Elviña, 15071 A, Coruña, Spain
| | - Federica Ponti
- genT_LΛB, Department of Chemistry, Materials and Chemical Engineering "G. Natta", Politecnico Di Milano, 20131, Milan, Italy
- Laboratory for Biomaterials and Bioengineering, Canada Research Chair I in Biomaterials and Bioengineering for the Innovation in Surgery, Department of Min-Met-Materials Engineering & Research Center of CHU de Quebec, Division of Regenerative Medicine, Laval University, Quebec City, QC, Canada
| | - Junquera Lopez-Seijas
- Gene & Cell Therapy Research Group (G-CEL). Centro Interdisciplinar de Química y Biología - CICA, Universidade da Coruña, As Carballeiras, S/N. Campus de Elviña, 15071 A, Coruña, Spain
| | - Diego Miranda-Balbuena
- Gene & Cell Therapy Research Group (G-CEL). Centro Interdisciplinar de Química y Biología - CICA, Universidade da Coruña, As Carballeiras, S/N. Campus de Elviña, 15071 A, Coruña, Spain
| | - Nina Bono
- genT_LΛB, Department of Chemistry, Materials and Chemical Engineering "G. Natta", Politecnico Di Milano, 20131, Milan, Italy
| | - Gabriele Candiani
- genT_LΛB, Department of Chemistry, Materials and Chemical Engineering "G. Natta", Politecnico Di Milano, 20131, Milan, Italy.
| | - Ana Rey-Rico
- Gene & Cell Therapy Research Group (G-CEL). Centro Interdisciplinar de Química y Biología - CICA, Universidade da Coruña, As Carballeiras, S/N. Campus de Elviña, 15071 A, Coruña, Spain.
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18
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Yura Y, Hamada M. Outline of Salivary Gland Pathogenesis of Sjögren's Syndrome and Current Therapeutic Approaches. Int J Mol Sci 2023; 24:11179. [PMID: 37446355 DOI: 10.3390/ijms241311179] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 06/30/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023] Open
Abstract
Sjögren's syndrome (SS) is an autoimmune disease characterized by the involvement of exocrine glands such as the salivary and lacrimal glands. The minor salivary glands, from which tissue samples may be obtained, are important for the diagnosis, evaluation of therapeutic efficacy, and genetic analyses of SS. In the onset of SS, autoantigens derived from the salivary glands are recognized by antigen-presenting dendritic cells, leading to the activation of T and B cells, cytokine production, autoantibody production by plasma cells, the formation of ectopic germinal centers, and the destruction of salivary gland epithelial cells. A recent therapeutic approach with immune checkpoint inhibitors for malignant tumors enhances the anti-tumor activity of cytotoxic effector T cells, but also induces SS-like autoimmune disease as an adverse event. In the treatment of xerostomia, muscarinic agonists and salivary gland duct cleansing procedure, as well as sialendoscopy, are expected to ameliorate symptoms. Clinical trials on biological therapy to attenuate the hyperresponsiveness of B cells in SS patients with systemic organ involvement have progressed. The efficacy of treatment with mesenchymal stem cells and chimeric antigen receptor T cells for SS has also been investigated. In this review, we will provide an overview of the pathogenesis of salivary gland lesions and recent trends in therapeutic approaches for SS.
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Affiliation(s)
- Yoshiaki Yura
- Department of Oral & Maxillofacial Oncology and Surgery, Osaka University Graduate School of Dentistry, Osaka 565-0871, Japan
| | - Masakazu Hamada
- Department of Oral & Maxillofacial Oncology and Surgery, Osaka University Graduate School of Dentistry, Osaka 565-0871, Japan
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19
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Chen SH, Wu CC, Tseng WL, Lu FI, Liu YH, Lin SP, Lin SC, Hsueh YY. Adipose-derived stem cells modulate neuroinflammation and improve functional recovery in chronic constriction injury of the rat sciatic nerve. Front Neurosci 2023; 17:1172740. [PMID: 37457010 PMCID: PMC10339833 DOI: 10.3389/fnins.2023.1172740] [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: 02/23/2023] [Accepted: 06/05/2023] [Indexed: 07/18/2023] Open
Abstract
Introduction Compressive neuropathy, a common chronic traumatic injury of peripheral nerves, leads to variable impairment in sensory and motor function. Clinical symptoms persist in a significant portion of patients despite decompression, with muscle atrophy and persistent neuropathic pain affecting 10%-25% of cases. Excessive inflammation and immune cell infiltration in the injured nerve hinder axon regeneration and functional recovery. Although adipose-derived stem cells (ASCs) have demonstrated neural regeneration and immunomodulatory potential, their specific effects on compressive neuropathy are still unclear. Methods We conducted modified CCI models on adult male Sprague-Dawley rats to induce irreversible neuropathic pain and muscle atrophy in the sciatic nerve. Intraneural ASC injection and nerve decompression were performed. Behavioral analysis, muscle examination, electrophysiological evaluation, and immunofluorescent examination of the injured nerve and associated DRG were conducted to explore axon regeneration, neuroinflammation, and the modulation of inflammatory gene expression. Transplanted ASCs were tracked to investigate potential beneficial mechanisms on the local nerve and DRG. Results Persistent neuropathic pain was induced by chronic constriction of the rat sciatic nerve. Local ASC treatment has demonstrated robust beneficial outcomes, including the alleviation of mechanical allodynia, improvement of gait, regeneration of muscle fibers, and electrophysiological recovery. In addition, locally transplanted ASCs facilitated axon remyelination, alleviated neuroinflammation, and reduced inflammatory cell infiltration of the injured nerve and associated dorsal root ganglion (DRG). Trafficking of the transplanted ASC preserved viability and phenotype less than 7 days but contributed to robust immunomodulatory regulation of inflammatory gene expression in both the injured nerve and DRG. Discussion Locally transplanted ASC on compressed nerve improve sensory and motor recoveries from irreversible chronic constriction injury of rat sciatic nerve via alleviation of both local and remote neuroinflammation, suggesting the promising role of adjuvant ASC therapies for clinical compressive neuropathy.
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Affiliation(s)
- Szu-Han Chen
- Division of Plastic and Reconstructive Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Center of Cell Therapy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- International Research Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Ching Wu
- International Research Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wan-Ling Tseng
- Division of Plastic and Reconstructive Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Fu-I Lu
- Department of Biotechnology and Bioindustry Science, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan
- The integrative Evolutionary Galliform Genomics (iEGG) and Animal Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
| | - Ya-Hsin Liu
- Department of Life Sciences, National Cheng Kung University, Tainan, Taiwan
| | - Shau-Ping Lin
- Institute of Biotechnology, College of Bio-Resources and Agriculture, National Taiwan University, Taipei, Taiwan
| | - Sheng-Che Lin
- Division of Plastic Surgery, Department of Surgery, An-Nan Hospital, China Medical University, Tainan, Taiwan
| | - Yuan-Yu Hsueh
- Division of Plastic and Reconstructive Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Center of Cell Therapy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- International Research Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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20
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Lee BW, Kwok SK. Mesenchymal Stem/Stromal Cell-Based Therapies in Systemic Rheumatic Disease: From Challenges to New Approaches for Overcoming Restrictions. Int J Mol Sci 2023; 24:10161. [PMID: 37373308 PMCID: PMC10299481 DOI: 10.3390/ijms241210161] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 06/10/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Systemic rheumatic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis, are chronic autoimmune diseases affecting multiple organs and tissues. Despite recent advances in treatment, patients still experience significant morbidity and disability. Mesenchymal stem/stromal cell (MSC)-based therapy is promising for treating systemic rheumatic diseases due to the regenerative and immunomodulatory properties of MSCs. However, several challenges need to be overcome to use MSCs in clinical practice effectively. These challenges include MSC sourcing, characterization, standardization, safety, and efficacy issues. In this review, we provide an overview of the current state of MSC-based therapies in systemic rheumatic diseases, highlighting the challenges and limitations associated with their use. We also discuss emerging strategies and novel approaches that can help overcome the limitations. Finally, we provide insights into the future directions of MSC-based therapies for systemic rheumatic diseases and their potential clinical applications.
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Affiliation(s)
| | - Seung-Ki Kwok
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
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Lin Y, Mu D. Immunomodulatory effect of human dedifferentiated fat cells: comparison with adipose-derived stem cells. Cytotechnology 2023; 75:231-242. [PMID: 37187946 PMCID: PMC10167088 DOI: 10.1007/s10616-023-00572-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 02/11/2023] [Indexed: 05/17/2023] Open
Abstract
Dedifferentiated fat cells (DFATs), which are originated by the dedifferentiation of adipocytes, display surface markers of mesenchymal stem cells and are able to differentiate into different cell types, thus, yielding a huge therapeutic potential in repairing damaged tissues and organs. The use of allogeneic stem cells from healthy donors constitutes the basis of a new strategy for cell therapy in the field of transplantation and the first requirement for allografts is determining their immunological properties. In this study, human DFATs and ADSCs were passaged as in vitro models to investigate their immunomodulatory effects. Phenotypic analysis of cell surface markers and three-line differentiation protocols were used to identify stem cells. The immunogenic phenotypes of DFATs and ADSCs were analyzed by flow cytometry and a mixed lymphocyte reaction was used to assess their immune function. The characteristics of stem cells were confirmed by phenotypic identification of cell surface markers and three-line differentiation. Flow cytometry analysis showed that P3 generation DFATs and ADSCs contained human leukocyte antigen (HLA) class I molecules, but did not express HLA class II molecules and costimulatory molecules CD40, CD80 and CD86. Moreover, allogeneic DFATs and ADSCs could not induce the proliferation of peripheral blood mononuclear cells (PBMCs). In addition, both populations were shown to inhibit the Concanavalin A-stimulated proliferation of PBMCs and act as third-party cells responsible for inhibiting the mixed lymphocyte response. DFATs have immunosuppressive properties similar to ADSCs. Based on this, allogeneic DFATs have potential applications in tissue repair or cell therapy.
