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Yang P, Chen X, Wen H, Yu M, Yu H, Wang L, Gong L, Zhao L. In vitro differentiation of common lymphoid progenitor cells into B cell using stromal cell free culture system. BMC Immunol 2025; 26:12. [PMID: 40038600 PMCID: PMC11877881 DOI: 10.1186/s12865-025-00694-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 02/25/2025] [Indexed: 03/06/2025] Open
Abstract
The OP9 culture system is an important in vitro model for B cell development. However, the complex nature of operations and the intrinsic variability of stromal cell functionality, which can be influenced by factors such as radiation exposure or contamination, pose considerable challenges to their wider application. Currently, there exists a paucity of studies documenting in vitro B cell differentiation culture systems that exclude stromal cells, and the experimental methodologies available for reference remain limited. This report elucidates a robust stromal cell-free culture system. Specifically, bovine serum albumin (BSA) or fetal bovine serum (FBS), in conjunction with interleukin-7 (IL-7), Flt3 ligand (Flt3L), and stem cell factor (SCF), were incorporated into X-VIVO15 medium. This system proficiently facilitates the directed differentiation of common lymphoid progenitor cells (CLP), defined as lineage-CD127 + CD117lowsca-1lowCD135+, into B lymphocytes in vitro, achieving an amplification factor of up to one hundredfold.We examined the roles of IL-7, Flt3L and SCF in differentiation of B cells from CLP in this culture system. Our findings indicate that IL-7 is a pivotal cytokine essential for B cell differentiation in vitro, demonstrating a notable synergistic impact when combined with SCF and FLT3L. Moreover, this system is capable of supporting the differentiation of hematopoietic stem cells (HSCs) and lymphoid-primed multipotent progenitor cells (LMPPs) into B cells in vitro. The findings substantiated the efficacy of the culture system in investigating the in vitro differentiation of bone marrow-derived progenitor cells into B cells and elucidated the specific roles of BSA, FBS and three cytokines (IL-7, FLT3L and SCF) in promoting efficient B lineage differentiation.
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Affiliation(s)
- Pan Yang
- Department of Respiratory And Critical Care Medicine, First Affiliated Hospital of Army Medical University, No. 30 Gaotan Yanzheng Street, Chongqing, 400038, China
| | - Xiaoling Chen
- Institute of Immunology PLA, Army Medical University, No. 30 Gaotan Yanzheng Street, Chongqing, 400038, China
| | - Hao Wen
- Institute of Immunology PLA, Army Medical University, No. 30 Gaotan Yanzheng Street, Chongqing, 400038, China
| | - Meiling Yu
- Institute of Immunology PLA, Army Medical University, No. 30 Gaotan Yanzheng Street, Chongqing, 400038, China
| | - Haili Yu
- Biomedical Analysis Center PLA, Army Medical University, Chongqing, 400038, China
| | - Li Wang
- Institute of Immunology PLA, Army Medical University, No. 30 Gaotan Yanzheng Street, Chongqing, 400038, China.
| | - Liang Gong
- Department of Respiratory And Critical Care Medicine, First Affiliated Hospital of Army Medical University, No. 30 Gaotan Yanzheng Street, Chongqing, 400038, China.
| | - Lintao Zhao
- Department of Respiratory And Critical Care Medicine, First Affiliated Hospital of Army Medical University, No. 30 Gaotan Yanzheng Street, Chongqing, 400038, China.
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Ren G, Sørensen MB, Porsborg SR, Fink T, Zachar V, Peng Q. Comparative analysis of cryopreserved adipose stem cells expanded in hollow fiber bioreactor versus conventional tissue culture flasks. Sci Rep 2024; 14:31853. [PMID: 39738501 PMCID: PMC11686135 DOI: 10.1038/s41598-024-83255-0] [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: 08/16/2024] [Accepted: 12/12/2024] [Indexed: 01/02/2025] Open
Abstract
Cryopreservation enhances the availability of "off-the-shelf" cell therapies. However, the choice between tissue culture polystyrene (TCP) and hollow fiber system (HFB) system for adipose-derived stem cell (ASC) production remains a critical decision, with implications for scalability, reproducibility, and the clinical efficacy. Therefore, the characteristics of ASCs expanded in TCP and HFB and cryopreserved were compared. TCP and HFB cultures were established, and cells were cryopreserved. Surface markers were analyzed to identify immunophenotypic changes and subpopulations. Clonogenicity, differentiation capability, and proliferation potentials were determined along with surrogate tests on wound healing. The expressions of the most markers were consistent before and after thawing for both systems. However, CD105 expression of TCP cells was significantly decreased by the freeze-thawing procedure. Also, CD274 was significantly less expressed on HFB-expanded cells before freezing, however, post-thawing, the proportion of CD274 positive cells was comparable to TCP cells. Besides, two expansions supported different subpopulations, influencing the heterogeneity within ASC cultures. Despite this heterogeneity, no statistical differences were observed as for ASC functional characteristics and the effects on fibroblasts. This study highlighted freeze-thaw does not interfere with the production of fully functional ASCs in either system, although it drives some differential changes in the subpopulations between systems.
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Affiliation(s)
- Guoqiang Ren
- The Affiliated LiHuiLi Hospital of Ningbo University, Ningbo University, Ningbo, 315040, China
| | | | - Simone Riis Porsborg
- Department of Health Science and Technology, Aalborg University, Gistrup, 9260, Denmark
| | - Trine Fink
- Department of Health Science and Technology, Aalborg University, Gistrup, 9260, Denmark
| | - Vladimir Zachar
- Department of Health Science and Technology, Aalborg University, Gistrup, 9260, Denmark
| | - Qiuyue Peng
- Department of Health Science and Technology, Aalborg University, Gistrup, 9260, Denmark.
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Pollard AE. New concepts in the roles of AMPK in adipocyte stem cell biology. Essays Biochem 2024; 68:349-361. [PMID: 39175418 DOI: 10.1042/ebc20240008] [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: 05/31/2024] [Revised: 08/09/2024] [Accepted: 08/13/2024] [Indexed: 08/24/2024]
Abstract
Obesity is a major risk factor for many life-threatening diseases. Adipose tissue dysfunction is emerging as a driving factor in the transition from excess adiposity to comorbidities such as metabolic-associated fatty liver disease, cardiovascular disease, Type 2 diabetes and cancer. However, the transition from healthy adipose expansion to the development of these conditions is poorly understood. Adipose stem cells, residing in the vasculature and stromal regions of subcutaneous and visceral depots, are responsible for the expansion and maintenance of organ function, and are now recognised as key mediators of pathological transformation. Impaired tissue expansion drives inflammation, dysregulation of endocrine function and the deposition of lipids in the liver, muscle and around vital organs, where it is toxic. Contrary to previous hypotheses, it is the promotion of healthy adipose tissue expansion and function, not inhibition of adipogenesis, that presents the most attractive therapeutic strategy in the treatment of metabolic disease. AMP-activated protein kinase, a master regulator of energy homeostasis, has been regarded as one such target, due to its central role in adipose tissue lipid metabolism, and its apparent inhibition of adipogenesis. However, recent studies utilising AMP-activated protein kinase (AMPK)-specific compounds highlight a more subtle, time-dependent role for AMPK in the process of adipogenesis, and in a previously unexplored repression of leptin, independent of adipocyte maturity. In this article, I discuss historic evidence for AMPK-mediated adipogenesis inhibition and the multi-faceted roles for AMPK in adipose tissue.
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Affiliation(s)
- Alice E Pollard
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, U.K
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Lauvrud AT, Giraudo MV, Wiberg R, Wiberg M, Kingham PJ, Brohlin M. The influence of xeno-free culture conditions on the angiogenic and adipogenic differentiation properties of adipose tissue-derived stem cells. Regen Ther 2024; 26:901-910. [PMID: 39822342 PMCID: PMC11736170 DOI: 10.1016/j.reth.2024.09.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 09/17/2024] [Accepted: 09/25/2024] [Indexed: 01/19/2025] Open
Abstract
Introduction Before performing cell therapy clinical trials, it is important to understand how cells are influenced by different growth conditions and to find optimal xeno-free medium formulations. In this study we have investigated the properties of adipose tissue-derived stem cells (ASCs) cultured under xeno-free conditions. Methods Human lipoaspirate samples were digested to yield the stromal vascular fraction cells which were then seeded in i) Minimum Essential Medium-α (MEM-α) supplemented with 10 % (v/v) fetal bovine serum (FBS), ii) MEM-α supplemented with 2 % (v/v) human platelet lysate (PLT) or iii) PRIME-XV MSC expansion XSFM xeno-free, serum free medium (XV). Flow cytometry for ASCs markers CD73, CD90 and CD105 together with the putative pericyte marker CD146 was performed. Growth rates were monitored over multiple passages and adipogenic differentiation performed at early and expanded passage culture. Growth factor gene expression was analyzed and an in vitro angiogenesis assay performed. Results Cells in FBS and PLT grew at similar rates whereas the cells cultured in XV medium proliferated significantly faster up to 60 days in culture. All cultures were >98 % positive for CD73, CD90 and CD105, whereas CD146 expression was significantly higher in XV cells. Adipogenic differentiation was most pronounced in cells which had been cultured in XV medium whilst cells grown in PLT were inferior compared with cells from the FBS cultures. IGF1 gene expression was highest in cells cultured in PLT whilst cells grown in XV medium showed 10-fold lower expression compared with FBS cells. In contrast, HGF gene expression was 90-fold greater in cells cultured in XV medium compared with those cultured in FBS. Conditioned medium from XV cultured cells showed the most angiogenic activity, inducing the greatest endothelial cell network formation and maturation. Conclusion Culture under different conditions alters the ASCs characteristics. Since cells cultured in XV medium showed the best adipogenic and angiogenic profile this might be a preferred medium formulation for preparing cells required for reconstructive surgical applications such as cell-assisted fat grafting.
