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Steven W. Dow

Bio: Steven W. Dow is an academic researcher. The author has contributed to research in topics: Mesenchymal stem cell & Bone marrow. The author has an hindex of 1, co-authored 1 publications receiving 100 citations.

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Journal ArticleDOI
TL;DR: Companion animals with naturally occurring diseases analogous to human conditions can be recruited into clinical trials and provide realistic insight into feasibility, safety, and biologic activity of novel stem cell therapies, however, improvements in the rigor of manufacturing, study design, and regulatory compliance will be needed to better utilize these models.
Abstract: Studies to evaluate the therapeutic potential of stem cells in humans would benefit from more realistic animal models. In veterinary medicine, companion animals naturally develop many diseases that resemble human conditions, therefore, representing a novel source of preclinical models. To understand how companion animal disease models are being studied for this purpose, we reviewed the literature between 2008 and 2015 for reports on stem cell therapies in dogs and cats, excluding laboratory animals, induced disease models, cancer, and case reports. Disease models included osteoarthritis, intervertebral disc degeneration, dilated cardiomyopathy, inflammatory bowel diseases, Crohn's fistulas, meningoencephalomyelitis (multiple sclerosis-like), keratoconjunctivitis sicca (Sjogren's syndrome-like), atopic dermatitis, and chronic (end-stage) kidney disease. Stem cells evaluated in these studies included mesenchymal stem-stromal cells (MSC, 17/19 trials), olfactory ensheathing cells (OEC, 1 trial), or neural lineage cells derived from bone marrow MSC (1 trial), and 16/19 studies were performed in dogs. The MSC studies (13/17) used adipose tissue-derived MSC from either allogeneic (8/13) or autologous (5/13) sources. The majority of studies were open label, uncontrolled studies. Endpoints and protocols were feasible, and the stem cell therapies were reportedly safe and elicited beneficial patient responses in all but two of the trials. In conclusion, companion animals with naturally occurring diseases analogous to human conditions can be recruited into clinical trials and provide realistic insight into feasibility, safety, and biologic activity of novel stem cell therapies. However, improvements in the rigor of manufacturing, study design, and regulatory compliance will be needed to better utilize these models. Stem Cells 2016;34:1709-1729.

128 citations


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TL;DR: A study in mice suggests that ES cells might be generated using a single-cell biopsy technique similar to that used for preimplantation genetic diagnosis (PGD) to create new stem cell lines without destroying embryos.
Abstract: At present it is necessary to destroy embryos ex utero to obtain human embryonic stem (hES) cells, but a study in mice suggests that ES cells might be generated using a single-cell biopsy technique similar to that used for preimplantation genetic diagnosis (PGD). This will not interfere with the developmental potential of the embryo. Overnight growth of a single blastomere could yield cells that may be used for both genetic testing and stem cell production without altering the clinical outcome. The investigators carried out ten experiments which, collectively, showed that hES cells can be derived from single blastomeres. Starting with unused embryos produced by in vitro fertilization, 19 ES-cell-like outgrowths and two stable hES cell lines were obtained. A majority of isolated blastomeres divided at least once, and about half formed vesicles or clumps that produced outgrowths within 2 days. The cells remained able to form derivatives of all three embryonic germ layers (primitive endoderm, mesoderm, ectoderm) in vitro and also in teratomas. Among the outcomes observed over several days were three that are typical when ES cells are derived from human embryos. Cells resembling trophectoderm dominated some cultures. Secondly, cells that initially resembled ES cells differentiated within cultures. Finally, ES-cell-like cells continued to proliferate without differentiating. Some hES cell lines proliferated without differentiating for longer than 8 months. Both karyotypes and the expression of markers of pluripotency were normal. The ability to create new stem cell lines without destroying embryos addresses the ethical concerns shared by many interested individuals. Potentially, matched tissues can be generated for children and siblings born from transferred PGD embryos. Further studies will be needed to learn whether blastomere-derived hES cell lines resemble conventional hES cell lines in their ability to form functional differentiated cell types. The investigators recommend that, until safety issues are resolved, this procedure be used only in the context of PGD.

129 citations

Journal ArticleDOI
TL;DR: iMSC administration improved overall intestinal health and healing with equivalent potency to treatment with adMSC, the first report of the effectiveness of iMSC in the treatment of IBD, along with a description of unique mechanisms of action with respect to intestinal healing and microbiome restoration.
Abstract: Cellular therapy with allogeneic or autologous mesenchymal stem cells (MSC) has emerged as a promising new therapeutic strategy for managing inflammatory bowel disease (IBD). However, MSC therapy ideally requires a convenient and relatively homogenous cell source (typically bone marrow or adipose tissues) and the ability to generate cells with stable phenotype and function. An alternative means of generating allogeneic MSC is to derive them from induced pluripotent stem cells (iPSC), which could in theory provide an indefinite supply of MSC with well-defined phenotype and function. Therefore, we compared the effectiveness of iPSC-derived MSC (iMSC) and adipose-derived MSC (adMSC) in a mouse model of IBD (dextran sodium sulfate-induced colitis), and investigated mechanisms of intestinal protection. We found that iMSC were equivalent to adMSC in terms of significantly improving clinical abnormalities in treated mice and reducing lesion scores and inflammation in the gut. Administration of iMSC also stimulated significant intestinal epithelial cell proliferation, increased in the numbers of Lgr5+ intestinal stem cells, and increased intestinal angiogenesis. In addition, the microbiome alterations present in mice with colitis were partially restored to resemble those of healthy mice following treatment with iMSC or adMSC. Thus, iMSC administration improved overall intestinal health and healing with equivalent potency to treatment with adMSC. This therefore is the first report of the effectiveness of iMSC in the treatment of IBD, along with a description of unique mechanisms of action with respect to intestinal healing and microbiome restoration. Stem Cells Translational Medicine 2018;7:456-467.