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Affiliation(s)
- Yan Lin
- Department of Aesthetic and Reconstructive Breast Surgery, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 33 Badachu Road, Shijingshan District, Beijing, 100144 People’s Republic of China
| | - Dali Mu
- Department of Aesthetic and Reconstructive Breast Surgery, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 33 Badachu Road, Shijingshan District, Beijing, 100144 People’s Republic of China
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Ai G, Meng M, Guo J, Li C, Zhu J, Liu L, Liu B, Yang W, Shao X, Cheng Z, Wang L. Adipose-derived stem cells promote the repair of chemotherapy-induced premature ovarian failure by inhibiting granulosa cells apoptosis and senescence. Stem Cell Res Ther 2023; 14:75. [PMID: 37038203 PMCID: PMC10088140 DOI: 10.1186/s13287-023-03297-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 03/23/2023] [Indexed: 04/12/2023] Open
Abstract
BACKGROUND Chemotherapeutic drugs, particularly alkylating cytotoxics such as cyclophosphamide (CTX), play an important role to induce premature ovarian failure (POF). Hormone replacement therapy (HRT) is a widely used treatment to improve hormone secretion. However, the long-term HRT increases the risk of breast cancer and cardiovascular disease are attracting concerns. Therefore, there is an urgent need to develop a safe and effective treatment for POF. METHOD Adipose-derived stem cells (ADSCs) were isolated and identified from human adipose tissue. For POF modeling, CTX were intraperitoneal injected into CTX-acute group, CTX-chronic group, CTX-acute + ADSCs group and CTX-chronic + ADSCs group rats; For transplantation, ADSCs were transplanted into POF rats through tail-vein. The control group rats were injected with PBS. The effects of POF modeling and transplantation were determined by estrous cycle analysis, histopathological analysis, immunohistochemical staining and apoptosis-related marker. To evaluate the effects of ADSC on granulosa cells in vitro, CTX-induced senescent KGN cells were co-cultured with ADSCs, and senescent-related marker expression was investigated by immunofluorescent staining. RESULTS In vivo studies revealed that ADSCs transplantation reduced the apoptosis of ovarian granulosa cells and secretion of follicle-stimulating hormone. The number of total follicles, primordial follicles, primary follicles, and mature follicles and secretion of anti-Müllerian hormone and estradiol (E2) were also increased by ADSCs. The estrous cycle was also improved by ADSC transplantation. Histopathological analysis showed that CTX-damaged ovarian microenvironment was improved by ADSCs. Furthermore, TUNEL staining indicated that apoptosis of granulosa cells was decreased by ADSCs. In vitro assay also demonstrated that ADSC markedly attenuated CTX-induced senescence and apoptosis of granulosa cell. Mechanistically, both in vivo and in vitro experiments proved that ADSC transplantation suppressed activation of the PI3K/Akt/mTOR axis. CONCLUSION Our experiment demonstrated that a single injection of high-dose CTX was a less damaging chemotherapeutic strategy than continuous injection of low-dose CTX, and tail-vein injection of ADSCs was a potential approach to promote the restoration of CTX-induced POF.
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Affiliation(s)
- Guihai Ai
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Meng Meng
- Department of Gynecology and Obstetrics, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China
| | - Jing Guo
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Caixia Li
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Jihui Zhu
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Li Liu
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Biting Liu
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Wenhan Yang
- Department of Gynecology and Obstetrics, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China
| | - Xiaowen Shao
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Zhongping Cheng
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
- Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
- Tongji University School of Medicine, Shanghai, 200092, China.
| | - Lian Wang
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
- Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
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Lang E, Semon JA. Mesenchymal stem cells in the treatment of osteogenesis imperfecta. CELL REGENERATION (LONDON, ENGLAND) 2023; 12:7. [PMID: 36725748 PMCID: PMC9892307 DOI: 10.1186/s13619-022-00146-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 10/18/2022] [Indexed: 02/03/2023]
Abstract
Osteogenesis imperfecta (OI) is a disease caused by mutations in different genes resulting in mild, severe, or lethal forms. With no cure, researchers have investigated the use of cell therapy to correct the underlying molecular defects of OI. Mesenchymal stem cells (MSCs) are of particular interest because of their differentiation capacity, immunomodulatory effects, and their ability to migrate to sites of damage. MSCs can be isolated from different sources, expanded in culture, and have been shown to be safe in numerous clinical applications. This review summarizes the preclinical and clinical studies of MSCs in the treatment of OI. Altogether, the culmination of these studies show that MSCs from different sources: 1) are safe to use in the clinic, 2) migrate to fracture sites and growth sites in bone, 3) engraft in low levels, 4) improve clinical outcome but have a transient effect, 5) have a therapeutic effect most likely due to paracrine mechanisms, and 6) have a reduced therapeutic potential when isolated from patients with OI.
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Affiliation(s)
- Erica Lang
- grid.260128.f0000 0000 9364 6281Department of Biological Sciences, Missouri University of Science and Technology, 400 W 11th St., Rolla, MO USA
| | - Julie A. Semon
- grid.260128.f0000 0000 9364 6281Department of Biological Sciences, Missouri University of Science and Technology, 400 W 11th St., Rolla, MO USA
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Yang P, Zhang S, Yan T, Li F, Zhang S. The Therapeutic Application of Stem Cells and Their Derived Exosomes in the Treatment of Radiation-Induced Skin Injury. Radiat Res 2023; 199:182-201. [PMID: 36630584 DOI: 10.1667/rade-22-00023.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 12/05/2022] [Indexed: 01/13/2023]
Abstract
Radiation-induced skin injury (RISI) is a serious concern for nuclear accidents and cancer radiotherapy, which seriously affects the quality of life of patients. This injury differs from traditional wounds due to impaired healing and the propensity to recurrence and is divided into acute and chronic phases on the basis of the injury time. Unfortunately, there are few effective therapies for preventing or mitigating this injury. Over the last few decades, various studies have focused on the effects of stem cell-based therapies to address the tissue repair and regeneration of irradiated skin. These stem cells modulate inflammation and instigate tissue repair by differentiating into specific kinds of cells or releasing paracrine factors. Stem cell-based therapies, including bone marrow-derived stem cells (BMSCs), adipose-derived stem cells (ADSCs) and stromal vascular fraction (SVF), have been reported to facilitate wound healing after radiation exposure. Moreover, stem cell-derived exosomes have recently been suggested as an effective and cell-free approach to support skin regeneration, circumventing the concerns respecting direct application of stem cells. Based on the literature on stem cell-based therapies for radiation-induced skin injury, we summarize the characteristics of different stem cells and describe their latest animal and clinical applications, as well as potential mechanisms. The promise of stem-cell based therapies against radiation-induced skin injury contribute to our response to nuclear events and smooth progress of cancer radiotherapy.
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Affiliation(s)
- Ping Yang
- Laboratory of Radiation Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China.,Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Shuaijun Zhang
- Laboratory of Radiation Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Tao Yan
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China.,Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu 610051, China
| | - Fengsheng Li
- PLA Rocket Rorce Characteristic Medical Center, Beijing 100088, China
| | - Shuyu Zhang
- Laboratory of Radiation Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China.,Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China.,Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu 610051, China.,NHC Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, Mianyang 621099, China
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25
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Efficacy of Adipose-Derived Mesenchymal Stem Cells and Stromal Vascular Fraction Alone and Combined to Biomaterials in Tendinopathy or Tendon Injury: Systematic Review of Current Concepts. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:medicina59020273. [PMID: 36837474 PMCID: PMC9963687 DOI: 10.3390/medicina59020273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 01/20/2023] [Accepted: 01/25/2023] [Indexed: 02/05/2023]
Abstract
Background and Objectives: Tendon injury and tendinopathy are among the most frequent musculoskeletal diseases and represent a challenging issue for surgeons as well as a great socio-economic global burden. Despite the current treatments available, either surgical or conservative, the tendon healing process is often suboptimal and impaired. This is due to the inherent scarce ability of tendon tissue to repair and return itself to the original structure. Recently, Adipose-derived mesenchymal stem cells (ADSC) and stromal vascular fraction (SVF) have gained a central interest in the scientific community, demonstrating their effectiveness in treatments of acute and chronic tendon disorders in animals and humans. Either enzymatic or mechanical procedures to obtain ADSC and SVF have been described and used in current clinical practice. However, no unified protocols and processes have been established. Materials and Methods: This systematic review aims at providing a comprehensive update of the literature on the clinical application of ADSC enzymatically or mechanically processed to obtain SVF, alone and in association with biomaterials in the local treatment of tendinopathy and tendon injury in vivo, in animal models and humans. The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Results: Thirty-two articles met our inclusion criteria, with a total of 18 studies in animals, 10 studies in humans and 4 studies concerning the application of biomaterials in vivo in animals. The review of the literature suggests that ADSC/SVF therapy can represent a promising alternative in tendonregenerative medicine for the enhancement of tendon healing. Conclusions: Nevertheless, further investigations and randomized control trials are needed to improve the knowledge, standardize the procedures and extend the consensus on their use for such applications.