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Affiliation(s)
- Anne Therese Lauvrud
- Department of Medical and Translational Biology, Umeå University, SE-901 87 Umeå, Sweden
- Department of Diagnostics and Intervention, Umeå University, SE-901 87 Umeå, Sweden
| | - Maria Vittoria Giraudo
- Department of Medical and Translational Biology, Umeå University, SE-901 87 Umeå, Sweden
| | - Rebecca Wiberg
- Department of Medical and Translational Biology, Umeå University, SE-901 87 Umeå, Sweden
- Department of Diagnostics and Intervention, Umeå University, SE-901 87 Umeå, Sweden
| | - Mikael Wiberg
- Department of Medical and Translational Biology, Umeå University, SE-901 87 Umeå, Sweden
- Department of Diagnostics and Intervention, Umeå University, SE-901 87 Umeå, Sweden
| | - Paul J. Kingham
- Department of Medical and Translational Biology, Umeå University, SE-901 87 Umeå, Sweden
| | - Maria Brohlin
- Department of Medical and Translational Biology, Umeå University, SE-901 87 Umeå, Sweden
- Department of Clinical Microbiology, Umeå University, SE-901 87 Umeå, Sweden
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Gareev I, Beylerli O, Ilyasova T, Ahmad A, Shi H, Chekhonin V. Therapeutic application of adipose-derived stromal vascular fraction in myocardial infarction. iScience 2024; 27:109791. [PMID: 38736548 PMCID: PMC11088339 DOI: 10.1016/j.isci.2024.109791] [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] [Indexed: 05/14/2024] Open
Abstract
The insufficiency of natural regeneration processes in higher organisms, including humans, underlies myocardial infarction (MI), which is one of the main causes of disability and mortality in the population of developed countries. The solution to this problem lies in the field of revealing the mechanisms of regeneration and creating on this basis new technologies for stimulating endogenous regenerative processes or replacing lost parts of tissues and organs with transplanted cells. Of great interest is the use of the so-called stromal vascular fraction (SVF), derived from autologous adipose tissue. It is known that the main functions of SVF are angiogenetic, antiapoptotic, antifibrotic, immune regulation, anti-inflammatory, and trophic. This study presents data on the possibility of using SVF, targeted regulation of its properties and reparative potential, as well as the results of research studies on its use for the restoration of damaged ischemic tissue after MI.
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Affiliation(s)
- Ilgiz Gareev
- Bashkir State Medical University, Ufa 450008, Russian Federation
| | - Ozal Beylerli
- Bashkir State Medical University, Ufa 450008, Russian Federation
| | - Tatiana Ilyasova
- Bashkir State Medical University, Ufa 450008, Russian Federation
| | - Aamir Ahmad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Huaizhang Shi
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin 1500, China
| | - Vladimir Chekhonin
- Pirogov Russian National Research Medical University of the Ministry of Healthcare of Russian Federation, Moscow, Russian Federation
- Serbsky Federal Medical Research Centre of Psychiatry and Narcology of the Ministry of Healthcare of Russian Federation, Moscow, Russian Federation
- The National Medical Research Center for Endocrinology, Moscow, Russian Federation
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Casado-Losada I, Acosta M, Schädl B, Priglinger E, Wolbank S, Nürnberger S. Unlocking Potential: Low Bovine Serum Albumin Enhances the Chondrogenicity of Human Adipose-Derived Stromal Cells in Pellet Cultures. Biomolecules 2024; 14:413. [PMID: 38672430 PMCID: PMC11048491 DOI: 10.3390/biom14040413] [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: 02/21/2024] [Revised: 03/23/2024] [Accepted: 03/26/2024] [Indexed: 04/28/2024] Open
Abstract
Bovine serum albumin (BSA) plays a crucial role in cell culture media, influencing cellular processes such as proliferation and differentiation. Although it is commonly included in chondrogenic differentiation media, its specific function remains unclear. This study explores the effect of different BSA concentrations on the chondrogenic differentiation of human adipose-derived stromal/stem cells (hASCs). hASC pellets from six donors were cultured under chondrogenic conditions with three BSA concentrations. Surprisingly, a lower BSA concentration led to enhanced chondrogenesis. The degree of this effect was donor-dependent, classifying them into two groups: (1) high responders, forming at least 35% larger, differentiated pellets with low BSA in comparison to high BSA; (2) low responders, which benefitted only slightly from low BSA doses with a decrease in pellet size and marginal differentiation, indicative of low intrinsic differentiation potential. In all cases, increased chondrogenesis was accompanied by hypertrophy under low BSA concentrations. To the best of our knowledge, this is the first study showing improved chondrogenicity and the tendency for hypertrophy with low BSA concentration compared to standard levels. Once the tendency for hypertrophy is understood, the determination of BSA concentration might be used to tune hASC chondrogenic or osteogenic differentiation.
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Affiliation(s)
- Isabel Casado-Losada
- Department of Orthopedics and Trauma-Surgery, Division of Trauma-Surgery, Medical University of Vienna, 1090 Vienna, Austria; (I.C.-L.); (M.A.)
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria (E.P.); (S.W.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
| | - Melanie Acosta
- Department of Orthopedics and Trauma-Surgery, Division of Trauma-Surgery, Medical University of Vienna, 1090 Vienna, Austria; (I.C.-L.); (M.A.)
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria (E.P.); (S.W.)
| | - Barbara Schädl
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria (E.P.); (S.W.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
- University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria
| | - Eleni Priglinger
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria (E.P.); (S.W.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
- Department for Orthopedics and Traumatology, Kepler University Hospital GmbH, Johannes Kepler University Linz, 4020 Linz, Austria
| | - Susanne Wolbank
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria (E.P.); (S.W.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
| | - Sylvia Nürnberger
- Department of Orthopedics and Trauma-Surgery, Division of Trauma-Surgery, Medical University of Vienna, 1090 Vienna, Austria; (I.C.-L.); (M.A.)
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria (E.P.); (S.W.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
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Andersen C, Walters M, Bundgaard L, Berg LC, Vonk LA, Lundgren-Åkerlund E, Henriksen BL, Lindegaard C, Skovgaard K, Jacobsen S. Intraarticular treatment with integrin α10β1-selected mesenchymal stem cells affects microRNA expression in experimental post-traumatic osteoarthritis in horses. Front Vet Sci 2024; 11:1374681. [PMID: 38596460 PMCID: PMC11002141 DOI: 10.3389/fvets.2024.1374681] [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: 01/22/2024] [Accepted: 03/08/2024] [Indexed: 04/11/2024] Open
Abstract
Osteoarthritis (OA) remains a major cause of lameness in horses, which leads to lost days of training and early retirement. Still, the underlying pathological processes are poorly understood. MicroRNAs (miRNAs) are small non-coding RNAs that serve as regulators of many biological processes including OA. Analysis of miRNA expression in diseased joint tissues such as cartilage and synovial membrane may help to elucidate OA pathology. Since integrin α10β1-selected mesenchymal stem cell (integrin α10-MSC) have shown mitigating effect on equine OA we here investigated the effect of integrin α10-MSCs on miRNA expression. Cartilage and synovial membrane was harvested from the middle carpal joint of horses with experimentally induced, untreated OA, horses with experimentally induced OA treated with allogeneic adipose-derived MSCs selected for the marker integrin α10-MSCs, and from healthy control joints. miRNA expression in cartilage and synovial membrane was established by quantifying 70 pre-determined miRNAs by qPCR. Differential expression of the miRNAs was evaluated by comparing untreated OA and control, untreated OA and MSC-treated OA, and joints with high and low pathology score. A total of 60 miRNAs were successfully quantified in the cartilage samples and 55 miRNAs were quantified in the synovial membrane samples. In cartilage, miR-146a, miR-150 and miR-409 had significantly higher expression in untreated OA joints than in control joints. Expression of miR-125a-3p, miR-150, miR-200c, and miR-499-5p was significantly reduced in cartilage from MSC-treated OA joints compared to the untreated OA joints. Expression of miR-139-5p, miR-150, miR-182-5p, miR-200a, miR-378, miR-409-3p, and miR-7177b in articular cartilage reflected pathology score. Several of these miRNAs are known from research in human patients with OA and from murine OA models. Our study shows that these miRNAs are also differentially expressed in experimental equine OA, and that expression depends on OA severity. Moreover, MSC treatment, which resulted in less severe OA, also affected miRNA expression in cartilage.
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Affiliation(s)
- Camilla Andersen
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark
| | - Marie Walters
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark
| | - Louise Bundgaard
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark
| | - Lise Charlotte Berg
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark
| | | | | | | | - Casper Lindegaard
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark
| | - Kerstin Skovgaard
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark
| | - Stine Jacobsen
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark
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Tarapongpun T, Onlamoon N, Tabu K, Chuthapisith S, Taga T. The optimized priming effect of FGF-1 and FGF-2 enhances preadipocyte lineage commitment in human adipose-derived mesenchymal stem cells. Genes Cells 2024; 29:231-253. [PMID: 38253356 DOI: 10.1111/gtc.13095] [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: 10/17/2023] [Revised: 12/26/2023] [Accepted: 01/04/2024] [Indexed: 01/24/2024]
Abstract
The cell-assisted lipotransfer technique, integrating adipose-derived mesenchymal stem cells (ADMSCs), has transformed lipofilling, enhancing fat graft viability. However, the multipotent nature of ADMSCs poses challenges. To improve safety and graft vitality and to reduce unwanted lineage differentiation, this study refines the methodology by priming ADMSCs into preadipocytes-unipotent, self-renewing cells. We explored the impact of fibroblast growth factor-1 (FGF-1), fibroblast growth factor-2 (FGF-2), and epidermal growth factor (EGF), either alone or in combination, on primary human ADMSCs during the proliferative phase. FGF-2 emerged as a robust stimulator of cell proliferation, preserving stemness markers, especially when combined with EGF. Conversely, FGF-1, while not significantly affecting cell growth, influenced cell morphology, transitioning cells to a rounded shape with reduced CD34 expression. Furthermore, co-priming with FGF-1 and FGF-2 enhanced adipogenic potential, limiting osteogenic and chondrogenic tendencies, and possibly promoting preadipocyte commitment. These preadipocytes exhibited unique features: rounded morphology, reduced CD34, decreased preadipocyte factor 1 (Pref-1), and elevated C/EBPα and PPARγ, alongside sustained stemness markers (CD73, CD90, CD105). Mechanistically, FGF-1 and FGF-2 activated key adipogenic transcription factors-C/EBPα and PPARγ-while inhibiting GATA3 and Notch3, which are adipogenesis inhibitors. These findings hold the potential to advance innovative strategies for ADMSC-mediated lipofilling procedures.