108 citations

Journal ArticleDOI
TL;DR: The current research situation and progress of the mechanisms through which IVD stem/progenitor cells failed to repair IVD tissues during IVD degeneration are reviewed to provide an innovative research direction for endogenous repair and a new potential treatment strategy for IVd degeneration.

78 citations

Journal ArticleDOI
TL;DR: The administration of fresh, allogenic ASCs appeared to have lower clinical efficacy with a delayed response as compared to the fresh, autologous ASCs, and the mechanism(s) of action) may differ in this model of oral inflammation.
Abstract: Mesenchymal stem cells (MSCs) have potent immunomodulatory functions and are a promising therapy for immune-mediated inflammatory disorders. We previously demonstrated the efficacy of fresh, autologous, adipose-derived MSCs (ASCs) to treat feline chronic gingivostomatitis (FCGS), a chronic oral mucosal inflammatory disease similar to human oral lichen planus. Here, we investigate the use of fresh allogeneic ASCs for treatment of FCGS in seven cats. Radiolabeled ASCs were also tracked systemically. Each cat received two intravenous injections of 20 million ASCs, 1 month apart. Oral inflammation, blood lymphocyte subsets, anti-fetal bovine serum antibody levels, ASC crossmatching and serum proteins and cytokine concentrations were determined. Four of the 7 cats (57%) responded to treatment [complete clinical remission (n = 2) or substantial clinical improvement (n = 2)]. Three cats were nonresponders. Prior to therapy, most cats had increased circulating CD8+ T cells, decreased CD8lo cells, and a decreased CD4/CD8 ratio, however clinical resolution was not associated with normalization of these parameters. Nonresponders showed more severe systemic inflammation (neutrophilia, hyperglobulinemia and increased interferon gamma and tumor necrosis factor alpha concentration) prior to ASC therapy. Clinical remission took up to 20 months and no clinical relapse has occurred. A higher fraction of radiolabeled ASCs were identified in the oral cavity of FCGS affected cats than the control cat. The administration of fresh, allogenic ASCs appeared to have lower clinical efficacy with a delayed response as compared to the fresh, autologous ASCs. In addition, the mechanism(s) of action for autologous and allogenic ASCs may differ in this model of oral inflammation. Stem Cells Translational Medicine 2017;6:1710-1722.

65 citations

Journal ArticleDOI
TL;DR: While cMSCs from synovium, marrow, and adipose tissue share a number of similarities, important differences in proliferation and trilineage differentiation exist and should be considered when selecting c MSCs for translational studies.
Abstract: The dog represents an excellent large animal model for translational cell-based studies. Importantly, the properties of canine multipotent stromal cells (cMSCs) and the ideal tissue source for specific translational studies have yet to be established. The aim of this study was to characterize cMSCs derived from synovium, bone marrow, and adipose tissue using a donor-matched study design and a comprehensive series of in-vitro characterization, differentiation, and immunomodulation assays. Canine MSCs were isolated from five dogs with cranial cruciate ligament rupture. All 15 cMSC preparations were evaluated using colony forming unit (CFU) assays, flow cytometry analysis, RT-PCR for pluripotency-associated genes, proliferation assays, trilineage differentiation assays, and immunomodulation assays. Data were reported as mean ± standard deviation and compared using repeated-measures analysis of variance and Tukey post-hoc test. Significance was established at p < 0.05. All tissue samples produced plastic adherent, spindle-shaped preparations of cMSCs. Cells were negative for CD34, CD45, and STRO-1 and positive for CD9, CD44, and CD90, whereas the degree to which cells were positive for CD105 was variable depending on tissue of origin. Cells were positive for the pluripotency-associated genes NANOG, OCT4, and SOX2. Accounting for donor and tissue sources, there were significant differences in CFU potential, rate of proliferation, trilineage differentiation, and immunomodulatory response. Synovium and marrow cMSCs exhibited superior early osteogenic activity, but when assessing late-stage osteogenesis no significant differences were detected. Interestingly, bone morphogenic protein-2 (BMP-2) supplementation was necessary for early-stage and late-stage osteogenic differentiation, a finding consistent with other canine studies. Additionally, synovium and adipose cMSCs proliferated more rapidly, displayed higher CFU potential, and formed larger aggregates in chondrogenic assays, although proteoglycan and collagen type II staining were subjectively decreased in adipose pellets as compared to synovial and marrow pellets. Lastly, cMSCs derived from all three tissue sources modulated murine macrophage TNF-α and IL-6 levels in a lipopolysaccharide-stimulated coculture assay. While cMSCs from synovium, marrow, and adipose tissue share a number of similarities, important differences in proliferation and trilineage differentiation exist and should be considered when selecting cMSCs for translational studies. These results and associated methods will prove useful for future translational studies involving the canine model.

57 citations