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      Stem cell therapy for diabetic foot ulcers: a review of preclinical and clinical research

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          Abstract

          Background

          Diabetic foot ulcer (DFU) is a severe complication of diabetes, preceding most diabetes-related amputations. DFUs require over US$9 billion for yearly treatment and are now a global public health issue. DFU occurs in the setting of ischemia, infection, neuropathy, and metabolic disorders that result in poor wound healing and poor treatment options. Recently, stem cell therapy has emerged as a new interventional strategy to treat DFU and appears to be safe and effective in both preclinical and clinical trials. However, variability in the stem cell type and origin, route and protocol for administration, and concomitant use of angioplasty confound easy interpretation and generalization of the results.

          Methods

          The PubMed, Google Scholar, and EMBASE databases were searched and 89 preclinical and clinical studies were selected for analysis.

          Results

          There was divergence between preclinical and clinical studies regarding stem cell type, origin, and delivery techniques. There was heterogeneous preclinical and clinical study design and few randomized clinical trials. Granulocyte-colony stimulating factor was employed in some studies but with differing protocols. Concomitant performance of angioplasty with stem cell therapy showed increased efficiency compared to either therapy alone.

          Conclusions

          Stem cell therapy is an effective treatment for diabetic foot ulcers and is currently used as an alternative to amputation for some patients without other options for revascularization. Concordance between preclinical and clinical studies may help design future randomized clinical trials.

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          Most cited references91

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          Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 1: normal and chronic wounds: biology, causes, and approaches to care.

          This is the first installment of 2 articles that discuss the biology and pathophysiology of wound healing, review the role that growth factors play in this process, and describe current ways of growth factor delivery into the wound bed. Part 1 discusses the latest advances in clinicians' understanding of the control points that regulate wound healing. Importantly, biological similarities and differences between acute and chronic wounds are considered, including the signaling pathways that initiate cellular and tissue responses after injury, which may be impeded during chronic wound healing.
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            Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type.

            Mesenchymal stem cells (MSCs) can differentiate not only into mesenchymal lineage cells but also into various other cell lineages. As MSCs can easily be isolated from bone marrow, they can be used in various tissue engineering strategies. In this study, we assessed whether MSCs can differentiate into multiple skin cell types including keratinocytes and contribute to wound repair. First, we found keratin 14-positive cells, presumed to be keratinocytes that transdifferentiated from MSCs in vitro. Next, we assessed whether MSCs can transdifferentiate into multiple skin cell types in vivo. At sites of mouse wounds that had been i.v. injected with MSCs derived from GFP transgenic mice, we detected GFP-positive cells associated with specific markers for keratinocytes, endothelial cells, and pericytes. Because MSCs are predominantly located in bone marrow, we investigated the main MSC recruitment mechanism. MSCs expressed several chemokine receptors; especially CCR7, which is a receptor of SLC/CCL21, that enhanced MSC migration. Finally, MSC-injected mice underwent rapid wound repaired. Furthermore, intradermal injection of SLC/CCL21 increased the migration of MSCs, which resulted in an even greater acceleration of wound repair. Taken together, we have demonstrated that MSCs contribute to wound repair via processes involving MSCs differentiation various cell components of the skin.
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              Pathogenesis and treatment of impaired wound healing in diabetes mellitus: new insights.

              Diabetic foot ulcers (DFUs) are one of the most common and serious complications of diabetes mellitus, as wound healing is impaired in the diabetic foot. Wound healing is a dynamic and complex biological process that can be divided into four partly overlapping phases: hemostasis, inflammation, proliferative and remodeling. These phases involve a large number of cell types, extracellular components, growth factors and cytokines. Diabetes mellitus causes impaired wound healing by affecting one or more biological mechanisms of these processes. Most often, it is triggered by hyperglycemia, chronic inflammation, micro- and macro-circulatory dysfunction, hypoxia, autonomic and sensory neuropathy, and impaired neuropeptide signaling. Research focused on thoroughly understanding these mechanisms would allow for specifically targeted treatment of diabetic foot ulcers. The main principles for DFU treatment are wound debridement, pressure off-loading, revascularization and infection management. New treatment options such as bioengineered skin substitutes, extracellular matrix proteins, growth factors, and negative pressure wound therapy, have emerged as adjunctive therapies for ulcers. Future treatment strategies include stem cell-based therapies, delivery of gene encoding growth factors, application of angiotensin receptors analogs and neuropeptides like substance P, as well as inhibition of inflammatory cytokines. This review provides an outlook of the pathophysiology in diabetic wound healing and summarizes the established and adjunctive treatment strategies, as well as the future therapeutic options for the treatment of DFUs.
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                Author and article information

                Contributors
                laraminchillo@gmail.com
                ocean.setia@yale.edu
                afsha.aurshina@yale.edu
                shirley.liu@yale.edu
                haidi.hu@yale.edu
                toshihiko.isaji@yale.edu
                haiyang.liu@yale.edu
                tun.wang@yale.edu
                shun.ono@yale.edu
                xiangjiang.guo@yale.edu
                bogdan.yatsula@yale.edu
                guojianming@aliyun.com
                15901598209@163.com
                tulio.navarro@gmail.com
                alan.dardik@yale.edu
                Journal
                Stem Cell Res Ther
                Stem Cell Res Ther
                Stem Cell Research & Therapy
                BioMed Central (London )
                1757-6512
                11 July 2018
                11 July 2018
                2018
                : 9
                : 188
                Affiliations
                [1 ]ISNI 0000000419368710, GRID grid.47100.32, Vascular Biology and Therapeutics Program and Department of Surgery , , Yale School of Medicine, Yale University, ; New Haven, CT USA
                [2 ]ISNI 0000 0001 2181 4888, GRID grid.8430.f, Faculty of Medicine, , Federal University of Minas Gerais, ; Belo Horizonte, Brazil
                [3 ]ISNI 0000 0004 0369 153X, GRID grid.24696.3f, Department of Vascular Surgery, Xuanwu Hospital, , Capital Medical University, ; Beijing, China
                [4 ]ISNI 0000 0004 0419 3073, GRID grid.281208.1, VA Connecticut Healthcare System, ; West Haven, CT USA
                Article
                938
                10.1186/s13287-018-0938-6
                6042254
                29996912
                ffe5c385-943e-45ac-a623-8c4048716132
                © The Author(s). 2018

                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.

                History
                : 11 May 2018
                : 15 June 2018
                : 20 June 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000009, Foundation for the National Institutes of Health;
                Award ID: R01-HL128406
                Award Recipient :
                Funded by: Sarnoff Cardiovascular Foundation Fellowship
                Funded by: VA Connecticut Healthcare System
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Molecular medicine
                stem cell therapy,cell therapy,diabetic foot ulcer,diabetic wound,critical limb ischemia,wound healing,amputation

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