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Affiliation(s)
- Tanakorn Tarapongpun
- Division of Head Neck and Breast Surgery, Faculty of Medicine Siriraj Hospital, Department of Surgery, Mahidol University, Bangkok, Thailand
- Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Nattawat Onlamoon
- Department of Research, Faculty of Medicine Siriraj Hospital, Siriraj Research Group in Immunobiology and Therapeutic Sciences, Mahidol University, Bangkok, Thailand
| | - Kouichi Tabu
- Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Suebwong Chuthapisith
- Division of Head Neck and Breast Surgery, Faculty of Medicine Siriraj Hospital, Department of Surgery, Mahidol University, Bangkok, Thailand
| | - Tetsuya Taga
- Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
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Andersen C, Jacobsen S, Uvebrant K, Griffin JF, Vonk LA, Walters M, Berg LC, Lundgren-Åkerlund E, Lindegaard C. Integrin α10β1-Selected Mesenchymal Stem Cells Reduce Pain and Cartilage Degradation and Increase Immunomodulation in an Equine Osteoarthritis Model. Cartilage 2023:19476035231209402. [PMID: 37990503 DOI: 10.1177/19476035231209402] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2023] Open
Abstract
OBJECTIVE Integrin α10β1-selected mesenchymal stem cells (integrin α10-MSCs) have previously shown potential in treating cartilage damage and osteoarthritis (OA) in vitro and in animal models in vivo. The aim of this study was to further investigate disease-modifying effects of integrin α10-MSCs. DESIGN OA was surgically induced in 17 horses. Eighteen days after surgery, horses received 2 × 107 integrin α10-MSCs intra-articularly or were left untreated. Lameness and response to carpal flexion was assessed weekly along with synovial fluid (SF) analysis. On day 52 after treatment, horses were euthanized, and carpi were evaluated by computed tomography (CT), MRI, histology, and for macroscopic pathology and integrin α10-MSCs were traced in the joint tissues. RESULTS Lameness and response to carpal flexion significantly improved over time following integrin α10-MSC treatment. Treated horses had milder macroscopic cartilage pathology and lower cartilage histology scores than the untreated group. Prostaglandin E2 and interleukin-10 increased in the SF after integrin α10-MSC injection. Integrin α10-MSCs were found in SF from treated horses up to day 17 after treatment, and in the articular cartilage and subchondral bone from 5 of 8 treated horses after euthanasia at 52 days after treatment. The integrin α10-MSC injection did not cause joint flare. CONCLUSION This study demonstrates that intra-articular (IA) injection of integrin α10-MSCs appears to be safe, alleviate pathological changes in the joint, and improve joint function in an equine post-traumatic osteoarthritis (PTOA) model. The results suggest that integrin α10-MSCs hold promise as a disease-modifying osteoarthritis drug (DMOAD).
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Affiliation(s)
- Camilla Andersen
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark
- Xintela AB, Lund, Sweden
| | - Stine Jacobsen
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark
| | | | - John F Griffin
- Department of Large Animal Clinical Sciences, Texas A&M University, College Station, TX, USA
| | | | - Marie Walters
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark
| | - Lise Charlotte Berg
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark
| | | | - Casper Lindegaard
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark
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Bogov (jr.) AA, Akhtyamov IF, Danilov VI, Starostina IG, Khannanova IG, Bogov AA. Treatment of a damaged brachial plexus with help of stromal vascular fraction cell from adipose tissue. BULLETIN OF THE MEDICAL INSTITUTE "REAVIZ" (REHABILITATION, DOCTOR AND HEALTH) 2022. [DOI: 10.20340/vmi-rvz.2023.1.clin.3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
Abstract
The aim of the study – to accelerate the repair of the damaged brachial plexus using cells of the stromal vascular fraction isolated from adipose tissue.Materials and methods. The study was carried out in 62 patients using stromal-vascular fraction cells from adipose tissue and classical methods of treatment for brachial plexus injury. The effectiveness of regeneration was evaluated using electromyographic examination and positive recovery of motor and sensory function.Results and discussion. Assessment of the results of surgical treatment with stromal vascular fraction cells from adipose tissue after brachial plexus neurolysis revealed the restoration of early M3-M5 and S3-S4 functions in 90 % of patients, and in the comparison group – 68 % respectively. The number of patients with M4-M5 functions in the group using the stromal vascular fraction for brachial plexus neurotization was 85 %, while in the control group it was 64 %, respectively. Electroneuromyography data also indicated an increase in the average number of motor units by 30 % after using cells of the stromal-vascular fraction from adipose tissue, in contrast to the comparison group.Conclusion. Stromal vascular cells isolated from adipose tissue appear to be promising stimulants of brachial plexus injury repair.
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Affiliation(s)
- A. A. Bogov (jr.)
- Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan
| | | | - V. I. Danilov
- Cazan State Medical University; Interregional Clinical Diagnostic Center
| | | | - I. G. Khannanova
- Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan
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Saffari TM, Saffari S, Vyas KS, Mardini S, Shin AY. Role of adipose tissue grafting and adipose-derived stem cells in peripheral nerve surgery. Neural Regen Res 2022; 17:2179-2184. [PMID: 35259826 PMCID: PMC9083182 DOI: 10.4103/1673-5374.336870] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
The application of autologous fat grafting in reconstructive surgery is commonly used to improve functional form. This review aims to provide an overview of the scientific evidence on the biology of adipose tissue, the role of adipose-derived stem cells, and the indications of adipose tissue grafting in peripheral nerve surgery. Adipose tissue is easily accessible through the lower abdomen and inner thighs. Non-vascularized adipose tissue grafting does not support oxidative and ischemic stress, resulting in variable survival of adipocytes within the first 24 hours. Enrichment of adipose tissue with a stromal vascular fraction is purported to increase the number of adipose-derived stem cells and is postulated to augment the long-term stability of adipose tissue grafts. Basic science nerve research suggests an increase in nerve regeneration and nerve revascularization, and a decrease in nerve fibrosis after the addition of adipose-derived stem cells or adipose tissue. In clinical studies, the use of autologous lipofilling is mostly applied to secondary carpal tunnel release revisions with promising results. Since the use of adipose-derived stem cells in peripheral nerve reconstruction is relatively new, more studies are needed to explore safety and long-term effects on peripheral nerve regeneration. The Food and Drug Administration stipulates that adipose-derived stem cell transplantation should be minimally manipulated, enzyme-free, and used in the same surgical procedure, e.g. adipose tissue grafts that contain native adipose-derived stem cells or stromal vascular fraction. Future research may be shifted towards the use of tissue-engineered adipose tissue to create a supportive microenvironment for autologous graft survival. Shelf-ready alternatives could be enhanced with adipose-derived stem cells or growth factors and eliminate the need for adipose tissue harvest.
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Affiliation(s)
- Tiam M Saffari
- Department of Orthopedic Surgery, Division of Microvascular and Hand Surgery, Mayo Clinic, Rochester, MN, USA; Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Plastic Surgery, Nijmegen, The Netherlands
| | - Sara Saffari
- Department of Orthopedic Surgery, Division of Microvascular and Hand Surgery, Mayo Clinic, Rochester, MN, USA; Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Plastic Surgery, Nijmegen, The Netherlands
| | - Krishna S Vyas
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Mayo Clinic, Rochester, MN, USA
| | - Samir Mardini
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Mayo Clinic, Rochester, MN, USA
| | - Alexander Y Shin
- Department of Orthopedic Surgery, Division of Microvascular and Hand Surgery, Mayo Clinic, Rochester, MN, USA
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12
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Poliwoda S, Noor N, Downs E, Schaaf A, Cantwell A, Ganti L, Kaye AD, Mosel LI, Carroll CB, Viswanath O, Urits I. Stem cells: a comprehensive review of origins and emerging clinical roles in medical practice. Orthop Rev (Pavia) 2022; 14:37498. [PMID: 36034728 PMCID: PMC9404248 DOI: 10.52965/001c.37498] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/10/2023] Open
Abstract
Stem cells are types of cells that have unique ability to self-renew and to differentiate into more than one cell lineage. They are considered building blocks of tissues and organs. Over recent decades, they have been studied and utilized for repair and regenerative medicine. One way to classify these cells is based on their differentiation capacity. Totipotent stem cells can give rise to any cell of an embryo but also to extra-embryonic tissue as well. Pluripotent stem cells are limited to any of the three embryonic germ layers; however, they cannot differentiate into extra-embryonic tissue. Multipotent stem cells can only differentiate into one germ line tissue. Oligopotent and unipotent stem cells are seen in adult organ tissues that have committed to a cell lineage. Another way to differentiate these cells is based on their origins. Stem cells can be extracted from different sources, including bone marrow, amniotic cells, adipose tissue, umbilical cord, and placental tissue. Stem cells began their role in modern regenerative medicine in the 1950's with the first bone marrow transplantation occurring in 1956. Stem cell therapies are at present indicated for a range of clinical conditions beyond traditional origins to treat genetic blood diseases and have seen substantial success. In this regard, emerging use for stem cells is their potential to treat pain states and neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Stem cells offer hope in neurodegeneration to replace neurons damaged during certain disease states. This review compares stem cells arising from these different sources of origin and include clinical roles for stem cells in modern medical practice.