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Loss of multipotency in adipose-derived stem cells after culture in temperature-responsive injectable polymer hydrogels. Polym J 2022. [DOI: 10.1038/s41428-022-00739-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
AbstractAdipose-derived stem cells (AdSCs), a type of mesenchymal stem cell, are expected to be applicable to regenerative medicine and cellular delivery systems. The maintenance of cell multipotency and control of the differentiation direction are important for these applications. However, the differentiation direction of these cells is widely believed to depend on the physical properties of their scaffold. In this study, we explored whether the multipotency of AdSCs, that is, their ability to differentiate into multiple cells, is maintained when they are removed from injectable polymer (IP) hydrogels with various degrees of cross-linking and induced to differentiate into osteoblasts and adipocytes. We confirmed that AdSCs cultured in IP hydrogels maintained an undifferentiated state. However, their differentiation into osteoblasts and adipocytes cannot be ensured; specifically, the multipotency of AdSCs may decrease when they are cultured in IP hydrogels. When cultured in an IP hydrogel with extreme softness and poor cell adhesion properties, the AdSCs remained in an undifferentiated state, but their multipotency was reduced. These results provide important insights into stem cell delivery systems using IP hydrogels.
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Pezzanite LM, Chow L, Strumpf A, Johnson V, Dow SW. Immune Activated Cellular Therapy for Drug Resistant Infections: Rationale, Mechanisms, and Implications for Veterinary Medicine. Vet Sci 2022; 9:610. [PMID: 36356087 PMCID: PMC9695672 DOI: 10.3390/vetsci9110610] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/18/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
Antimicrobial resistance and biofilm formation both present challenges to treatment of bacterial infections with conventional antibiotic therapy and serve as the impetus for development of improved therapeutic approaches. Mesenchymal stromal cell (MSC) therapy exerts an antimicrobial effect as demonstrated in multiple acute bacterial infection models. This effect can be enhanced by pre-conditioning the MSC with Toll or Nod-like receptor stimulation, termed activated cellular therapy (ACT). The purpose of this review is to summarize the current literature on mechanisms of antimicrobial activity of MSC with emphasis on enhanced effects through receptor agonism, and data supporting use of ACT in treatment of bacterial infections in veterinary species including dogs, cats, and horses with implications for further treatment applications. This review will advance the field's understanding of the use of activated antimicrobial cellular therapy to treat infection, including mechanisms of action and potential therapeutic applications.
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Affiliation(s)
- Lynn M. Pezzanite
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA
| | - Lyndah Chow
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA
| | - Alyssa Strumpf
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, The Ohio State University, Columbus, OH 43210, USA
| | - Valerie Johnson
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Michigan State University, Lansing, MI 48824, USA
| | - Steven W. Dow
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA
- Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA
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Adipose-Derived Stem Cell Exosomes Inhibit Hypertrophic Scaring Formation by Regulating Th17/Treg Cell Balance. BIOMED RESEARCH INTERNATIONAL 2022; 2022:9899135. [PMID: 36277890 PMCID: PMC9581674 DOI: 10.1155/2022/9899135] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 08/31/2022] [Accepted: 09/09/2022] [Indexed: 12/05/2022]
Abstract
Aiming to reveal the role of ADCS-Exos in secretion of inflammatory factors, Th17 and regulatory T (Treg) cell differentiation from naïve CD4+ T cells in hypertrophic scaring formation and maturation is explored. ELISA, qRT-PCR, and immunoblotting are performed to assay the local inflammatory factors IL-6, IL-10, IL-17A, and TNF-α, and transcriptional factors of RORϒt and Foxp3, in scaring tissue from patients and mice wound models treated with or without ADCS-Exos. Immunohistochemistry staining and immunoblotting are conducted to assay the extracellular matrix (ECM) deposition in vitro and in vivo. The results show that IL-6, IL-10, IL-17A, TNF-α, RORϒt, and Foxp3 are increased on mRNA and protein levels in hypertrophic scaring compared with atrophic scaring and normal skin. Naïve CD4+ T cells treated with ADCS-Exos in vitro can produce significantly less IL-6, IL-17A, TNF-α, and RORϒt and more IL-10 and Foxp3 on mRNA and protein levels. In addition, mice in ADSC-Exos-treated group demonstrate less collagen deposition; decreased IL-17A, TNF-α, and RORϒt; and increased IL-10 and Foxp3 production.
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Hoang VT, Nguyen HP, Nguyen VN, Hoang DM, Nguyen TST, Nguyen Thanh L. “Adipose-derived mesenchymal stem cell therapy for the management of female sexual dysfunction: Literature reviews and study design of a clinical trial”. Front Cell Dev Biol 2022; 10:956274. [PMID: 36247008 PMCID: PMC9554747 DOI: 10.3389/fcell.2022.956274] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/29/2022] [Indexed: 11/25/2022] Open
Abstract
Hormone imbalance and female sexual dysfunction immensely affect perimenopausal female health and quality of life. Hormone therapy can improve female hormone deficiency, but long-term use increases the risk of cardiovascular diseases and cancer. Therefore, it is necessary to develop a novel effective treatment to achieve long-term improvement in female general and sexual health. This study reviewed factors affecting syndromes of female sexual dysfunction and its current therapy options. Next, the authors introduced research data on mesenchymal stromal cell/mesenchymal stem cell (MSC) therapy to treat female reproductive diseases, including Asherman’s syndrome, premature ovarian failure/primary ovarian insufficiency, and vaginal atrophy. Among adult tissue-derived MSCs, adipose tissue-derived stem cells (ASCs) have emerged as the most potent therapeutic cell therapy due to their abundant presence in the stromal vascular fraction of fat, high proliferation capacity, superior immunomodulation, and strong secretion profile of regenerative factors. Potential mechanisms and side effects of ASCs for the treatment of female sexual dysfunction will be discussed. Our phase I clinical trial has demonstrated the safety of autologous ASC therapy for women and men with sexual hormone deficiency. We designed the first randomized controlled crossover phase II trial to investigate the safety and efficacy of autologous ASCs to treat female sexual dysfunction in perimenopausal women. Here, we introduce the rationale, trial design, and methodology of this clinical study. Because aging and metabolic diseases negatively impact the bioactivity of adult-derived MSCs, this study will use ASCs cultured in physiological oxygen tension (5%) to cope with these challenges. A total of 130 perimenopausal women with sexual dysfunction will receive two intravenous infusions of autologous ASCs in a crossover design. The aims of the proposed study are to evaluate 1) the safety of cell infusion based on the frequency and severity of adverse events/serious adverse events during infusion and follow-up and 2) improvements in female sexual function assessed by the Female Sexual Function Index (FSFI), the Utian Quality of Life Scale (UQOL), and the levels of follicle-stimulating hormone (FSH) and estradiol. In addition, cellular aging biomarkers, including plasminogen activator inhibitor-1 (PAI-1), p16 and p21 expression in T cells and the inflammatory cytokine profile, will also be characterized. Overall, this study will provide essential insights into the effects and potential mechanisms of ASC therapy for perimenopausal women with sexual dysfunction. It also suggests direction and design strategies for future research.
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Affiliation(s)
- Van T. Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
| | - Hoang-Phuong Nguyen
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
| | - Viet Nhan Nguyen
- Vinmec International Hospital—Times City, Vinmec Health Care System, Hanoi, Vietnam
- College of Health Science, Vin University, Vinhomes Ocean Park, Hanoi, Vietnam
| | - Duc M. Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
| | - Tan-Sinh Thi Nguyen
- Vinmec International Hospital—Times City, Vinmec Health Care System, Hanoi, Vietnam
| | - Liem Nguyen Thanh
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
- Vinmec International Hospital—Times City, Vinmec Health Care System, Hanoi, Vietnam
- College of Health Science, Vin University, Vinhomes Ocean Park, Hanoi, Vietnam
- *Correspondence: Liem Nguyen Thanh,
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Bunnell BA, Martin EC, Matossian MD, Brock CK, Nguyen K, Collins-Burow B, Burow ME. The effect of obesity on adipose-derived stromal cells and adipose tissue and their impact on cancer. Cancer Metastasis Rev 2022; 41:549-573. [PMID: 35999486 DOI: 10.1007/s10555-022-10063-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 08/16/2022] [Indexed: 11/24/2022]
Abstract
The significant increase in the incidence of obesity represents the next global health crisis. As a result, scientific research has focused on gaining deeper insights into obesity and adipose tissue biology. As a result of the excessive accumulation of adipose tissue, obesity results from hyperplasia and hypertrophy within the adipose tissue. The functional alterations in the adipose tissue are a confounding contributing factor to many diseases, including cancer. The increased incidence and aggressiveness of several cancers, including colorectal, postmenopausal breast, endometrial, prostate, esophageal, hematological, malignant melanoma, and renal carcinomas, result from obesity as a contributing factor. The increased morbidity and mortality of obesity-associated cancers are attributable to increased hormones, adipokines, and cytokines produced by the adipose tissue. The increased adipose tissue levels observed in obese patients result in more adipose stromal/stem cells (ASCs) distributed throughout the body. ASCs have been shown to impact cancer progression in vitro and in preclinical animal models. ASCs influence tumor biology via multiple mechanisms, including the increased recruitment of ASCs to the tumor site and increased production of cytokines and growth factors by ASCs and other cells within the tumor stroma. Emerging evidence indicates that obesity induces alterations in the biological properties of ASCs, subsequently leading to enhanced tumorigenesis and metastasis of cancer cells. As the focus of this review is the interaction and impact of ASCs on cancer, the presentation is limited to preclinical data generated on cancers in which there is a demonstrated role for ASCs, such as postmenopausal breast, colorectal, prostate, ovarian, multiple myeloma, osteosarcoma, cervical, bladder, and gastrointestinal cancers. Our group has investigated the interactions between obesity and breast cancer and the mechanisms that regulate ASCs and adipocytes in these different contexts through interactions between cancer cells, immune cells, and other cell types present in the tumor microenvironment (TME) are discussed. The reciprocal and circular feedback loop between obesity and ASCs and the mechanisms by which ASCs from obese patients alter the biology of cancer cells and enhance tumorigenesis will be discussed. At present, the evidence for ASCs directly influencing human tumor growth is somewhat limited, though recent clinical studies suggest there may be some link.
