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      Adipose tissue-derived mesenchymal stem cells and platelet-rich plasma: stem cell transplantation methods that enhance stemness

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      Stem Cell Research & Therapy
      BioMed Central

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          Abstract

          Because of their ease of isolation and relative abundance, adipose-derived mesenchymal stem cells (ASCs) are a particularly attractive autologous cell source for various therapeutic purposes. ASCs retain a high proliferation capacity in vitro and have the ability to undergo extensive differentiation into multiple cell lineages. Moreover, ASCs secrete a wide range of growth factors that can stimulate tissue regeneration. Therefore, the clinical use of ASCs is feasible. However, the potential of ASCs differs depending on the donor’s medical condition, including diseases such as diabetes. Recent studies demonstrated that ASCs from diabetic donors exhibit reduced proliferative potential and a smaller proportion of stem cell marker-positive cells. Therefore, to ensure the success of regenerative medicine, tissue engineering methods must be improved by the incorporation of factors that increase the proliferation and differentiation of stem/progenitor cells when autologous cells are used. Platelet-rich plasma (PRP), which contains high levels of diverse growth factors that can stimulate stem cell proliferation and cell differentiation in the context of tissue regeneration, has recently been identified as a biological material that could be applied to tissue regeneration. Thus, co-transplantation of ASCs and PRP represents a promising novel approach for cell therapy in regenerative medicine. In this review, we describe the potential benefits of adding PRP to ASCs and preclinical and clinical studies of this approach in various medical fields. We also discuss the mechanisms of PRP action and future cell-based therapies using co-transplantation of ASCs and PRP.

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          Most cited references55

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          Macrophage Dysfunction Impairs Resolution of Inflammation in the Wounds of Diabetic Mice

          Background Chronic inflammation is a characteristic feature of diabetic cutaneous wounds. We sought to delineate novel mechanisms involved in the impairment of resolution of inflammation in diabetic cutaneous wounds. At the wound-site, efficient dead cell clearance (efferocytosis) is a pre-requisite for the timely resolution of inflammation and successful healing. Methodology/Principal Findings Macrophages isolated from wounds of diabetic mice showed significant impairment in efferocytosis. Impaired efferocytosis was associated with significantly higher burden of apoptotic cells in wound tissue as well as higher expression of pro-inflammatory and lower expression of anti-inflammatory cytokines. Observations related to apoptotic cell load at the wound site in mice were validated in the wound tissue of diabetic and non-diabetic patients. Forced Fas ligand driven elevation of apoptotic cell burden at the wound site augmented pro-inflammatory and attenuated anti-inflammatory cytokine response. Furthermore, successful efferocytosis switched wound macrophages from pro-inflammatory to an anti-inflammatory mode. Conclusions/Significance Taken together, this study presents first evidence demonstrating that diabetic wounds suffer from dysfunctional macrophage efferocytosis resulting in increased apoptotic cell burden at the wound site. This burden, in turn, prolongs the inflammatory phase and complicates wound healing.
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            Expansion of human adult stem cells from bone marrow stroma: conditions that maximize the yields of early progenitors and evaluate their quality.

            There is considerable interest in the biology and therapeutic potential of adult stem cells from bone marrow stroma, variously referred to as mesenchymal stem cells or marrow stromal cells (MSCs). Human MSCs can expand rapidly in culture, but the rate of expansion and the yields of multipotential progenitors are inversely related to the plating density and incubation time of each passage. We have defined conditions for optimizing the yields of cultures enriched for early progenitors. Also, we developed a simple method for assessing the quality of the cultures by phase-contrast microscopy and image analysis or by forward light scatter in a flow cytometer. The cells expanded most rapidly on day 4 after plating, with a minimum average doubling time of about 10 hours for cells initially plated at 10 or 50 cells/cm(2). After plating the cells at 1 to 1000 cells/cm(2), the cultures underwent a time-dependent transition from early progenitors, defined as thin, spindle-shaped cells (RS-1A), to wider, spindle-shaped cells (RS-1B), and to still wider, spindle-shaped cells (RS-1C). Assays for adipogenesis demonstrated that the adipogenic potential of cultures was directly related to their ability to generate single-cell-derived colonies and their enrichment for RS-1A cells. In contrast, cultures enriched for RS-1B cells showed the greatest potential to differentiate into cartilage in a serum-free system. The results indicate that, when preparing cultures of human MSCs, it is necessary to compromise between conditions that provide the highest overall yields and those that provide the highest content of early progenitor cells.
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              Mesenchymal stem cell injections improve symptoms of knee osteoarthritis.

              The purpose of this study was to evaluate the clinical and imaging results of patients who received intra-articular injections of autologous mesenchymal stem cells for the treatment of knee osteoarthritis. The study group comprised 18 patients (6 men and 12 women), among whom the mean age was 54.6 years (range, 41 to 69 years). In each patient the adipose synovium was harvested from the inner side of the infrapatellar fat pad by skin incision extension at the arthroscopic lateral portal site after the patient underwent arthroscopic debridement. After stem cells were isolated, a mean of 1.18 × 10(6) stem cells (range, 0.3 × 10(6) to 2.7 × 10(6) stem cells) were prepared with approximately 3.0 mL of platelet-rich plasma (with a mean of 1.28 × 10(6) platelets per microliter) and injected into the selected knees of patients. Clinical outcome was evaluated with the Western Ontario and McMaster Universities Osteoarthritis Index, the Lysholm score, and the visual analog scale (VAS) for grading knee pain. We also compared magnetic resonance imaging (MRI) data collected both preoperatively and at the final follow-up. Western Ontario and McMaster Universities Osteoarthritis Index scores decreased significantly (P < .001) from 49.9 points preoperatively to 30.3 points at the final follow-up (mean follow-up, 24.3 months; range, 24 to 26 months). Lysholm scores also improved significantly (P < .001) by the last follow-up visit, increasing from a mean preoperative value of 40.1 points to 73.4 points by the end of the study. Likewise, changes in VAS scores throughout the follow-up period were also significant (P = .005); the mean VAS score decreased from 4.8 preoperatively to 2.0 at the last follow-up visit. Radiography showed that, at the final follow-up point, the whole-organ MRI score had significantly improved from 60.0 points to 48.3 points (P < .001). Particularly notable was the change in cartilage whole-organ MRI score, which improved from 28.3 points to 21.7 points (P < .001). Further analysis showed that improvements in clinical and MRI results were positively related to the number of stem cells injected. The results of our study are encouraging and show that intra-articular injection of infrapatellar fat pad-derived mesenchymal stem cells is effective for reducing pain and improving knee function in patients being treated for knee osteoarthritis. Level IV, therapeutic case series. Copyright © 2013 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                hmizuno@juntendo.ac.jp
                Journal
                Stem Cell Res Ther
                Stem Cell Res Ther
                Stem Cell Research & Therapy
                BioMed Central (London )
                1757-6512
                5 November 2015
                5 November 2015
                2015
                : 6
                : 215
                Affiliations
                Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo, Tokyo 1138421 Japan
                Article
                217
                10.1186/s13287-015-0217-8
                4635588
                26541973
                4a1c5092-9df8-4d54-9b14-c905cc0cef53
                © Tobita et al. 2015

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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                Molecular medicine
                Molecular medicine

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