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Affiliation(s)
| | - Nazir Noor
- Department of Anesthesiology, Mount Sinai Medical Center
| | - Evan Downs
- LSU Health Science Center Shreveport School of Medicine, Shreveport, LA
| | - Amanda Schaaf
- University of Arizona College of Medicine-Phoenix, Phoenix, AZ
| | | | - Latha Ganti
- Department of Emergency Medicine, University of Central Florida
| | - Alan D Kaye
- Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport
| | - Luke I Mosel
- Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport
| | - Caroline B Carroll
- Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport
| | - Omar Viswanath
- Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport, Innovative Pain and Wellness, Creighton University School of Medicine
| | - Ivan Urits
- Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport
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13
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Enhanced Repaired Enthesis Using Tenogenically Differentiated Adipose-Derived Stem Cells in a Murine Rotator Cuff Injury Model. Stem Cells Int 2022; 2022:1309684. [PMID: 35607399 PMCID: PMC9124132 DOI: 10.1155/2022/1309684] [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: 07/21/2021] [Accepted: 01/10/2022] [Indexed: 11/18/2022] Open
Abstract
Rotator cuff tear (RCT) is among the most common shoulder injuries and is prone to rerupture after surgery. Selecting suitable subpopulations of stem cells as a new specific cell type of mesenchymal stem cells has been increasingly used as a potential therapeutic tool in regenerative medicine. In this study, murine adipose-derived SSEA-4+CD90+PDGFRA+ subpopulation cells were successfully sorted, extracted, and identified. These cells showed good proliferation and differentiation potential, especially in the direction of tendon differentiation, as evidenced by qRT-PCR and immunofluorescence. Subsequently, we established a murine rotator cuff injury model and repaired it with subpopulation cells. Our results showed that the subpopulation cells embedded in a fibrin sealant significantly improved the histological score, as well as the biomechanical strength of the repaired tendon enthesis at four weeks after surgery, compared with the other groups. Hence, these findings indicated that the subpopulation of cells could augment the repaired enthesis and lead to better outcomes, thereby reducing the retear rate after rotator cuff repair. Our study provides a potential therapeutic strategy for rotator cuff healing in the future.
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14
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Peng Q, Ren G, Xuan Z, Duda M, Pennisi CP, Porsborg SR, Fink T, Zachar V. Distinct Dominant Lineage from In Vitro Expanded Adipose-Derived Stem Cells (ASCs) Exhibits Enhanced Wound Healing Properties. Cells 2022; 11:cells11071236. [PMID: 35406800 PMCID: PMC8998068 DOI: 10.3390/cells11071236] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 04/03/2022] [Accepted: 04/04/2022] [Indexed: 12/16/2022] Open
Abstract
It has been suggested that immunophenotypically defined lineages within the in vitro expanded adipose-derived stem cell (ASC) may play a beneficial role from the perspective of a personalized intervention. Therefore, to better understand the implications of different surface marker profiles for the functionality, we set out to examine the evolution of ASC-variants based on the co-expression of five bright or eight dim epitopes. At passages P1, P4, and P8, the co-localization of five bright markers (CD73, CD90, CD105, CD166, and CD201), or eight dim markers (CD34, CD36, CD200, CD248, CD271, CD274, CD146, and the Stro-1), was investigated by flow cytometry. Selected subpopulations were isolated using the fluorescence-activated cells sorting from the cryopreserved P4 and analyzed in terms of proliferative and clonogenic properties, trilineage differentiation, and wound healing potential. Only two of the dim epitopes were found in representative subpopulations (SP), and from the P4 onwards, two major combinations featuring the CD274+ (SP1) or the CD274+ CD146+ (SP2) emerged. Upon sorting and growth, both subpopulations assumed new but highly similar clonal profiles, consisting of the CD274+ CD146+ and the CD274+ CD146+ CD248+ phenotypes. The functional analysis revealed that the SP2 surpassed SP1 and the unfractionated cells regarding the growth rate, clonogenic activity, and the wound closure and endothelial tube formation potential. The surface epitopes may be considered a tool to enrich specific functionality and thus improve therapeutic outcomes in dedicated circumstances.
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15
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Clarke EJ, Johnson E, Caamaño Gutierrez E, Andersen C, Berg LC, Jenkins RE, Lindegaard C, Uvebrant K, Lundgren-Åkerlund E, Turlo A, James V, Jacobsen S, Peffers MJ. Temporal extracellular vesicle protein changes following intraarticular treatment with integrin α10β1-selected mesenchymal stem cells in equine osteoarthritis. Front Vet Sci 2022; 9:1057667. [PMID: 36504839 PMCID: PMC9730043 DOI: 10.3389/fvets.2022.1057667] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 11/10/2022] [Indexed: 11/25/2022] Open
Abstract
Introduction Equine osteoarthritis (OA) is a heterogeneous, degenerative disease of the musculoskeletal system with multifactorial causation, characterized by a joint metabolic imbalance. Extracellular vesicles are nanoparticles involved in intracellular communication. Mesenchymal stem cell (MSC) therapy is a form of regenerative medicine that utilizes their properties to repair damaged tissues. Despite its wide use in veterinary practice, the exact mechanism of action of MSCs is not fully understood. The aim of this study was to determine the synovial fluid extracellular vesicle protein cargo following integrin α10β1-selected mesenchymal stem cell (integrin α10-MSC) treatment in an experimental model of equine osteoarthritis with longitudinal sampling. Methods Adipose tissue derived, integrin α10-MSCs were injected intraarticularly in six horses 18 days after experimental induction of OA. Synovial fluid samples were collected at day 0, 18, 21, 28, 35, and 70. Synovial fluid was processed and extracellular vesicles were isolated and characterized. Extracellular vesicle cargo was then analyzed using data independent acquisition mass spectrometry proteomics. Results A total of 442 proteins were identified across all samples, with 48 proteins differentially expressed (FDR ≤ 0.05) between sham-operated control joint without MSC treatment and OA joint treated with MSCs. The most significant pathways following functional enrichment analysis of the differentially abundant protein dataset were serine endopeptidase activity (p = 0.023), complement activation (classical pathway) (p = 0.023), and collagen containing extracellular matrix (p = 0.034). Due to the lack of an OA group without MSC treatment, findings cannot be directly correlated to only MSCs. Discussion To date this is the first study to quantify the global extracellular vesicle proteome in synovial fluid following MSC treatment of osteoarthritis. Changes in the proteome of the synovial fluid-derived EVs following MSC injection suggest EVs may play a role in mediating the effect of cell therapy through altered joint homeostasis. This is an important step toward understanding the potential therapeutic mechanisms of MSC therapy, ultimately enabling the improvement of therapeutic efficacy.
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Affiliation(s)
- Emily J Clarke
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Emily Johnson
- Computational Biology Facility, Liverpool Shared Research Facilities, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Eva Caamaño Gutierrez
- Computational Biology Facility, Liverpool Shared Research Facilities, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Camilla Andersen
- Department of Veterinary Clinical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lise C Berg
- Department of Veterinary Clinical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Rosalind E Jenkins
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, Centre for Drug Safety Science Bioanalytical Facility, Liverpool Shared Research Facilities, University of Liverpool, Liverpool, United Kingdom
| | - Casper Lindegaard
- Department of Veterinary Clinical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | | | - Agnieszka Turlo
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Victoria James
- School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom
| | - Stine Jacobsen
- Department of Veterinary Clinical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mandy J Peffers
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
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16
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Xu X, Kong DS, Tian YP, Xie YL, Zhang JK, Huang XH. Autocross-linked hyaluronic acid gel and adipose-derived mesenchymal stem cell composites for the treatment intrauterine adhesions. Taiwan J Obstet Gynecol 2021; 60:1031-1037. [PMID: 34794733 DOI: 10.1016/j.tjog.2021.09.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/08/2021] [Indexed: 10/19/2022] Open
Abstract
OBJECTIVE To evaluate the effect of adding adipose-derived mesenchymal stem cells (ASCs) to autocross-linked hyaluronic acid (HA) gel for intrauterine adhesion (IUA) treatment. METHODS A rat IUA model was established by mechanical curettage and infection, and then different treatments were administered to the rats on day 7 after modeling. Ninety-six rats were randomly divided into the following groups: IUA model group, gel therapy group, and combination therapy group (HA gel combined with ASCs). Eight rats per group were sacrificed on days 7, 10, 14 and 21 for the subsequent experiments. Morphological changes were determined by hematoxylin-eosin staining and Masson staining. Smad3 and leukocyte inhibitory factor (LIF) were analyzed by quantitative real-time polymerase chain reaction and immunohistochemistry. RESULTS The endometrial lines in the gel therapy group and the combination therapy group were more complete than those in the model group. Masson staining showed that fibrosis area rates in the gel therapy group and the combination therapy group were significantly lower than those in the model group on day 7(P < 0.05). During the observation period, the fibrosis area rates in the combination therapy group remained lower than those in the model group (P < 0.05). The mRNA expression of Smad3 in the combination therapy group was lower than that in the model group and gel therapy group during the observation period (P < 0.05). The mRNA expression level of LIF in the combination therapy group was higher than that in the model group and the gel therapy group throughout the observation period (P < 0.05). CONCLUSIONS HA gel was effective in preventing the IUA adhesion formation at the early stage of the observation period, while ASC enhanced this effect throughout the observation period. Gel and ASC composites helped to improve endometrial receptivity.
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Affiliation(s)
- Xin Xu
- Department of Gynecology and Obstetrics, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - De-Sheng Kong
- Department of Gynecology and Obstetrics, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yan-Peng Tian
- Department of Gynecology and Obstetrics, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yan-Ling Xie
- Department of Gynecology and Obstetrics, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jing-Kun Zhang
- Department of Gynecology and Obstetrics, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiang-Hua Huang
- Department of Gynecology and Obstetrics, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
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17
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Rahmani-Moghadam E, Zarrin V, Mahmoodzadeh A, Owrang M, Talaei-Khozani T. Comparison of the Characteristics of Breast Milk-derived Stem Cells with the Stem Cells Derived from the Other Sources: A Comparative Review. Curr Stem Cell Res Ther 2021; 17:71-90. [PMID: 34161214 DOI: 10.2174/1574888x16666210622125309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/14/2021] [Accepted: 03/28/2021] [Indexed: 11/22/2022]
Abstract
Breast milk (BrM) not only supplies nutrition, but it also contains a diverse population of cells. It has been estimated that up to 6% of the cells in human milk possess the characteristics of mesenchymal stem cells (MSC). Available data also indicate that these cells are multipotent and capable of self-renewal and differentiation with other cells. In this review, we have compared different characteristics, such as CD markers, differentiation capacity, and morphology of stem cells, derived from human breast milk (hBr-MSC) with human bone marrow (hBMSC), Wharton's jelly (WJMSC), and human adipose tissue (hADMSC). Through the literature review, it was revealed that human breast milk-derived stem cells specifically express a group of cell surface markers, including CD14, CD31, CD45, and CD86. Importantly, a group of markers, CD13, CD29, CD44, CD105, CD106, CD146, and CD166, were identified, which were common in the four sources of stem cells. WJMSC, hBMSC, hADMSC, and hBr-MSC are potently able to differentiate into the mesoderm, ectoderm, and endoderm cell lineages. The ability of hBr-MSCs todifferentiate into the neural stem cells, neurons, adipocyte, hepatocyte, chondrocyte, osteocyte, and cardiomyocytes has made these cells a promising source of stem cells in regenerative medicine, while isolation of stem cells from the commonly used sources, such as bone marrow, requires invasive procedures. Although autologous breast milk-derived stem cells are an accessible source for women who are in the lactation period, breast milk can be considered as a source of stem cells with high differentiation potential without any ethical concern.