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Affiliation(s)
- Bruce A Bunnell
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA.
| | - Elizabeth C Martin
- Department of Biological and Agricultural Engineering, Louisiana State University, Baton Rouge, LA, USA
| | - Margarite D Matossian
- Department of Microbiology, Immunology and Genetics, University of Chicago, IL, Chicago, USA
| | - Courtney K Brock
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Khoa Nguyen
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Bridgette Collins-Burow
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Matthew E Burow
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
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Zhang G, Wang Y, Lin J, Wang B, Mohsin A, Cheng Z, Hao W, Gao WQ, Xu H, Guo M. Biological activity reduction and mitochondrial and lysosomal dysfunction of mesenchymal stem cells aging in vitro. Stem Cell Res Ther 2022; 13:411. [PMID: 35964126 PMCID: PMC9375398 DOI: 10.1186/s13287-022-03107-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 08/01/2022] [Indexed: 12/06/2022] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have been extensively used for the treatment of various diseases in preclinical and clinical trials. In vitro propagation is needed to attain enough cells for clinical use. However, cell aging and viability reduction caused by long-time culture have not been thoroughly investigated, especially for the function of mitochondria and lysosomes. Therefore, this study was designed to detect mitochondrial and lysosomal activity, morphological and functional changes in human umbilical cord MSCs (UMSCs) after long-time culture. METHODS First, we examined cell activities, including proliferation and immigration ability, differentiation potential, and immunosuppressive capacity of UMSCs at an early and late passages as P4 (named UMSC-P4) and P9 (named UMSC-P9), respectively. Then, we compared the mitochondrial morphology of UMSC-P4 and UMSC-P9 using the electronic microscope and MitoTracker Red dyes. Furthermore, we investigated mitochondrial function, including mitochondrial membrane potential, antioxidative ability, apoptosis, and ferroptosis detected by respective probe. Cell energy metabolism was tested by mass spectrometry. In addition, we compared the lysosomal morphology of UMSC-P4 and UMSC-P9 by electronic microscope and lysoTracker Red dyes. Finally, the transcriptome sequence was performed to analyze the total gene expression of these cells. RESULTS It was found that UMSC-P9 exhibited a reduced biological activity and showed an impaired mitochondrial morphology with disordered structure, reduced mitochondrial crista, and mitochondrial fragments. They also displayed decreased mitochondrial membrane potential, antioxidative ability, tricarboxylic acid cycle activity and energy production. At the same time, apoptosis and ferroptosis were increased. In addition, UMSC-P9, relative to UMSC-P4, showed undegraded materials in their lysosomes, the enhancement in lysosomal membrane permeability, the reduction in autophagy and phagocytosis. Moreover, transcriptome sequence analysis also revealed a reduction of cell function, metabolism, mitochondrial biogenesis, DNA replication and repair, and an increase of gene expression related to cell senescence, cancer, diseases, and infection in UMSC-P9. CONCLUSION This study indicates that in vitro long-time culturing of MSCs can cause mitochondrial and lysosomal dysfunction, probably contributing to the decline of cell activity and cell aging. Therefore, the morphology and function of mitochondria and lysosomes can be regarded as two important parameters to monitor cell viability, and they can also serve as two important indicators for optimizing in vitro culture conditions.
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Affiliation(s)
- Ge Zhang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, P.O. Box 329#, 130 Meilong Road, Shanghai, 200237, People's Republic of China.,State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Yuli Wang
- Department of Vascular Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Jianhua Lin
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Bo Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, P.O. Box 329#, 130 Meilong Road, Shanghai, 200237, People's Republic of China.,State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Ali Mohsin
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, P.O. Box 329#, 130 Meilong Road, Shanghai, 200237, People's Republic of China
| | - Zhimin Cheng
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Weijie Hao
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Wei-Qiang Gao
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China. .,Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China.
| | - Huiming Xu
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China.
| | - Meijin Guo
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, P.O. Box 329#, 130 Meilong Road, Shanghai, 200237, People's Republic of China.
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Adipose-Derived Stem Cell Exosomes as a Novel Anti-Inflammatory Agent and the Current Therapeutic Targets for Rheumatoid Arthritis. Biomedicines 2022; 10:biomedicines10071725. [PMID: 35885030 PMCID: PMC9312519 DOI: 10.3390/biomedicines10071725] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/15/2022] [Accepted: 07/15/2022] [Indexed: 11/17/2022] Open
Abstract
Patients with rheumatoid arthritis (RA), a chronic inflammatory joint disorder, may not respond adequately to current RA treatments. Mesenchymal stem cells (MSCs) elicit several immunomodulatory and anti-inflammatory effects and, thus, have therapeutic potential. Specifically, adipose-derived stem cell (ADSC)-based RA therapy may have considerable potency in modulating the immune response, and human adipose tissue is abundant and easy to obtain. Paracrine factors, such as exosomes (Exos), contribute to ADSCs’ immunomodulatory function. ADSC-Exo-based treatment can reproduce ADSCs’ immunomodulatory function and overcome the limitations of traditional cell therapy. ADSC-Exos combined with current drug therapies may provide improved therapeutic effects. Using ADSC-Exos, instead of ADSCs, to treat RA may be a promising cell-free treatment strategy. This review summarizes the current knowledge of medical therapies, ADSC-based therapy, and ADSC-Exos for RA and discusses the anti-inflammatory properties of ADSCs and ADSC-Exos. Finally, this review highlights the expanding role and potential immunomodulatory activity of ADSC-Exos in patients with RA.
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Interleukin-10-Modified Adipose-Derived Mesenchymal Stem Cells Prevent Hypertrophic Scar Formation via Regulating the Biological Characteristics of Fibroblasts and Inflammation. Mediators Inflamm 2022; 2022:6368311. [PMID: 35774067 PMCID: PMC9239815 DOI: 10.1155/2022/6368311] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 03/16/2022] [Accepted: 03/22/2022] [Indexed: 11/17/2022] Open
Abstract
Hypertrophic scar causes serious functional and cosmetic problem, but no treatment method is known to achieve a satisfactory therapeutic effect. However, mesenchymal stem cells show a possible cure prospect. Here, we investigated the effect of interleukin-10-modified adipose-derived mesenchymal stem cells (IL-10-ADMSC) on the formation of hypertrophic scar. In vitro, IL-10-ADMSC could highly express IL-10 and exhibited stronger inhibition of hypertrophic scar fibroblasts (HSFs) proliferation, migration, and extracellular matrix synthesis (the expression of collagen I, collagen III, FN, and α-SMA protein) than ADMSC. In vivo, we found that IL-10-ADMSC speeded up wound healing time and reduced scar area and scar outstanding height. Same as in vitro, IL-10-ADMSC also exhibited stronger inhibition of extracellular matrix synthesis (the expression of collagen I, collagen III protein) in wound than ADMSC. In addition, we also found that IL-10-ADMSC is also a stronger inhibitory effect on inflammation in wound than ADMSC, and IL-10-ADMSC inhibited TGF-β/Smads and NF-κB pathway. In conclusion, IL-10-ADMSC demonstrated the ability to prevent hypertrophic scar formation. And its possible molecular mechanism might be related to IL-10-ADMSC inhibiting the proliferation and migration of the synthesis of extracellular matrix of HSFs, and IL-10-ADMSC inhibited the inflammation during the wound healing.
