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      The biological and clinical basis for the use of adipose-derived stem cells in the field of wound healing

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          Abstract

          Worldwide, hard-to-heal lower limb wounds are estimated to affect 1.5–3% of the adult population with a treatment-related annual cost of $10 billion. Thus, chronic skin ulcers of the lower limb are a matter of economic and public concern. Over the years, multiple medical and surgical approaches have been proposed but they are still inadequate, and no effective therapy yet exists. Regenerative medicine and stem cell-based therapies hold great promise for wound healing. Recently, many plastic surgeons have studied the potential clinical application of adipose-derived stem cells (ASCs), which are a readily available adult stem cell population that can undergo multilineage differentiation and secrete growth factors that can enhance wound-healing processes by promoting angiogenesis, and hence increase local blood supply. ASCs have been widely studied in vitro and in vivo in animal models. However, there are few randomized clinical trials on humans, and these are still ongoing or recruiting patients. Moreover, there is no consensus on a common isolation protocol that is clinically feasible and which would ensure reproducible results. The authors aim to provide readers with an overview of the biological properties of ASCs as well as their clinical application, to help better understanding of present and future strategies for the treatment of hard-to-heal wounds by means of stem cell-based therapies.

          Highlights

          • Worldwide, hard-to-heal wounds are a matter of economic and public concern.

          • The emerging fields of regenerative medicine and stem cell-based therapies hold great promise for wound healing.

          • ASCs can potentially give the support necessary for recovery of hard-to-heal wounds.

          • ASCs can be easily harvested from adipose tissue by means of standard wet liposuction technique.

          • ASCs have been widely studied in vitro and in vivo to demonstrate their potential and safety.

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          Most cited references86

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          Vascular-specific growth factors and blood vessel formation.

          A recent explosion in newly discovered vascular growth factors has coincided with exploitation of powerful new genetic approaches for studying vascular development. An emerging rule is that all of these factors must be used in perfect harmony to form functional vessels. These new findings also demand re-evaluation of therapeutic efforts aimed at regulating blood vessel growth in ischaemia, cancer and other pathological settings.
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            Generation of human induced pluripotent stem cells from dermal fibroblasts.

            The generation of patient-specific pluripotent stem cells has the potential to accelerate the implementation of stem cells for clinical treatment of degenerative diseases. Technologies including somatic cell nuclear transfer and cell fusion might generate such cells but are hindered by issues that might prevent them from being used clinically. Here, we describe methods to use dermal fibroblasts easily obtained from an individual human to generate human induced pluripotent stem (iPS) cells by ectopic expression of the defined transcription factors KLF4, OCT4, SOX2, and C-MYC. The resultant cell lines are morphologically indistinguishable from human embryonic stem cells (HESC) generated from the inner cell mass of a human preimplantation embryo. Consistent with these observations, human iPS cells share a nearly identical gene-expression profile with two established HESC lines. Importantly, DNA fingerprinting indicates that the human iPS cells were derived from the donor material and are not a result of contamination. Karyotypic analyses demonstrate that reprogramming of human cells by defined factors does not induce, or require, chromosomal abnormalities. Finally, we provide evidence that human iPS cells can be induced to differentiate along lineages representative of the three embryonic germ layers indicating the pluripotency of these cells. Our findings are an important step toward manipulating somatic human cells to generate an unlimited supply of patient-specific pluripotent stem cells. In the future, the use of defined factors to change cell fate may be the key to routine nuclear reprogramming of human somatic cells.
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              Topical vascular endothelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow-derived cells.

              Diminished production of vascular endothelial growth factor (VEGF) and decreased angiogenesis are thought to contribute to impaired tissue repair in diabetic patients. We examined whether recombinant human VEGF(165) protein would reverse the impaired wound healing phenotype in genetically diabetic mice. Paired full-thickness skin wounds on the dorsum of db/db mice received 20 microg of VEGF every other day for five doses to one wound and vehicle (phosphate-buffered saline) to the other. We demonstrate significantly accelerated repair in VEGF-treated wounds with an average time to resurfacing of 12 days versus 25 days in untreated mice. VEGF-treated wounds were characterized by an early leaky, malformed vasculature followed by abundant granulation tissue deposition. The VEGF-treated wounds demonstrated increased epithelialization, increased matrix deposition, and enhanced cellular proliferation, as assessed by uptake of 5-bromodeoxyuridine. Analysis of gene expression by real-time reverse transcriptase-polymerase chain reaction demonstrates a significant up-regulation of platelet-derived growth factor-B and fibroblast growth factor-2 in VEGF-treated wounds, which corresponds with the increased granulation tissue in these wounds. These experiments also demonstrated an increase in the rate of repair of the contralateral phosphate-buffered saline-treated wound when compared to wounds in diabetic mice never exposed to VEGF (18 days versus 25 days), suggesting that topical VEGF had a systemic effect. We observed increased numbers of circulating VEGFR2(+)/CD11b(-) cells in the VEGF-treated mice by fluorescence-activated cell sorting analysis, which likely represent an endothelial precursor population. In diabetic mice with bone marrow replaced by that of tie2/lacZ mice we demonstrate that the local recruitment of bone marrow-derived endothelial lineage lacZ+ cells was augmented by topical VEGF. We conclude that topical VEGF is able to improve wound healing by locally up-regulating growth factors important for tissue repair and by systemically mobilizing bone marrow-derived cells, including a population that contributes to blood vessel formation, and recruiting these cells to the local wound environment where they are able to accelerate repair. Thus, VEGF therapy may be useful in the treatment of diabetic complications characterized by impaired neovascularization.
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                Author and article information

                Contributors
                Journal
                Ann Med Surg (Lond)
                Ann Med Surg (Lond)
                Annals of Medicine and Surgery
                Elsevier
                2049-0801
                23 June 2017
                August 2017
                23 June 2017
                : 20
                : 41-48
                Affiliations
                [a ]Department of Medicine and Surgery, Plastic Surgery Division, University of Parma, Via Gramsci, 14, 43126, Parma, Italy
                [b ]Cutaneous, Mininvasive, Regenerative and Plastic Surgery Unit, Parma University Hospital, Via Gramsci, 14, 43126, Parma, Italy
                Author notes
                []Corresponding author. Department of Medicine and Surgery, Plastic Surgery Division, University of Parma, Via Gramsci, 14, 43126, Parma, Italy; Cutaneous, Mininvasive, Regenerative and Plastic Surgery Unit, Parma University Hospital, Via Gramsci, 14, 43126, Parma, Italy.Department of Medicine and SurgeryPlastic Surgery DivisionUniversity of ParmaVia Gramsci, 14Parma43126Italy nicolo.bertozzi@ 123456yahoo.com
                Article
                S2049-0801(17)30238-8
                10.1016/j.amsu.2017.06.058
                5491486
                28702186
                f27b15c9-aef4-459b-ad22-86e0e59d37f3
                © 2017 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 12 February 2017
                : 21 June 2017
                : 21 June 2017
                Categories
                Review

                regenerative medicine,tissue engineering,adipose-derived stem cells,wound healing

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