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Affiliation(s)
- Ebrahim Rahmani-Moghadam
- Department of Anatomical sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Vahideh Zarrin
- Laboratory for Stem Cell Research, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Mahmoodzadeh
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Marzieh Owrang
- Department of Anatomical sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tahereh Talaei-Khozani
- Department of Anatomical sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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18
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Ong WK, Chakraborty S, Sugii S. Adipose Tissue: Understanding the Heterogeneity of Stem Cells for Regenerative Medicine. Biomolecules 2021; 11:biom11070918. [PMID: 34206204 PMCID: PMC8301750 DOI: 10.3390/biom11070918] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 06/17/2021] [Accepted: 06/17/2021] [Indexed: 12/13/2022] Open
Abstract
Adipose-derived stem cells (ASCs) have been increasingly used as a versatile source of mesenchymal stem cells (MSCs) for diverse clinical investigations. However, their applications often become complicated due to heterogeneity arising from various factors. Cellular heterogeneity can occur due to: (i) nomenclature and criteria for definition; (ii) adipose tissue depots (e.g., subcutaneous fat, visceral fat) from which ASCs are isolated; (iii) donor and inter-subject variation (age, body mass index, gender, and disease state); (iv) species difference; and (v) study design (in vivo versus in vitro) and tools used (e.g., antibody isolation and culture conditions). There are also actual differences in resident cell types that exhibit ASC/MSC characteristics. Multilineage-differentiating stress-enduring (Muse) cells and dedifferentiated fat (DFAT) cells have been reported as an alternative or derivative source of ASCs for application in regenerative medicine. In this review, we discuss these factors that contribute to the heterogeneity of human ASCs in detail, and what should be taken into consideration for overcoming challenges associated with such heterogeneity in the clinical use of ASCs. Attempts to understand, define, and standardize cellular heterogeneity are important in supporting therapeutic strategies and regulatory considerations for the use of ASCs.
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Affiliation(s)
- Wee Kiat Ong
- School of Pharmacy, Monash University Malaysia, Subang Jaya 47500, Selangor, Malaysia
- Correspondence: (W.K.O.); (S.S.)
| | - Smarajit Chakraborty
- Institute of Bioengineering and Bioimaging (IBB), A*STAR, 31 Biopolis Way, Singapore 138669, Singapore;
| | - Shigeki Sugii
- Institute of Bioengineering and Bioimaging (IBB), A*STAR, 31 Biopolis Way, Singapore 138669, Singapore;
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
- Correspondence: (W.K.O.); (S.S.)
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19
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Effect of Biomedical Materials in the Implementation of a Long and Healthy Life Policy. Processes (Basel) 2021. [DOI: 10.3390/pr9050865] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
This paper is divided into seven main parts. Its purpose is to review the literature to demonstrate the importance of developing bioengineering and global production of biomaterials to care for the level of healthcare in the world. First, the general description of health as a universal human value and assumptions of a long and healthy life policy is presented. The ethical aspects of the mission of medical doctors and dentists were emphasized. The coronavirus, COVID-19, pandemic has had a significant impact on health issues, determining the world’s health situation. The scope of the diseases is given, and specific methods of their prevention are discussed. The next part focuses on bioengineering issues, mainly medical engineering and dental engineering, and the need for doctors to use technical solutions supporting medicine and dentistry, taking into account the current stage Industry 4.0 of the industrial revolution. The concept of Dentistry 4.0 was generally presented, and a general Bioengineering 4.0 approach was suggested. The basics of production management and the quality loop of the product life cycle were analyzed. The general classification of medical devices and biomedical materials necessary for their production was presented. The paper contains an analysis of the synthesis and characterization of biomedical materials supporting medicine and dentistry, emphasizing additive manufacturing methods. Numerous examples of clinical applications supported considerations regarding biomedical materials. The economic conditions for implementing various biomedical materials groups were supported by forecasts for developing global markets for biomaterials, regenerative medicine, and tissue engineering. In the seventh part, recapitulation and final remarks against the background of historical retrospection, it was emphasized that the technological processes of production and processing of biomedical materials and the systematic increase in their global production are a determinant of the implementation of a long and healthy policy.
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20
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Lin D, Scheller SH, Robinson MM, Izadpanah R, Alt EU, Braun SE. Increased Efficiency for Biallelic Mutations of the CCR5 Gene by CRISPR-Cas9 Using Multiple Guide RNAs As a Novel Therapeutic Option for Human Immunodeficiency Virus. CRISPR J 2021; 4:92-103. [PMID: 33616448 PMCID: PMC8713505 DOI: 10.1089/crispr.2020.0019] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
CCR5 is a coreceptor of human immunodeficiency virus type 1 (HIV-1). Transplantation of hematopoietic stem cells homozygous for a 32-bp deletion in CCR5 resulted in a loss of detectable HIV-1 in two patients, suggesting that genetic strategies to knockout CCR5 expression would be a promising gene therapy approach for HIV-1-infected patients. In this study, we targeted CCR5 by CRISPR-Cas9 with a single-guide (sgRNA) and observed 35% indel frequency. When we expressed hCas9 and two gRNAs, the Surveyor assay showed that Cas9-mediated cleavage was increased by 10% with two sgRNAs. Genotype analysis on individual clones showed 11 of 13 carried biallelic mutations, where 4 clones had frameshift (FS) mutations. Taken together, these results indicate that the efficiency of biallelic FS mutations and the knockout of the CCR5 necessary to prevent viral replication were significantly increased with two sgRNAs. These studies demonstrate the knockout of CCR5 and the potential for translational development.
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Affiliation(s)
- Dong Lin
- Applied Stem Cell Laboratory,
Medicine/Heart and Vascular Institute, Tulane National Primate Research Center,
New Orleans, Louisiana, USA
- Department of Surgery, Tulane University
Health Science Center, New Orleans, Louisiana, USA
| | - Stefan H. Scheller
- Applied Stem Cell Laboratory,
Medicine/Heart and Vascular Institute, Tulane National Primate Research Center,
New Orleans, Louisiana, USA
| | - Madeline M. Robinson
- Applied Stem Cell Laboratory,
Medicine/Heart and Vascular Institute, Tulane National Primate Research Center,
New Orleans, Louisiana, USA
| | - Reza Izadpanah
- Applied Stem Cell Laboratory,
Medicine/Heart and Vascular Institute, Tulane National Primate Research Center,
New Orleans, Louisiana, USA
- Department of Surgery, Tulane University
Health Science Center, New Orleans, Louisiana, USA
| | - Eckhard U. Alt
- Applied Stem Cell Laboratory,
Medicine/Heart and Vascular Institute, Tulane National Primate Research Center,
New Orleans, Louisiana, USA
- Isar Klinikum Munich, Munich,
Germany
| | - Stephen E. Braun
- Applied Stem Cell Laboratory,
Medicine/Heart and Vascular Institute, Tulane National Primate Research Center,
New Orleans, Louisiana, USA
- Department of Pharmacology, Tulane
University Health Science Center, New Orleans, Louisiana, USA
- Division of Immunology, Tulane National
Primate Research Center, Covington, Louisiana, USA
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21
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Ntege EH, Sunami H, Shimizu Y. Advances in regenerative therapy: A review of the literature and future directions. Regen Ther 2020; 14:136-153. [PMID: 32110683 PMCID: PMC7033303 DOI: 10.1016/j.reth.2020.01.004] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 01/14/2020] [Accepted: 01/26/2020] [Indexed: 12/14/2022] Open
Abstract
There is enormous global anticipation for stem cell-based therapies that are safe and effective. Numerous pre-clinical studies present encouraging results on the therapeutic potential of different cell types including tissue derived stem cells. Emerging evidences in different fields of research suggest several cell types are safe, whereas their therapeutic application and effectiveness remain challenged. Multiple factors that influence treatment outcomes are proposed including immunocompatibility and potency, owing to variations in tissue origin, ex-vivo methodologies for preparation and handling of the cells. This communication gives an overview of literature data on the different types of cells that are potentially promising for regenerative therapy. As a case in point, the recent trends in research and development of the mesenchymal stem cells (MSCs) for cell therapy are considered in detail. MSCs can be isolated from a variety of tissues and organs in the human body including bone marrow, adipose, synovium, and perinatal tissues. However, MSC products from the different tissue sources exhibit unique or varied levels of regenerative abilities. The review finally focuses on adipose tissue-derived MSCs (ASCs), with the unique properties such as easier accessibility and abundance, excellent proliferation and differentiation capacities, low immunogenicity, immunomodulatory and many other trophic properties. The suitability and application of the ASCs, and strategies to improve the innate regenerative capacities of stem cells in general are highlighted among others.