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Yu P, Guo J, Li J, Shi X, Xu N, Jiang Y, Chen W, Hu Q. lncRNA-H19 in Fibroblasts Promotes Wound Healing in Diabetes. Diabetes 2022; 71:1562-1578. [PMID: 35472819 DOI: 10.2337/db21-0724] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 04/04/2022] [Indexed: 11/13/2022]
Abstract
Cutaneous wound healing in diabetes is impaired and would develop into nonhealing ulcerations. However, the molecular mechanism underlying the wound-healing process remains largely obscure. Here, we found that cutaneous PDGFRα+ fibroblast-expressing lncRNA-H19 (lncH19) accelerates the wound-healing process via promoting dermal fibroblast proliferation and macrophage infiltration in injured skin. PDGFRα+ cell-derived lncH19, which is lower in contents in the wound-healing cutaneous tissue of patients and mice with type 2 diabetes, is required for wound healing through promoting proliferative capacity of dermis fibroblasts as well as macrophage recruitments. Mechanistically, lncH19 relieves the cell cycle arrest of fibroblasts and increases macrophage infiltration in injured tissues via inhibiting p53 activity and GDF15 releasement. Furthermore, exosomes derived from adipocyte progenitor cells efficiently restore the impaired diabetic wound healing via delivering lncH19 to injured tissue. Therefore, our study reveals a new role for lncRNA in regulating cutaneous tissue repair and provides a novel promising insight for developing clinical treatment of diabetes.
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Affiliation(s)
- Pijun Yu
- Department of Plastic and Cosmetic Surgery, Shanghai Eighth People's Hospital, Shanghai, China
| | - Jian Guo
- Department of Plastic and Cosmetic Surgery, Shanghai Eighth People's Hospital, Shanghai, China
| | - Junjie Li
- Department of Plastic and Cosmetic Surgery, Shanghai Eighth People's Hospital, Shanghai, China
| | - Xiao Shi
- Department of Plastic and Cosmetic Surgery, Shanghai Eighth People's Hospital, Shanghai, China
| | - Ning Xu
- Department of Plastic and Cosmetic Surgery, Shanghai Eighth People's Hospital, Shanghai, China
| | - Yongkang Jiang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wei Chen
- Department of Plastic and Cosmetic Surgery, Shanghai Eighth People's Hospital, Shanghai, China
| | - Qin Hu
- Department of Gynecology, Fudan University Shanghai Cancer Center, Shanghai, China
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Lee J, Park L, Kim H, Rho BI, Han RT, Kim S, Kim HJ, Na HS, Back SK. Adipose-derived stem cells decolonize skin Staphylococcus aureus by enhancing phagocytic activity of peripheral blood mononuclear cells in the atopic rats. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY 2022; 26:287-295. [PMID: 35766006 PMCID: PMC9247705 DOI: 10.4196/kjpp.2022.26.4.287] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/16/2022] [Accepted: 06/16/2022] [Indexed: 11/15/2022]
Abstract
Staphylococcus aureus (S. aureus) is known to induce apoptosis of host immune cells and impair phagocytic clearance, thereby being pivotal in the pathogenesis of atopic dermatitis (AD). Adipose-derived stem cells (ASCs) exert therapeutic effects against inflammatory and immune diseases. In the present study, we investigated whether systemic administration of ASCs restores the phagocytic activity of peripheral blood mononuclear cells (PBMCs) and decolonizes cutaneous S. aureus under AD conditions. AD was induced by injecting capsaicin into neonatal rat pups. ASCs were extracted from the subcutaneous adipose tissues of naïve rats and administered to AD rats once a week for a month. Systemic administration of ASCs ameliorated AD-like symptoms, such as dermatitis scores, serum IgE, IFN-γ+/IL-4+ cell ratio, and skin colonization by S. aureus in AD rats. Increased FasL mRNA and annexin V+/7-AAD+ cells in the PBMCs obtained from AD rats were drastically reversed when co-cultured with ASCs. In contrast, both PBMCs and CD163+ cells bearing fluorescent zymosan particles significantly increased in AD rats treated with ASCs. Additionally, the administration of ASCs led to an increase in the mRNA levels of antimicrobial peptides, such as cathelicidin and β-defensin, in the skin of AD rats. Our results demonstrate that systemic administration of ASCs led to decolonization of S. aureus by attenuating apoptosis of immune cells in addition to restoring phagocytic activity. This contributes to the improvement of skin conditions in AD rats. Therefore, administration of ASCs may be helpful in the treatment of patients with intractable AD.
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Affiliation(s)
- Jaehee Lee
- Neuroscience Research Institute and Department of Physiology, Korea University College of Medicine, Seoul 02841, Korea
| | | | - Hyeyoung Kim
- Neuroscience Research Institute and Department of Physiology, Korea University College of Medicine, Seoul 02841, Korea
| | | | - Rafael Taeho Han
- Neuroscience Research Institute and Department of Physiology, Korea University College of Medicine, Seoul 02841, Korea
| | - Sewon Kim
- Department of Microbiology, Korea University College of Medicine, Seoul 02841, Korea
| | - Hee Jin Kim
- Division of Biological Science and Technology, Science and Technology College, Yonsei University Mirae Campus, Wonju 26493, Korea
| | - Heung Sik Na
- Neuroscience Research Institute and Department of Physiology, Korea University College of Medicine, Seoul 02841, Korea
| | - Seung Keun Back
- Department of Biomedical Laboratory Science, College of Medical Science, Konyang University, Daejeon 35365, Korea
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Zhang C, Wu S, Chen E, Yu L, Wang J, Wu M. ALX1-transcribed LncRNA AC132217.4 promotes osteogenesis and bone healing via IGF-AKT signaling in mesenchymal stem cells. Cell Mol Life Sci 2022; 79:328. [PMID: 35639207 PMCID: PMC11073114 DOI: 10.1007/s00018-022-04338-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/23/2022] [Accepted: 04/29/2022] [Indexed: 11/03/2022]
Abstract
The osteogenic potential of bone marrow mesenchymal stem cells (BMSCs) is critical for bone formation and regeneration. A high non-/delayed-union rate of fracture healing still occurs in specific populations, implying an urgent need to discover novel targets for promoting osteogenesis and bone regeneration. Long non-coding (lnc)RNAs are emerging regulators of multiple physiological processes, including osteogenesis. Based on differential expression analysis of RNA sequencing data, we found that lncRNA AC132217.4, a 3'UTR-overlapping lncRNA of insulin growth factor 2 (IGF2), was highly induced during osteogenic differentiation of BMSCs. Afterward, both gain-of-function and loss-of-function experiments proved that AC132217.4 promotes osteoblast development from BMSCs. As for its molecular mechanism, we found that AC132217.4 binds with IGF2 mRNA to regulate its expression and downstream AKT activation to control osteoblast maturation and function. Furthermore, we identified two splicing factors, splicing component 35 KDa (SC35) and heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), which regulate the biogenesis of AC132217.4 at the post-transcriptional level. We also identified a transcription factor, ALX1, which regulates AC132217.7 expression at the transcriptional level to promote osteogenesis. Importantly, in-vivo over-expression of AC132217.4 essentially promotes the bone healing process in a murine tibial drill-hole model. Our study demonstrates that lncRNA AC132217.4 is a novel anabolic regulator of BMSC osteogenesis and could be a plausible therapeutic target for improving bone regeneration.
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Affiliation(s)
- Cui Zhang
- Department of Cell and Developmental Biology, College of Life Sciences, Zhejiang University, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shali Wu
- Department of Cell and Developmental Biology, College of Life Sciences, Zhejiang University, Hangzhou, China
| | - Erman Chen
- Department of Orthopedics, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Luyang Yu
- Department of Cell and Developmental Biology, College of Life Sciences, Zhejiang University, Hangzhou, China
| | - Jinfu Wang
- Department of Cell and Developmental Biology, College of Life Sciences, Zhejiang University, Hangzhou, China.
| | - Mengrui Wu
- Department of Cell and Developmental Biology, College of Life Sciences, Zhejiang University, Hangzhou, China.
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Kuca-Warnawin E, Plebańczyk M, Ciechomska M, Olesińska M, Szczęsny P, Kontny E. Impact of Adipose-Derived Mesenchymal Stem Cells (ASCs) of Rheumatic Disease Patients on T Helper Cell Differentiation. Int J Mol Sci 2022; 23:ijms23105317. [PMID: 35628127 PMCID: PMC9140468 DOI: 10.3390/ijms23105317] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/27/2022] [Accepted: 05/03/2022] [Indexed: 11/16/2022] Open
Abstract
Complex pathogenesis of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is associated with an imbalance of various Th-cell subpopulations. Mesenchymal stem cells (MSCs) have the ability to restore this balance. However, bone marrow-derived MSCs of SLE and SSc patients exhibit many abnormalities, whereas the properties of adipose derived mesenchymal stem cells (ASCS) are much less known. Therefore, we examined the effect of ASCs obtained from SLE (SLE/ASCs) and SSc (SSc/ASCs) patients on Th subset differentiation, using cells from healthy donors (HD/ASCs) as controls. ASCs were co-cultured with activated CD4+ T cells or peripheral blood mononuclear cells. Expression of transcription factors defining Th1, Th2, Th17, and regulatory T cell (Tregs) subsets, i.e., T-bet, GATA3, RORc, and FoxP3, were analysed by quantitative RT-PCR, the concentrations of subset-specific cytokines were measured by ELISA, and Tregs formation by flow cytometry. Compared with HD/ASCs, SLE/ASCs and especially SSc/ASCs triggered Th differentiation which was disturbed at the transcription levels of genes encoding Th1- and Tregs-related transcription factors. However, we failed to find functional consequences of this abnormality, because all tested ASCs similarly switched differentiation from Th1 to Th2 direction with accompanying IFNγ/IL-4 ratio decrease, up-regulated Th17 formation and IL-17 secretion, and up-regulated classical Tregs generation.
