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      Netrin-1 improves adipose-derived stem cell proliferation, migration, and treatment effect in type 2 diabetic mice with sciatic denervation

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          Abstract

          Background

          Diabetic peripheral neurovascular diseases (DPNVs) are complex, lacking effective treatment. Autologous/allogeneic transplantation of adipose-derived stem cells (ADSCs) is a promising strategy for DPNVs. Nonetheless, the transplanted ADSCs demonstrate unsatisfying viability, migration, adhesion, and differentiation in vivo, which reduce the treatment efficiency. Netrin-1 secreted as an axon guidance molecule and served as an angiogenic factor, demonstrating its ability in enhancing cell proliferation, migration, adhesion, and neovascularization.

          Methods

          ADSCs acquired from adipose tissue were modified by Netrin-1 gene ( NTN-1) using the adenovirus method (N-ADSCs) and proliferation, migration, adhesion, and apoptosis examined under high-glucose condition. The sciatic denervated mice (db/db) with type 2 diabetes mellitus (T2DM) were transplanted with N-ADSCs and treatment efficiency assessed based on the laser Doppler perfusion index, immunofluorescence, and histopathological assay. Also, the molecular mechanisms underlying Netrin-1-mediated proliferation, migration, adhesion, differentiation, proangiogenic capacity, and apoptosis of ADSCs were explored.

          Results

          N-ADSCs improved the proliferation, migration, and adhesion and inhibited the apoptosis of ADSCs in vitro in the condition of high glucose. The N-ADSCs group demonstrated an elevated laser Doppler perfusion index in the ADSCs and control groups. N-ADSCs analyzed by immunofluorescence and histopathological staining demonstrated the distribution of the cells in the injected limb muscles, indicating chronic ischemia; capillaries and endothelium were formed by differentiation of N-ADSCs. The N-ADSCs group showed a significantly high density of the microvessels than the ADSCs group. The upregulation of AKT/PI3K/eNOS/P-38/NF-κB signaling pathways and secretion of multiple growth factors might explain the positive effects of Netrin-1 on ADSCs.

          Conclusion

          The overexpression of Netrin-1 in ADSCs improves proliferation, migration, and treatment effect in type 2 diabetic mice with sciatic denervation, which directs the clinical treatment of patients with DPNVs.

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          Most cited references32

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          The management of diabetic foot: A clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine.

          Diabetes mellitus continues to grow in global prevalence and to consume an increasing amount of health care resources. One of the key areas of morbidity associated with diabetes is the diabetic foot. To improve the care of patients with diabetic foot and to provide an evidence-based multidisciplinary management approach, the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine developed this clinical practice guideline.
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            Neuronal and vascular interactions.

            The brain, which represents 2% of body mass but consumes 20% of body energy at rest, has a limited capacity to store energy and is therefore highly dependent on oxygen and glucose supply from the blood stream. Normal functioning of neural circuits thus relies on adequate matching between metabolic needs and blood supply. Moreover, not only does the brain need to be densely vascularized, it also requires a tightly controlled environment free of toxins and pathogens to provide the proper chemical composition for synaptic transmission and neuronal function. In this review, we focus on three major factors that ensure optimal brain perfusion and function: the patterning of vascular networks to efficiently deliver blood and nutrients, the function of the blood-brain barrier to maintain brain homeostasis, and the regulation of cerebral blood flow to adequately couple energy supply to neural function.
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              Neural migration. Structures of netrin-1 bound to two receptors provide insight into its axon guidance mechanism.

              Netrins are secreted proteins that regulate axon guidance and neuronal migration. Deleted in colorectal cancer (DCC) is a well-established netrin-1 receptor mediating attractive responses. We provide evidence that its close relative neogenin is also a functional netrin-1 receptor that acts with DCC to mediate guidance in vivo. We determined the structures of a functional netrin-1 region, alone and in complexes with neogenin or DCC. Netrin-1 has a rigid elongated structure containing two receptor-binding sites at opposite ends through which it brings together receptor molecules. The ligand/receptor complexes reveal two distinct architectures: a 2:2 heterotetramer and a continuous ligand/receptor assembly. The differences result from different lengths of the linker connecting receptor domains fibronectin type III domain 4 (FN4) and FN5, which differs among DCC and neogenin splice variants, providing a basis for diverse signaling outcomes. Copyright © 2014, American Association for the Advancement of Science.
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                Author and article information

                Contributors
                3117119013@sjtu.edu.cn
                qinjb@aliyun.com
                wangxin2012@sjtu.edu.cn
                guo_2015_xin@163.com
                ljcmoving@163.com
                18337163728@163.com
                wxy_cmu@aliyun.com
                +86-13651839016 , luxinwu@shsmu.edu.cn
                +86-13651839016 , liweimin9hospital@163.com
                +86-13651839016 , benny_liuxb@163.com
                Journal
                Stem Cell Res Ther
                Stem Cell Res Ther
                Stem Cell Research & Therapy
                BioMed Central (London )
                1757-6512
                25 October 2018
                25 October 2018
                2018
                : 9
                : 285
                Affiliations
                ISNI 0000 0004 0368 8293, GRID grid.16821.3c, Department of Vascular Surgery, Shanghai Ninth People’s Hospital, , Shanghai Jiao Tong University School of Medicine, ; Shanghai, 200011 China
                Author information
                http://orcid.org/0000-0001-6503-5210
                Article
                1020
                10.1186/s13287-018-1020-0
                6202825
                30359296
                6a6a8f76-5ea5-410c-8b40-30ebcd4beba6
                © 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
                : 22 June 2018
                : 16 September 2018
                : 27 September 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81601621
                Award ID: 81570432
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Molecular medicine
                netrin-1,adipose-derived stem cells,denervation,t2dm,cell transplantation,angiogenesis

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