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Affiliation(s)
- Edward H. Ntege
- Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, University of the Ryukyus, Japan
- Research Center for Regenerative Medicine, School of Medicine, University of the Ryukyus, Japan
| | - Hiroshi Sunami
- Research Center for Regenerative Medicine, School of Medicine, University of the Ryukyus, Japan
| | - Yusuke Shimizu
- Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, University of the Ryukyus, Japan
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22
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The Effect of Early Rounds of ex vivo Expansion and Cryopreservation on the Adipogenic Differentiation Capacity of Adipose-Derived Stromal/Stem Cells. Sci Rep 2019; 9:15943. [PMID: 31685852 PMCID: PMC6828715 DOI: 10.1038/s41598-019-52086-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 10/11/2019] [Indexed: 12/13/2022] Open
Abstract
Multipotent adipose-derived stromal/stem cells (ASCs) are candidates for use in cellular therapies for the treatment of a variety of conditions/diseases. Ex vivo expansion of freshly isolated ASCs may be necessary prior to clinical application to ensure that clinically relevant cell numbers are administered during treatment. In addition, cryopreserving cells at early passages allows for storage of freshly isolated cells for extended periods of time before expanding these cells for clinical usage. There are however several concerns that these laboratory-based procedures may alter the characteristics of the cells and in so doing decrease their regenerative potential. In this study we report on the impact of early rounds of cryopreservation (P0) and ex vivo expansion (P0 to P5) on the phenotypic characteristics and adipogenic differentiation potential of ASCs. Our results show that ASCs that upregulate CD36 expression during adipogenic differentiation gradually decrease with increasing expansion rounds. The consequent decrease in adipogenic differentiation capacity was evident in both gene expression and flow cytometry-based phenotypic studies. Successive rounds of expansion did not however alter cell surface marker expression of the cells. We also show that early cryopreservation of ASCs (at P0) does not affect the adipogenic differentiation potential of the cells.
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Zhang X, Liu L. Applications of single cell RNA sequencing to research of stem cells. World J Stem Cells 2019; 11:722-728. [PMID: 31692946 PMCID: PMC6828599 DOI: 10.4252/wjsc.v11.i10.722] [Citation(s) in RCA: 6] [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: 05/05/2019] [Revised: 08/12/2019] [Accepted: 09/11/2019] [Indexed: 02/06/2023] Open
Abstract
Stem cells (SCs) with their self-renewal and pluripotent differentiation potential, show great promise for therapeutic applications to some refractory diseases such as stroke, Parkinsonism, myocardial infarction, and diabetes. Furthermore, as seed cells in tissue engineering, SCs have been applied widely to tissue and organ regeneration. However, previous studies have shown that SCs are heterogeneous and consist of many cell subpopulations. Owing to this heterogeneity of cell states, gene expression is highly diverse between cells even within a single tissue, making precise identification and analysis of biological properties difficult, which hinders their further research and applications. Therefore, a defined understanding of the heterogeneity is a key to research of SCs. Traditional ensemble-based sequencing approaches, such as microarrays, reflect an average of expression levels across a large population, which overlook unique biological behaviors of individual cells, conceal cell-to-cell variations, and cannot understand the heterogeneity of SCs radically. The development of high throughput single cell RNA sequencing (scRNA-seq) has provided a new research tool in biology, ranging from identification of novel cell types and exploration of cell markers to the analysis of gene expression and predicating developmental trajectories. scRNA-seq has profoundly changed our understanding of a series of biological phenomena. Currently, it has been used in research of SCs in many fields, particularly for the research of heterogeneity and cell subpopulations in early embryonic development. In this review, we focus on the scRNA-seq technique and its applications to research of SCs.
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Affiliation(s)
- Xiao Zhang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lei Liu
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China.
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24
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Gonçalves AI, Berdecka D, Rodrigues MT, Eren AD, de Boer J, Reis RL, Gomes ME. Evaluation of tenogenic differentiation potential of selected subpopulations of human adipose-derived stem cells. J Tissue Eng Regen Med 2019; 13:2204-2217. [PMID: 31606945 DOI: 10.1002/term.2967] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 09/11/2019] [Accepted: 09/25/2019] [Indexed: 12/24/2022]
Abstract
Identification of a suitable cell source and bioactive agents guiding cell differentiation towards tenogenic phenotype represents a prerequisite for advancement of cell-based therapies for tendon repair. Human adipose-derived stem cells (hASCs) are a promising, yet intrinsically heterogenous population with diversified differentiation capacities. In this work, we investigated antigenically-defined subsets of hASCs expressing markers related to tendon phenotype or associated with pluripotency that might be more prone to tenogenic differentiation, when compared to unsorted hASCs. Subpopulations positive for tenomodulin (TNMD+ hASCs) and stage specific early antigen 4 (SSEA-4+ hASCs), as well as unsorted ASCs were cultured up to 21 days in basic medium or media supplemented with TGF-β3 (10 ng/ml), or GDF-5 (50 ng/ml). Cell response was evaluated by analysis of expression of tendon-related markers at gene level and protein level by real time RT-PCR, western blot, and immunocytochemistry. A significant upregulation of scleraxis was observed for both subpopulations and unsorted hASCs in the presence of TGF-β3. More prominent alterations in gene expression profile in response to TGF-β3 were observed for TNMD+ hASCs. Subpopulations evidenced an increased collagen III and TNC deposition in basal medium conditions in comparison with unsorted hASCs. In the particular case of TNMD+ hASCs, GDF-5 seems to influence more the deposition of TNC. Within hASCs populations, discrete subsets could be distinguished offering varied sensitivity to specific biochemical stimulation leading to differential expression of tenogenic components suggesting that cell subsets may have distinctive roles in the complex biological responses leading to tenogenic commitment to be further explored in cell based strategies for tendon tissues.
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Affiliation(s)
- Ana I Gonçalves
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga, Portugal
| | - Dominika Berdecka
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga, Portugal
| | - Márcia T Rodrigues
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga, Portugal.,The Discoveries Centre for Regenerative and Precision Medicine, Headquarters at University of Minho, Guimarães, Portugal
| | - Aysegul Dede Eren
- MERLN Institute for Technology-Inspired Regenerative Medicine, Department of Cell Biology-Inspired Tissue Engineering, Maastricht, The Netherlands
| | - Jan de Boer
- MERLN Institute for Technology-Inspired Regenerative Medicine, Department of Cell Biology-Inspired Tissue Engineering, Maastricht, The Netherlands
| | - Rui L Reis
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga, Portugal.,The Discoveries Centre for Regenerative and Precision Medicine, Headquarters at University of Minho, Guimarães, Portugal
| | - Manuela E Gomes
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga, Portugal.,The Discoveries Centre for Regenerative and Precision Medicine, Headquarters at University of Minho, Guimarães, Portugal
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25
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Perspectives for Clinical Translation of Adipose Stromal/Stem Cells. Stem Cells Int 2019; 2019:5858247. [PMID: 31191677 PMCID: PMC6525805 DOI: 10.1155/2019/5858247] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 02/26/2019] [Accepted: 03/07/2019] [Indexed: 12/15/2022] Open
Abstract
Adipose stromal/stem cells (ASCs) are an ideal cell type for regenerative medicine applications, as they can easily be harvested from adipose tissue in large quantities. ASCs have excellent proliferation, differentiation, and immunoregulatory capacities that have been demonstrated in numerous studies. Great interest and investment have been placed in efforts to exploit the allogeneic use and immunomodulatory and anti-inflammatory effects of ASCs. However, bridging the gap between in vitro and in vivo studies and moving into clinical practice remain a challenge. For the clinical translation of ASCs, several issues must be considered, including how to characterise such a heterogenic cell population and how to ensure their safety and efficacy. This review explores the different phases of in vitro and preclinical ASC characterisation and describes the development of appropriate potency assays. In addition, good manufacturing practice requirements are discussed, and cell-based medicinal products holding marketing authorisation in the European Union are reviewed. Moreover, the current status of clinical trials applying ASCs and the patent landscape in the field of ASC research are presented. Overall, this review highlights the applicability of ASCs for clinical cell therapies and discusses their potential.
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26
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Kouroupis D, Sanjurjo-Rodriguez C, Jones E, Correa D. Mesenchymal Stem Cell Functionalization for Enhanced Therapeutic Applications. TISSUE ENGINEERING PART B-REVIEWS 2018; 25:55-77. [PMID: 30165783 DOI: 10.1089/ten.teb.2018.0118] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
IMPACT STATEMENT Culture expansion of MSCs has detrimental effects on various cell characteristics and attributes (e.g., phenotypic changes and senescence), which, in addition to inherent interdonor variability, negatively impact the standardization and reproducibility of their therapeutic potential. The identification of innate distinct functional MSC subpopulations, as well as the description of ex vivo protocols aimed at maintaining phenotypes and enhancing specific functions have the potential to overcome these limitations. The incorporation of those approaches into cell-based therapy would significantly impact the field, as more reproducible clinical outcomes may be achieved.
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Affiliation(s)
- Dimitrios Kouroupis
- 1 Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, Florida.,2 Diabetes Research Institute & Cell Transplant Center, University of Miami Miller School of Medicine, Miami, Florida
| | - Clara Sanjurjo-Rodriguez
- 3 Leeds Institute of Rheumatic and Musculoskeletal Disease, Saint James University Hospital, University of Leeds, Leeds, United Kingdom.,4 Department of Biomedical Sciences, Medicine and Physiotherapy, University of A Coruña, CIBER-BBN-Institute of Biomedical Research of A Coruña (INIBIC), A Coruña, Spain
| | - Elena Jones
- 3 Leeds Institute of Rheumatic and Musculoskeletal Disease, Saint James University Hospital, University of Leeds, Leeds, United Kingdom
| | - Diego Correa
- 1 Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, Florida.,2 Diabetes Research Institute & Cell Transplant Center, University of Miami Miller School of Medicine, Miami, Florida
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27
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Goodarzi P, Alavi-Moghadam S, Sarvari M, Tayanloo Beik A, Falahzadeh K, Aghayan H, Payab M, Larijani B, Gilany K, Rahim F, Adibi H, Arjmand B. Adipose Tissue-Derived Stromal Cells for Wound Healing. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1119:133-149. [PMID: 29858972 DOI: 10.1007/5584_2018_220] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Skin as the outer layer covers the body. Wounds can affect this vital organ negatively and disrupt its functions. Wound healing as a biological process is initiated immediately after an injury. This process consists of three stages: inflammation, proliferation, remodeling. Generally, these three stages occur continuously and timely. However, some factors such as infection, obesity and diabetes mellitus can interfere with these stages and impede the normal healing process which results in chronic wounds. Financial burden on both patients and health care systems, negative biologic effect on the patient's general health status and reduction in quality of life are a number of issues which make chronic wounds as a considerable challenge. During recent years, along with advances in the biomedical sciences, various surgical and non-surgical therapeutic methods have been suggested. All of these suggested treatments have their own advantages and disadvantages. Recently, cell-based therapies and regenerative medicine represent promising approaches to wound healing. Accordingly, several types of mesenchymal stem cells have been used in both preclinical and clinical settings for the treatment of wounds. Adipose-derived stromal cells are a cost-effective source of mesenchymal stem cells in wound management which can be easily harvest from adipose tissues through the less invasive processes with high yield rates. In addition, their ability to secrete multiple cytokines and growth factors, and differentiation into skin cells make them an ideal cell type to use in wound treatment. This is a concise overview on the application of adipose-derived stromal cells in wound healing and their role in the treatment of chronic wounds.