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Affiliation(s)
- Ewa Kuca-Warnawin
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland; (M.P.); (M.C.); (E.K.)
- Correspondence:
| | - Magdalena Plebańczyk
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland; (M.P.); (M.C.); (E.K.)
| | - Marzena Ciechomska
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland; (M.P.); (M.C.); (E.K.)
| | - Marzena Olesińska
- Clinic of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (M.O.); (P.S.)
| | - Piotr Szczęsny
- Clinic of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (M.O.); (P.S.)
| | - Ewa Kontny
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland; (M.P.); (M.C.); (E.K.)
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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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Tran TDX, Pham VQ, Tran NNT, Dang HCN, Tran NTA, Vu NB, Van Pham P. Stromal Vascular Fraction and Mesenchymal Stem Cells from Human Adipose Tissue: A Comparison of Immune Modulation and Angiogenic Potential. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022:47-61. [PMID: 35389201 DOI: 10.1007/5584_2022_708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
INTRODUCTION In recent years, both stromal vascular fraction (SVF) from adipose tissue and mesenchymal stem cells (MSC) from adipose tissues were extensively used in both preclinical and clinical treatment for various diseases. Some studies reported differences in treatment efficacy between SVFs and MSCs in animals as well as in humans. Therefore, this study is aimed to evaluate the immune modulation and angiogenic potential of SVFs and MSCs from the same SVF samples to support an explanation when SVFs or MSCs should be used. METHODS The adipose tissue samples from ten female donors with consent forms were collected. SVFs from these samples were isolated according to the published protocols. The existence of mesenchymal cells that positive with CD44, CD73, CD90, and CD105 and endothelial progenitor cells that positive with CD31 and CD34 was determined using flow cytometry. Three samples of SVFs with similar percentages of mesenchymal cell portion and endothelial progenitor cell portion were used to isolate MSCs. Obtained MSCs were confirmed as MSCs using the ISCT minimal criteria. To compare the immune modulation of SVF and MSCs, the mixed lymphocyte assay was used. The lymphocyte proliferation, as well as IFN-gamma and TNF-alpha concentrations, were determined. To compare the angiogenic potential, the angiogenesis in quail embryo assay was used. The angiogenesis efficacy was measured based on the vessel areas formed in the embryos after 7 days. RESULTS The results showed that all SVF samples contained the portions of mesenchymal cells and endothelial progenitor cells. MSCs from SVFs meet all minimal criteria of MSCs that suggested by ISCT. MSCs from SVFs efficiently suppressed the immune cell proliferation compared to the SVFs, especially at ratios of 1:4 (1 MSCs: 4 immune cells). MSCs also inhibited the IFN-gamma and TNF-alpha production more efficiently than SVFs (p < 0.05). However, in quail embryo models, SVFs triggered the angiogenesis and neovessel formation better than MSCs with more significant vessel areas after 7 days (p < 0.05). CONCLUSION This study suggested that SVFs and MSCs have different potentials for immune modulation and angiogenesis. SVFs help the angiogenesis better than MSCs, while MSCs displayed the more significant immune modulation. These results can guide the usage of SVFs or MSCs in disease treatment.
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Affiliation(s)
- Tung Dang Xuan Tran
- NTT Hi-Tech Institute - Nguyen Tat Thanh University, Ho Chi Minh City, Viet Nam.
- Stem Cells Unit, Van Hanh Hospital, Ho Chi Minh City, Viet Nam.
| | - Viet Quoc Pham
- Stem Cell Institute, University of Science Ho Chi Minh City, Ho Chi Minh City, Viet Nam
- Viet Nam National University Ho Chi Minh City, Ho Chi Minh City, Viet Nam
| | - Nhan Ngo-The Tran
- Viet Nam National University Ho Chi Minh City, Ho Chi Minh City, Viet Nam
- Laboratory of Stem Cell Research and Application, University of Science Ho Chi Minh City, Ho Chi Minh City, Viet Nam
| | | | | | - Ngoc Bich Vu
- Stem Cell Institute, University of Science Ho Chi Minh City, Ho Chi Minh City, Viet Nam
- Viet Nam National University Ho Chi Minh City, Ho Chi Minh City, Viet Nam
| | - Phuc Van Pham
- Stem Cell Institute, University of Science Ho Chi Minh City, Ho Chi Minh City, Viet Nam
- Viet Nam National University Ho Chi Minh City, Ho Chi Minh City, Viet Nam
- Laboratory of Stem Cell Research and Application, University of Science Ho Chi Minh City, Ho Chi Minh City, Viet Nam
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Deo D, Marchioni M, Rao P. Mesenchymal Stem/Stromal Cells in Organ Transplantation. Pharmaceutics 2022; 14:pharmaceutics14040791. [PMID: 35456625 PMCID: PMC9029865 DOI: 10.3390/pharmaceutics14040791] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/02/2022] [Accepted: 04/04/2022] [Indexed: 02/07/2023] Open
Abstract
Organ transplantation is essential and crucial for saving and enhancing the lives of individuals suffering from end-stage organ failure. Major challenges in the medical field include the shortage of organ donors, high rates of organ rejection, and long wait times. To address the current limitations and shortcomings, cellular therapy approaches have been developed using mesenchymal stem/stromal cells (MSC). MSC have been isolated from various sources, have the ability to differentiate to important cell lineages, have anti-inflammatory and immunomodulatory properties, allow immunosuppressive drug minimization, and induce immune tolerance towards the transplanted organ. Additionally, rapid advances in the fields of tissue engineering and regenerative medicine have emerged that focus on either generating new organs and organ sources or maximizing the availability of existing organs. This review gives an overview of the various properties of MSC that have enabled its use as a cellular therapy for organ preservation and transplant. We also highlight emerging fields of tissue engineering and regenerative medicine along with their multiple sub-disciplines, underlining recent advances, widespread clinical applications, and potential impact on the future of tissue and organ transplantation.
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Abstract
Rheumatoid arthritis (RA) is a heterogeneous autoimmune disorder that leads to severe joint deformities, negatively affecting the patient's quality of life. Extracellular vesicles (EVs), which include exosomes and ectosomes, act as intercellular communication mediators in several physiological and pathological processes in various diseases including RA. In contrast, EVs secreted by mesenchymal stem cells perform an immunomodulatory function and stimulate cartilage repair, showing promising therapeutic results in animal models of RA. EVs from other sources, including dendritic cells, neutrophils and myeloid-derived suppressor cells, also influence the biological function of immune and joint cells. This review describes the role of EVs in the pathogenesis of RA and presents evidence supporting future studies on the therapeutic potential of EVs from different sources. This information will contribute to a better understanding of RA development, as well as a starting point for exploring cell-free-based therapies for RA.
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Smakaj A, De Mauro D, Rovere G, Pietramala S, Maccauro G, Parolini O, Lattanzi W, Liuzza F. Clinical Application of Adipose Derived Stem Cells for the Treatment of Aseptic Non-Unions: Current Stage and Future Perspectives-Systematic Review. Int J Mol Sci 2022; 23:3057. [PMID: 35328476 PMCID: PMC8950719 DOI: 10.3390/ijms23063057] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/08/2022] [Accepted: 03/08/2022] [Indexed: 12/18/2022] Open
Abstract
Fracture non-union is a challenging orthopaedic issue and a socio-economic global burden. Several biological therapies have been introduced to improve traditional surgical approaches. Among these, the latest research has been focusing on adipose tissue as a powerful source of mesenchymal stromal cells, namely, adipose-derived stem cells (ADSCs). ADSC are commonly isolated from the stromal vascular fraction (SVF) of liposuctioned hypodermal adipose tissue, and their applications have been widely investigated in many fields, including non-union fractures among musculoskeletal disorders. This review aims at providing a comprehensive update of the literature on clinical application of ADSCs for the treatment of non-unions in humans. The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Only three articles met our inclusion criteria, with a total of 12 cases analyzed for demographics and harvesting, potential manufacturing and implantation of ADSCs. The review of the literature suggests that adipose derived cell therapy can represent a promising alternative in bone regenerative medicine for the enhancement of non-unions and bone defects. The low number of manuscripts reporting ADSC-based therapies for long bone fracture healing suggests some critical issues that are discussed in this review. Nevertheless, further investigations on human ADSC therapies are needed to improve the knowledge on their translational potential and to possibly achieve a consensus on their use for such applications.
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Affiliation(s)
- Amarildo Smakaj
- Department of Aging, Neurological, Orthopaedic and Head-Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (A.S.); (D.D.M.); (G.R.); (S.P.); (G.M.)
- Department of Geriatrics and Orthopaedic Sciences, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Domenico De Mauro
- Department of Aging, Neurological, Orthopaedic and Head-Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (A.S.); (D.D.M.); (G.R.); (S.P.); (G.M.)
- Department of Geriatrics and Orthopaedic Sciences, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Giuseppe Rovere
- Department of Aging, Neurological, Orthopaedic and Head-Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (A.S.); (D.D.M.); (G.R.); (S.P.); (G.M.)
- Department of Geriatrics and Orthopaedic Sciences, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Silvia Pietramala
- Department of Aging, Neurological, Orthopaedic and Head-Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (A.S.); (D.D.M.); (G.R.); (S.P.); (G.M.)
- Department of Geriatrics and Orthopaedic Sciences, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Giulio Maccauro
- Department of Aging, Neurological, Orthopaedic and Head-Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (A.S.); (D.D.M.); (G.R.); (S.P.); (G.M.)
- Department of Geriatrics and Orthopaedic Sciences, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Ornella Parolini
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
- Fondazione Policlinico A. Gemelli IRCCS, 00168 Rome, Italy
| | - Wanda Lattanzi
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
- Fondazione Policlinico A. Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Liuzza
- Department of Aging, Neurological, Orthopaedic and Head-Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (A.S.); (D.D.M.); (G.R.); (S.P.); (G.M.)
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Switching Roles: Beneficial Effects of Adipose Tissue-Derived Mesenchymal Stem Cells on Microglia and Their Implication in Neurodegenerative Diseases. Biomolecules 2022; 12:biom12020219. [PMID: 35204722 PMCID: PMC8961583 DOI: 10.3390/biom12020219] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/14/2022] [Accepted: 01/22/2022] [Indexed: 01/08/2023] Open
Abstract
Neurological disorders, including neurodegenerative diseases, are often characterized by neuroinflammation, which is largely driven by microglia, the resident immune cells of the central nervous system (CNS). Under these conditions, microglia are able to secrete neurotoxic substances, provoking neuronal cell death. However, microglia in the healthy brain carry out CNS-supporting functions. This is due to the ability of microglia to acquire different phenotypes that can play a neuroprotective role under physiological conditions or a pro-inflammatory, damaging one during disease. Therefore, therapeutic strategies focus on the downregulation of these neuroinflammatory processes and try to re-activate the neuroprotective features of microglia. Mesenchymal stem cells (MSC) of different origins have been shown to exert such effects, due to their immunomodulatory properties. In recent years, MSC derived from adipose tissue have been made the center of attention because of their easy availability and extraction methods. These cells induce a neuroprotective phenotype in microglia and downregulate neuroinflammation, resulting in an improvement of clinical symptoms in a variety of animal models for neurological pathologies, e.g., Alzheimer’s disease, traumatic brain injury and ischemic stroke. In this review, we will discuss the application of adipose tissue-derived MSC and their conditioned medium, including extracellular vesicles, in neurological disorders, their beneficial effect on microglia and the signaling pathways involved.
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Trébol J, Georgiev-Hristov T, Pascual-Miguelañez I, Guadalajara H, García-Arranz M, García-Olmo D. Stem cell therapy applied for digestive anastomosis: Current state and future perspectives. World J Stem Cells 2022; 14:117-141. [PMID: 35126832 PMCID: PMC8788180 DOI: 10.4252/wjsc.v14.i1.117] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/21/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Digestive tract resections are usually followed by an anastomosis. Anastomotic leakage, normally due to failed healing, is the most feared complication in digestive surgery because it is associated with high morbidity and mortality. Despite technical and technological advances and focused research, its rates have remained almost unchanged the last decades. In the last two decades, stem cells (SCs) have been shown to enhance healing in animal and human studies; hence, SCs have emerged since 2008 as an alternative to improve anastomoses outcomes. AIM To summarise the published knowledge of SC utilisation as a preventative tool for hollow digestive viscera anastomotic or suture leaks. METHODS PubMed, Science Direct, Scopus and Cochrane searches were performed using the key words "anastomosis", "colorectal/colonic anastomoses", "anastomotic leak", "stem cells", "progenitor cells", "cellular therapy" and "cell therapy" in order to identify relevant articles published in English and Spanish during the years of 2000 to 2021. Studies employing SCs, performing digestive anastomoses in hollow viscera or digestive perforation sutures and monitoring healing were finally included. Reference lists from the selected articles were reviewed to identify additional pertinent articles.Given the great variability in the study designs, anastomotic models, interventions (SCs, doses and vehicles) and outcome measures, performing a reliable meta-analysis was considered impossible, so we present the studies, their results and limitations. RESULTS Eighteen preclinical studies and three review papers were identified; no clinical studies have been published and there are no registered clinical trials. Experimental studies, mainly in rat and porcine models and occasionally in very adverse conditions such as ischaemia or colitis, have been demonstrated SCs as safe and have shown some encouraging morphological, functional and even clinical results. Mesenchymal SCs are mostly employed, and delivery routes are mainly local injections and cell sheets followed by biosutures (sutures coated by SCs) or purely topical. As potential weaknesses, animal models need to be improved to make them more comparable and equivalent to clinical practice, and the SC isolation processes need to be standardised. There is notable heterogeneity in the studies, making them difficult to compare. Further investigations are needed to establish the indications, the administration system, potential adjuvants, the final efficacy and to confirm safety and exclude definitively oncological concerns. CONCLUSION The future role of SC therapy to induce healing processes in digestive anastomoses/sutures still needs to be determined and seems to be currently far from clinical use.
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Affiliation(s)
- Jacobo Trébol
- Servicio de Cirugía General y del Aparato Digestivo, Complejo Asistencial Universitario de Salamanca, Salamanca 37007, Spain
- Departamento de Anatomía e Histología Humanas, Universidad de Salamanca, Salamanca 37007, Spain.
| | - Tihomir Georgiev-Hristov
- Servicio de Cirugía General y del Aparato Digestivo, Hospital General Universitario de Villalba, Madrid 28400, Spain
| | - Isabel Pascual-Miguelañez
- Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario La Paz, Madrid 28046, Spain
| | - Hector Guadalajara
- Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario Fundación Jiménez Díaz, Madrid 28040, Spain
| | - Mariano García-Arranz
- Grupo de Investigación en Nuevas Terapias, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid 28040, Spain
- Departamento de Cirugía, Universidad Autónoma de Madrid, Madrid 28029, Spain
| | - Damian García-Olmo
- Departamento de Cirugía, Universidad Autónoma de Madrid, Madrid 28029, Spain
- Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario Fundación Jiménez Díaz y Grupo Quiron-Salud Madrid, Madrid 28040, Spain
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Immunomodulation of Skin Repair: Cell-Based Therapeutic Strategies for Skin Replacement (A Comprehensive Review). Biomedicines 2022; 10:biomedicines10010118. [PMID: 35052797 PMCID: PMC8773777 DOI: 10.3390/biomedicines10010118] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 12/30/2021] [Accepted: 12/31/2021] [Indexed: 12/12/2022] Open
Abstract
The immune system has a crucial role in skin wound healing and the application of specific cell-laden immunomodulating biomaterials emerged as a possible treatment option to drive skin tissue regeneration. Cell-laden tissue-engineered skin substitutes have the ability to activate immune pathways, even in the absence of other immune-stimulating signals. In particular, mesenchymal stem cells with their immunomodulatory properties can create a specific immune microenvironment to reduce inflammation, scarring, and support skin regeneration. This review presents an overview of current wound care techniques including skin tissue engineering and biomaterials as a novel and promising approach. We highlight the plasticity and different roles of immune cells, in particular macrophages during various stages of skin wound healing. These aspects are pivotal to promote the regeneration of nonhealing wounds such as ulcers in diabetic patients. We believe that a better understanding of the intrinsic immunomodulatory features of stem cells in implantable skin substitutes will lead to new translational opportunities. This, in turn, will improve skin tissue engineering and regenerative medicine applications.
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Yuan X, Li L, Liu H, Luo J, Zhao Y, Pan C, Zhang X, Chen Y, Gou M. Strategies for improving adipose-derived stem cells for tissue regeneration. BURNS & TRAUMA 2022; 10:tkac028. [PMID: 35992369 PMCID: PMC9382096 DOI: 10.1093/burnst/tkac028] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/27/2022] [Indexed: 11/13/2022]
Abstract
Abstract
Adipose-derived stem cells (ADSCs) have promising applications in tissue regeneration. Currently, there are only a few ADSC products that have been approved for clinical use. The clinical application of ADSCs still faces many challenges. Here, we review emerging strategies to improve the therapeutic efficacy of ADSCs in tissue regeneration. First, a great quantity of cells is often needed for the stem cell therapies, which requires the advanced cell expansion technologies. In addition cell-derived products are also required for the development of ‘cell-free’ therapies to overcome the drawbacks of cell-based therapies. Second, it is necessary to strengthen the regenerative functions of ADSCs, including viability, differentiation and paracrine ability, for the tissue repair and regeneration required for different physiological and pathophysiological conditions. Third, poor delivery efficiency also restricts the therapeutic effect of ADSCs. Effective methods to improve cell delivery include alleviating harsh microenvironments, enhancing targeting ability and prolonging cell retention. Moreover, we also point out some critical issues about the sources, effectiveness and safety of ADSCs. With these advanced strategies to improve the therapeutic efficacy of ADSCs, ADSC-based treatment holds great promise for clinical applications in tissue regeneration.