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Affiliation(s)
- Parisa Goodarzi
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Alavi-Moghadam
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Sarvari
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Akram Tayanloo Beik
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Khadijeh Falahzadeh
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamidreza Aghayan
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Moloud Payab
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Kambiz Gilany
- Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Fakher Rahim
- Health Research Institute, Thalassemia and Hemoglobinopathy Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hossein Adibi
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran. .,Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
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28
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Brett E, Chung N, Leavitt WT, Momeni A, Longaker MT, Wan DC. A Review of Cell-Based Strategies for Soft Tissue Reconstruction. TISSUE ENGINEERING PART B-REVIEWS 2017; 23:336-346. [PMID: 28372485 DOI: 10.1089/ten.teb.2016.0455] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Soft tissue reconstruction to restore volume to damaged or deficient tissue beneath the skin remains a challenging endeavor. Current techniques are centered around autologous fat transfer, or the use of synthetic substitutes, however, a great deal of scientific inquiry has been made into both the molecular mechanisms involved in, and limitations of, de novo adipogenesis, that is, the formation of new adipose tissue from precursor cells. To best comprehend these mechanisms, an understanding of defined markers for adipogenic differentiation, and knowledge of both commercially available and primary cell lines that enable in vitro and in vivo studies is necessary. We review the growth factors, proteins, cytokines, drugs, and molecular pathways that have shown promise in enhancing adipogenesis and vasculogenesis, in addition to the multitude of scaffolds that act as delivery vehicles to support these processes. While progress continues on these fronts, equally important is how researchers are optimizing clinically employed strategies such as autologous fat transfer through cell-based intervention, and the potential to augment this approach through isolation of preferentially adipogenic or angiogenic precursor subpopulations, which exists on the horizon. This review will highlight the novel molecular and synthetic modifications currently being studied for inducing adipose tissue regeneration on a cellular level, which will expand our arsenal of techniques for approaching soft tissue reconstruction.
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Affiliation(s)
- Elizabeth Brett
- 1 Hagey Laboratory for Pediatric Regenerative Medicine, Plastic and Reconstructive Surgery Division, Department of Surgery, Stanford University School of Medicine , Stanford, California
| | - Natalie Chung
- 1 Hagey Laboratory for Pediatric Regenerative Medicine, Plastic and Reconstructive Surgery Division, Department of Surgery, Stanford University School of Medicine , Stanford, California
| | - William Tripp Leavitt
- 1 Hagey Laboratory for Pediatric Regenerative Medicine, Plastic and Reconstructive Surgery Division, Department of Surgery, Stanford University School of Medicine , Stanford, California
| | - Arash Momeni
- 1 Hagey Laboratory for Pediatric Regenerative Medicine, Plastic and Reconstructive Surgery Division, Department of Surgery, Stanford University School of Medicine , Stanford, California
| | - Michael T Longaker
- 1 Hagey Laboratory for Pediatric Regenerative Medicine, Plastic and Reconstructive Surgery Division, Department of Surgery, Stanford University School of Medicine , Stanford, California.,2 Institute for Stem Cell Biology and Regenerative Medicine, Stanford University , Stanford, California
| | - Derrick C Wan
- 1 Hagey Laboratory for Pediatric Regenerative Medicine, Plastic and Reconstructive Surgery Division, Department of Surgery, Stanford University School of Medicine , Stanford, California
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29
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Elçin AE, Parmaksiz M, Dogan A, Seker S, Durkut S, Dalva K, Elçin YM. Differential gene expression profiling of human adipose stem cells differentiating into smooth muscle-like cells by TGFβ1/BMP4. Exp Cell Res 2017; 352:207-217. [DOI: 10.1016/j.yexcr.2017.02.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 02/02/2017] [Accepted: 02/05/2017] [Indexed: 12/18/2022]
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30
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Chen YW, Wang JR, Liao X, Li SH, Xiao LL, Cheng B, Xie GH, Song JX, Liu HW. Effect of suction pressures on cell yield and functionality of the adipose-derived stromal vascular fraction. J Plast Reconstr Aesthet Surg 2017; 70:257-266. [DOI: 10.1016/j.bjps.2016.10.028] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Revised: 10/09/2016] [Accepted: 10/31/2016] [Indexed: 12/29/2022]
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31
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Nielsen FM, Riis SE, Andersen JI, Lesage R, Fink T, Pennisi CP, Zachar V. Discrete adipose-derived stem cell subpopulations may display differential functionality after in vitro expansion despite convergence to a common phenotype distribution. Stem Cell Res Ther 2016; 7:177. [PMID: 27906060 PMCID: PMC5134234 DOI: 10.1186/s13287-016-0435-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 09/14/2016] [Accepted: 11/03/2016] [Indexed: 01/01/2023] Open
Abstract
Background Complex immunophenotypic repertoires defining discrete adipose-derived stem cell (ASC) subpopulations may hold a key toward identifying predictors of clinical utility. To this end, we sorted out of the freshly established ASCs four subpopulations (SPs) according to a specific pattern of co-expression of six surface markers, the CD34, CD73, CD90, CD105, CD146, and CD271, using polychromatic flow cytometry. Method Using flow cytometry-associated cell sorting and analysis, gating parameters were set to select for a CD73+CD90+CD105+ phenotype plus one of the four following combinations, CD34−CD146−CD271− (SP1), CD34−CD146+CD271− (SP2), CD34+CD146+CD271− (SP3), and CD34−CD146+CD271+ (SP4). The SPs were expanded 700- to 1000-fold, and their surface repertoire, trilineage differentiation, and clonogenic potential, and the capacity to support wound healing were assayed. Results Upon culturing, the co-expression of major epitopes, the CD73, CD90, and CD105 was maintained, while regarding the minor markers, all SPs reverted to resemble the pre-sorted population with CD34−CD146−CD271− and CD34−CD146+CD271− representing the most prevalent combinations, followed by less frequent CD34+CD146−CD271− and CD34+CD146+CD271− variants. There was no difference in the efficiency of adipo-, osteo-, or chondrogenesis by cytochemistry and real-time RT-PCR or the CFU capacity between the individual SPs, however, the SP2CD73+90+105+34-146+271- outperformed others in terms of wound healing. Conclusions Our study shows that ASCs upon culturing inherently maintain a stable distribution of immunophenotype variants, which may potentially disguise specific functional properties of particular downstream lines. Furthermore, the outlined approach suggests a paradigm whereby discrete subpopulations could be identified to provide for a therapeutically most relevant cell product. Electronic supplementary material The online version of this article (doi:10.1186/s13287-016-0435-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Frederik Mølgaard Nielsen
- Laboratory for Stem Cell Research, Department for Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Simone Elkjær Riis
- Laboratory for Stem Cell Research, Department for Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Jens Isak Andersen
- Laboratory for Stem Cell Research, Department for Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Raphaëlle Lesage
- Department of Bioengineering, Polytech Nice-Sophia Engineering School, Nice, France
| | - Trine Fink
- Laboratory for Stem Cell Research, Department for Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Cristian Pablo Pennisi
- Laboratory for Stem Cell Research, Department for Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Vladimir Zachar
- Laboratory for Stem Cell Research, Department for Health Science and Technology, Aalborg University, Aalborg, Denmark.
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Dessels C, Potgieter M, Pepper MS. Making the Switch: Alternatives to Fetal Bovine Serum for Adipose-Derived Stromal Cell Expansion. Front Cell Dev Biol 2016; 4:115. [PMID: 27800478 PMCID: PMC5065960 DOI: 10.3389/fcell.2016.00115] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Accepted: 09/30/2016] [Indexed: 12/28/2022] Open
Abstract
Adipose-derived stromal cells (ASCs) are being used extensively in clinical trials. These trials require that ASCs are prepared using good manufacturing practices (GMPs) and are safe for use in humans. The majority of clinical trials in which ASCs are expanded make use of fetal bovine serum (FBS). While FBS is used traditionally in the research setting for in vitro expansion, it does carry the risk of xenoimmunization and zoonotic transmission when used for expanding cells destined for therapeutic purposes. In order to ensure a GMP quality product for cellular therapy, in vitro expansion of ASCs has been undertaken using xeno-free (XF), chemically-defined, and human blood-derived alternatives. These investigations usually include the criteria proposed by the International Society of Cellular Therapy (ISCT) and International Fat Applied Technology Society (IFATS). The majority of studies use these criteria to compare plastic-adherence, morphology, the immunophenotype and the trilineage differentiation of ASCs under the different medium supplemented conditions. Based on these studies, all of the alternatives to FBS seem to be suitable replacements; however, each has its own advantages and drawbacks. Very few studies have investigated the effects of the supplements on the immunomodulation of ASCs; the transcriptome, proteome and secretome; and the ultimate effects in appropriate animal models. The selection of medium supplementation will depend on the downstream application of the ASCs and their efficacy and safety in preclinical studies.