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Affiliation(s)
- Xin Yuan
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , Chengdu, 610041, China
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University , Chengdu, 610041, China
| | - Li Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , Chengdu, 610041, China
| | - Haofan Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , Chengdu, 610041, China
| | - Jing Luo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , Chengdu, 610041, China
| | - Yongchao Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , Chengdu, 610041, China
| | - Cheng Pan
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University , Chengdu, 610041, China
| | - Xue Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , Chengdu, 610041, China
| | - Yuwen Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , Chengdu, 610041, China
| | - Maling Gou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , Chengdu, 610041, China
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Debreova M, Culenova M, Smolinska V, Nicodemou A, Csobonyeiova M, Danisovic L. Rheumatoid arthritis: From synovium biology to cell-based therapy. Cytotherapy 2022; 24:365-375. [DOI: 10.1016/j.jcyt.2021.10.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/23/2021] [Accepted: 10/14/2021] [Indexed: 12/18/2022]
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Sun Y, Chi X, Meng H, Ma M, Wang J, Feng Z, Quan Q, Liu G, Wang Y, Xie Y, Zheng Y, Peng J. Polylysine-decorated macroporous microcarriers laden with adipose-derived stem cells promote nerve regeneration in vivo. Bioact Mater 2021; 6:3987-3998. [PMID: 33997488 PMCID: PMC8082165 DOI: 10.1016/j.bioactmat.2021.03.029] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 03/08/2021] [Accepted: 03/12/2021] [Indexed: 12/14/2022] Open
Abstract
Cell transplantation is an effective strategy to improve the repair effect of nerve guide conduits (NGCs). However, problems such as low loading efficiency and cell anoikis undermine the outcomes. Microcarriers are efficient 3D cell culture scaffolds, which can also prevent cell anoikis by providing substrate for adhesion during transplantation. Here, we demonstrate for the first time microcarrier-based cell transplantation in peripheral nerve repair. We first prepared macroporous chitosan microcarriers (CSMCs) by the emulsion-phase separation method, and then decorated the CSMCs with polylysine (pl-CSMCs) to improve cell affinity. We then loaded the pl-CSMCs with adipose-derived stem cells (ADSCs) and injected them into electrospun polycaprolactone/chitosan NGCs to repair rat sciatic nerve defects. The ADSCs-laden pl-CSMCs effectively improved nerve regeneration as demonstrated by evaluation of histology, motor function recovery, electrophysiology, and gastrocnemius recovery. With efficient cell transplantation, convenient operation, and the multiple merits of ADSCs, the ADSCs-laden pl-CSMCs hold good potential in peripheral nerve repair.
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Affiliation(s)
- Yi Sun
- School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, 100083, PR China
- Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, PR China
| | - Xiaoqi Chi
- School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, 100083, PR China
| | - Haoye Meng
- School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, 100083, PR China
- Institute of Orthopedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Lab of Musculoskeletal Trauma & War Injuries, PLA, No.28 Fuxing Road, Beijing, 100853, PR China
| | - Mengjiao Ma
- School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, 100083, PR China
| | - Jing Wang
- Institute of Orthopedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Lab of Musculoskeletal Trauma & War Injuries, PLA, No.28 Fuxing Road, Beijing, 100853, PR China
| | - Zhaoxuan Feng
- School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, 100083, PR China
| | - Qi Quan
- Institute of Orthopedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Lab of Musculoskeletal Trauma & War Injuries, PLA, No.28 Fuxing Road, Beijing, 100853, PR China
| | - Guodong Liu
- School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, 100083, PR China
| | - Yansen Wang
- School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, 100083, PR China
| | - Yajie Xie
- School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, 100083, PR China
| | - Yudong Zheng
- School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, 100083, PR China
| | - Jiang Peng
- Institute of Orthopedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Lab of Musculoskeletal Trauma & War Injuries, PLA, No.28 Fuxing Road, Beijing, 100853, PR China
- Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, 226007, PR China
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Weiss JB, Phillips CJ, Malin EW, Gorantla VS, Harding JW, Salgar SK. Stem cell, Granulocyte-Colony Stimulating Factor and/or Dihexa to promote limb function recovery in a rat sciatic nerve damage-repair model: Experimental animal studies. Ann Med Surg (Lond) 2021; 71:102917. [PMID: 34703584 PMCID: PMC8524106 DOI: 10.1016/j.amsu.2021.102917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 10/05/2021] [Indexed: 11/04/2022] Open
Abstract
Background Optimizing nerve regeneration and re-innervation of target muscle/s is the key for improved functional recovery following peripheral nerve damage. We investigated whether administration of mesenchymal stem cell (MSC), Granulocyte-Colony Stimulating Factor (G-CSF) and/or Dihexa can improve recovery of limb function following peripheral nerve damage in rat sciatic nerve transection-repair model. Materials and methods There were 10 experimental groups (n = 6–8 rats/group). Bone marrow derived syngeneic MSCs (2 × 106; passage≤6), G-CSF (200–400 μg/kg b.wt.), Dihexa (2–4 mg/kg b.wt.) and/or Vehicle were administered to male Lewis rats locally via hydrogel at the site of nerve repair, systemically (i.v./i.p), and/or to gastrocnemius muscle. The limb sensory and motor functions were assessed at 1–2 week intervals post nerve repair until the study endpoint (16 weeks). Results The sensory function in all nerve boundaries (peroneal, tibial, sural) returned to nearly normal by 8 weeks (Grade 2.7 on a scale of Grade 0–3 [0 = No function; 3 = Normal function]) in all groups combined. The peroneal nerve function recovered quickly with return of function at one week (∼2.0) while sural nerve function recovered rather slowly at four weeks (∼1.0). Motor function at 8–16 weeks post-nerve repair as determined by walking foot print grades significantly (P < 0.05) improved with MSC + G-CSF or MSC + Dihexa administrations into gastrocnemius muscle and mitigated foot flexion contractures. Conclusions These findings demonstrate MSC, G-CSF and Dihexa are promising candidates for adjunct therapies to promote limb functional recovery after surgical nerve repair, and have implications in peripheral nerve injury and limb transplantation. IACUC No.215064.
G-CSF in combination with MSCs improved limb function recovery in sciatic nerve transection- repair model. Dihexa in combination with MSC improved limb function recovery in sciatic nerve transection- repair model. Foot flexion contractures were reduced with G-CSF & MSC or Dihexa & MSC administration into target muscle gastrocnemius. MSC, G-CSF or Dihexa combination therapy is attractive, feasible & promising in peripheral nerve injury repair and have implications in limb transplantation. The findings warrant further investigation to understand the cellular/molecular mechanisms.
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Affiliation(s)
- Jessica B Weiss
- Department of Surgery, Madigan Army Medical Center, Tacoma, Fort Lewis, Washington, USA
| | - Cody J Phillips
- Department of Surgery, Madigan Army Medical Center, Tacoma, Fort Lewis, Washington, USA
| | - Edward W Malin
- Department of Surgery, Madigan Army Medical Center, Tacoma, Fort Lewis, Washington, USA
| | - Vijay S Gorantla
- Department of Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Joseph W Harding
- Department of Integrative Physiology & Neuroscience, Washington State University, Pullman, WA, USA
| | - Shashikumar K Salgar
- Department of Clinical Investigation, Madigan Army Medical Center, Tacoma, Fort Lewis, Washington, USA
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Ng KLB, Hsieh MCW, Lin YN, Chen RF, Lin TM, Lin SD, Kuo YR. Application of nanofat grafting to rescue a severe ischaemic hand with thromboangiitis obliterans: A case report about promising salvage procedure. Medicine (Baltimore) 2021; 100:e27577. [PMID: 34678903 PMCID: PMC8542167 DOI: 10.1097/md.0000000000027577] [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: 07/27/2021] [Accepted: 10/07/2021] [Indexed: 11/25/2022] Open
Abstract
RATIONALE Currently, there is no consensus regarding the best treatment for patients with thromboangiitis obliterans (TAO). Regenerative medicine, such as bone marrow stem cells or adipose-derived stem cell (ASC) transplantation, have proven efficacy in improving tissue perfusion and wound healing in clinical trials. In this case, we used nanofat grafting to treat severe conditions in a patient with TAO, with promising outcomes. PATIENT CONCERNS This is a case of a 48-year-old smoker who presented with cyanosis in both hands and the right foot, with gangrenous changes. Investigative angiography showed severe vasospasm in the radial and ulnar arteries of the patient's left hand. Progressive cyanosis of the patient's left hand was noted which may eventually require amputation if left untreated. DIAGNOSES He was diagnosed with TAO under the Shionoya diagnostic criteria. INTERVENTIONS Fasciotomy and necrotic tissue debridement were performed, followed by centrifuged nanofat grafting. The nanofat graft was prepared using Pallua method and deployed with a MAFT-GUN (Dermato Plastica Beauty Co., Ltd., Kaohsiung, Taiwan). OUTCOMES Three months later, computed tomography angiography revealed a radial artery patency. The patient's wrist function was preserved with uneventful wound healing. LESSONS The regenerative ability of centrifuged nanofat grafts not only helps wound healing but also helps reverse vasospasm and preserve remnant tissue perfusion.
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Affiliation(s)
- Kwan Lok Benjamin Ng
- Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan
| | - Meng-Chien Willie Hsieh
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan
| | - Yun-Nan Lin
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan
| | - Rong-Fu Chen
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan
| | - Tsai-Ming Lin
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan
- Charming Institute of Aesthetic and Regenerative Surgery (CIARS), Kaohsiung City, Taiwan
| | - Sin-Daw Lin
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan
- Department of Surgery, Kaohsiung Municipal Siaogang Hospital, Kaohsiung City, Taiwan
| | - Yur-Ren Kuo
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan
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