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Affiliation(s)
- Carla Dessels
- South African Medical Research Council, Extramural Unit for Stem Cell Research and Therapy, and Department of Immunology, Faculty of Health Sciences, Institute for Cellular and Molecular Medicine, University of Pretoria Pretoria, South Africa
| | - Marnie Potgieter
- South African Medical Research Council, Extramural Unit for Stem Cell Research and Therapy, and Department of Immunology, Faculty of Health Sciences, Institute for Cellular and Molecular Medicine, University of Pretoria Pretoria, South Africa
| | - Michael S Pepper
- South African Medical Research Council, Extramural Unit for Stem Cell Research and Therapy, and Department of Immunology, Faculty of Health Sciences, Institute for Cellular and Molecular Medicine, University of Pretoria Pretoria, South Africa
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33
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Kagami H. Potential application of tissue engineering for the reconstruction of facial bones. Oral Dis 2016; 23:689-691. [DOI: 10.1111/odi.12581] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- H Kagami
- Department of Oral and Maxillofacial Surgery; School of Dentistry; Matsumoto Dental University; Shiojiri
- Department of Advanced Medical Science; IMSUT Hospital; The Institute of Medical Science; The University of Tokyo; Tokyo Japan
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34
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Bajek A, Gurtowska N, Olkowska J, Kazmierski L, Maj M, Drewa T. Adipose-Derived Stem Cells as a Tool in Cell-Based Therapies. Arch Immunol Ther Exp (Warsz) 2016; 64:443-454. [PMID: 27178663 PMCID: PMC5085986 DOI: 10.1007/s00005-016-0394-x] [Citation(s) in RCA: 130] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 01/20/2016] [Indexed: 02/06/2023]
Abstract
Recent development in stem cell isolation methods and expansion under laboratory conditions create an opportunity to use those aforementioned cells in tissue engineering and regenerative medicine. Particular attention is drawn towards mesenchymal stem cells (MSCs) being multipotent progenitors exhibiting several unique characteristics, including high proliferation potential, self-renewal abilities and multilineage differentiation into cells of mesodermal and non-mesodermal origin. High abundance of MSCs found in adipose tissue makes it a very attractive source of adult stem cells for further use in regenerative medicine applications. Despite immunomodulating properties of adipose-derived stem cells (ASCs) and a secretion of a wide variety of paracrine factors that facilitate tissue regeneration, effectiveness of stem cell therapy was not supported by the results of clinical trials. Lack of a single, universal stem cell marker, patient-to-patient variability, heterogeneity of ASC population combined with multiple widely different protocols of cell isolation and expansion hinder the ability to precisely identify and analyze biological properties of stem cells. The above issues contribute to conflicting data reported in literature. We will review the comprehensive information concerning characteristic features of ASCs. We will also review the regenerative potential and clinical application based on various clinical trials.
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Affiliation(s)
- Anna Bajek
- Department of Tissue Engineering, Nicolaus Copernicus University, Karłowicza 24, 85-092, Bydgoszcz, Poland.
| | - Natalia Gurtowska
- Department of Tissue Engineering, Nicolaus Copernicus University, Karłowicza 24, 85-092, Bydgoszcz, Poland
| | - Joanna Olkowska
- Department of Tissue Engineering, Nicolaus Copernicus University, Karłowicza 24, 85-092, Bydgoszcz, Poland
| | - Lukasz Kazmierski
- Department of Tissue Engineering, Nicolaus Copernicus University, Karłowicza 24, 85-092, Bydgoszcz, Poland
| | - Malgorzata Maj
- Department of Tissue Engineering, Nicolaus Copernicus University, Karłowicza 24, 85-092, Bydgoszcz, Poland
| | - Tomasz Drewa
- Department of Tissue Engineering, Nicolaus Copernicus University, Karłowicza 24, 85-092, Bydgoszcz, Poland.,Department of Urology, Nicolaus Copernicus Hospital, Torun, Poland
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35
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Combellack EJ, Jessop ZM, Naderi N, Griffin M, Dobbs T, Ibrahim A, Evans S, Burnell S, Doak SH, Whitaker IS. Adipose regeneration and implications for breast reconstruction: update and the future. Gland Surg 2016; 5:227-41. [PMID: 27047789 PMCID: PMC4791352 DOI: 10.3978/j.issn.2227-684x.2016.01.01] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 10/17/2015] [Indexed: 12/20/2022]
Abstract
The evolution of breast reconstruction and management of breast cancer has evolved significantly since the earliest descriptions in the Edwin Smith Papyrus (3,000 BC). The development of surgical and scientific expertise has changed the way that women are managed, and plastic surgeons are now able to offer a wide range of reconstructive options to suit individual needs. Beyond the gold standard autologous flap based reconstructions, regenerative therapies promise the elimination of donor site morbidity whilst providing equivalent aesthetic and functional outcomes. Future research aims to address questions regarding ideal cell source, optimisation of scaffold composition and interaction of de novo adipose tissue in the microenvironment of breast cancer.
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36
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Faroni A, Smith RJP, Lu L, Reid AJ. Human Schwann-like cells derived from adipose-derived mesenchymal stem cells rapidly de-differentiate in the absence of stimulating medium. Eur J Neurosci 2016; 43:417-30. [PMID: 26309136 PMCID: PMC4744694 DOI: 10.1111/ejn.13055] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Revised: 08/13/2015] [Accepted: 08/20/2015] [Indexed: 01/24/2023]
Abstract
Finding a viable cell-based therapy to address peripheral nerve injury holds promise for enhancing the currently suboptimal microsurgical approaches to peripheral nerve repair. Autologous nerve grafting is the current gold standard for surgical repair of nerve gaps; however, this causes donor nerve morbidity in the patient, and the results remain unsatisfactory. Transplanting autologous Schwann cells (SCs) results in similar morbidity, as well as limited cell numbers and restricted potential for expansion in vitro. Adipose-derived stem cells (ASCs), 'differentiated' towards an SC-like phenotype in vitro (dASCs), have been presented as an alternative to SC therapies. The differentiation protocol stimulates ASCs to mimic the SC phenotype; however, the efficacy of dASCs in nerve repair is not yet convincing, and the practicality of the SC-like phenotype is unproven. Here, we examined the stability of dASCs by withdrawing differentiation medium for 72 h after the full 18-day differentiation protocol, and measuring changes in morphology, gene expression, and protein levels. Withdrawal of differentiation medium from dASCs resulted in a rapid reversion to stem cell-like characteristics. Quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay analyses demonstrated a significant reduction in gene and protein expression of growth factors that were expressed at high levels following 'differentiation'. Therefore, we question the relevance of differentiation to an SC-like phenotype, as withdrawal of differentiation medium, a model of transplantation into an injured nerve, results in rapid reversion of the dASC phenotype to stem cell-like characteristics. Further investigation into the differentiation process and the response of dASCs to an injured environment must be undertaken prior to the use of dASCs in peripheral nerve repair therapies.
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Affiliation(s)
- Alessandro Faroni
- Blond McIndoe Laboratories, Stopford BuildingCentre for Tissue Injury and RepairInstitute of Inflammation and RepairUniversity of ManchesterOxford RoadManchesterM13 9PTUK
| | - Richard J. P. Smith
- Blond McIndoe Laboratories, Stopford BuildingCentre for Tissue Injury and RepairInstitute of Inflammation and RepairUniversity of ManchesterOxford RoadManchesterM13 9PTUK
| | - Li Lu
- Blond McIndoe Laboratories, Stopford BuildingCentre for Tissue Injury and RepairInstitute of Inflammation and RepairUniversity of ManchesterOxford RoadManchesterM13 9PTUK
- Department of PharmacologySchool of Basic MedicineLanzhou UniversityLanzhouChina
| | - Adam J. Reid
- Blond McIndoe Laboratories, Stopford BuildingCentre for Tissue Injury and RepairInstitute of Inflammation and RepairUniversity of ManchesterOxford RoadManchesterM13 9PTUK
- Department of Plastic Surgery & BurnsUniversity Hospital of South ManchesterManchesterUK
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Wang L, Hu J, Sorek CE, Chen EY, Ma PX, Yang B. Fabrication of tissue-engineered vascular grafts with stem cells and stem cell-derived vascular cells. Expert Opin Biol Ther 2015; 16:317-30. [PMID: 26560995 PMCID: PMC4928489 DOI: 10.1517/14712598.2016.1118460] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Cardiovascular disease is the leading cause of mortality worldwide. Current surgical treatments for cardiovascular disease include vascular bypass grafting and replacement with autologous blood vessels or synthetic vascular grafts. However, there is a call for better alternative biological grafts. AREAS COVERED Tissue-engineered vascular grafts (TEVGs) are promising novel alternatives to replace diseased vessels. However, obtaining enough functional and clinically usable vascular cells for fabrication of TEVGs remains a major challenge. New findings in adult stem cells and recent advances in pluripotent stem cells have opened a new avenue for stem cell-based vascular engineering. In this review, recent advances on stem cell sourcing for TEVGs including the use of adult stem cells and pluripotent stem cells and advantages, disadvantages, and possible future implementations of different types of stem cells will be discussed. In addition, current strategies used during the fabrication of TEVGs will be highlighted. EXPERT OPINION The application of patient-specific TEVGs constructed with vascular cells derived from immune-compatible stem cells possesses huge clinical potential. Advances in lineage-specific differentiation approaches and innovative vascular engineering strategies will promote the vascular regeneration field from bench to bedside.
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Affiliation(s)
- Lunchang Wang
- a Cardiac Surgery, University of Michigan , Ann Arbor , MI , USA
- b Vascular Surgery, The Second Xiangya Hospital , Xiangya School of Medicine, Central South University , Hunan , China
| | - Jiang Hu
- c Biologic and Materials Sciences, University of Michigan , Ann Arbor , MI , USA
| | - Claire E Sorek
- a Cardiac Surgery, University of Michigan , Ann Arbor , MI , USA
| | - Eugene Y Chen
- a Cardiac Surgery, University of Michigan , Ann Arbor , MI , USA
| | - Peter X Ma
- c Biologic and Materials Sciences, University of Michigan , Ann Arbor , MI , USA
- d Biomedical Engineering, University of Michigan , Ann Arbor , MI , USA
- e Macromolecular Science and Engineering Center, University of Michigan , Ann Arbor , MI , USA
- f Materials Science and Engineering, University of Michigan , Ann Arbor , MI , USA
| | - Bo Yang
- a Cardiac Surgery, University of Michigan , Ann Arbor , MI , USA
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