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      Autophagy promotes MSC-mediated vascularization in cutaneous wound healing via regulation of VEGF secretion

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          Abstract

          Vascularization deficiency caused a lot of diseases, such as diabetes ulcer and myocardial infarction. Mesenchymal stem cells (MSCs), with the self-renewal and multipotent differentiation capacities, have been used for many diseases treatment through regulation microenvironment. Numerous studies reported that MSCs transplantation could largely improve cutaneous wound healing via paracrine secretion of growth factors. However, whether MSCs take part in the angiogenesis process directly remains elusive. Previous study proved that autophagy inhibited immunosuppressive function of MSCs and prevented the degradation of MSCs function in inflammatory and senescent microenvironment. Here, we proved that autophagy determines the therapeutic effect of MSCs in cutaneous wound healing through promoting endothelial cells angiogenesis and demonstrated that the paracrine of vascular endothelial growth factor (VEGF) in MSCs was required in wound site. We further revealed that autophagy enhanced the VEGF secretion from MSCs through ERK phosphorylation directly. Collectively, we put forward that autophagy mediated paracrine of VEGF plays a central role in MSCs cured cutaneous wound healing and may provide a new therapeutic method for angiogenesis-related diseases.

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          Coordinated time-dependent modulation of AMPK/Akt/mTOR signaling and autophagy controls osteogenic differentiation of human mesenchymal stem cells.

          Kristina Janjetovic, Vladimir Trajkovic, Diana Bugarski … (2012)
          We investigated the role of AMP-activated protein kinase (AMPK), Akt, mammalian target of rapamycin (mTOR), autophagy and their interplay in osteogenic differentiation of human dental pulp mesenchymal stem cells. The activation of various members of AMPK, Akt and mTOR signaling pathways and autophagy was analyzed by immunoblotting, while osteogenic differentiation was assessed by alkaline phosphatase staining and real-time RT-PCR/immunoblot quantification of osteocalcin, Runt-related transcription factor 2 and bone morphogenetic protein 2 mRNA and/or protein levels. Osteogenic differentiation of mesenchymal stem cells was associated with early (day 1) activation of AMPK and its target Raptor, coinciding with the inhibition of mTOR and its substrate p70S6 kinase. The early induction of autophagy was demonstrated by accumulation of autophagosome-bound LC3-II, upregulation of proautophagic beclin-1 and a decrease in the selective autophagic target p62. This was followed by the late activation of Akt/mTOR at days 3-7 of differentiation. The RNA interference-mediated silencing of AMPK, mTOR or autophagy-essential LC3β, as well as the pharmacological inhibitors of AMPK (compound C), Akt (10-DEBC hydrochloride), mTOR (rapamycin) and autophagy (bafilomycin A1, chloroquine and ammonium chloride), each suppressed mesenchymal stem cell differentiation to osteoblasts. AMPK knockdown prevented early mTOR inhibition and autophagy induction, as well as late activation of Akt/mTOR signaling, while Akt inhibition suppressed mTOR activation without affecting AMPK phosphorylation. Our data indicate that AMPK controls osteogenic differentiation of human mesenchymal stem cells through both early mTOR inhibition-mediated autophagy and late activation of Akt/mTOR signaling axis. Copyright © 2012 Elsevier Inc. All rights reserved.
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            VEGF receptor signal transduction.

            T Matsumoto, L Claesson (2001)
            The family of vascular endothelial growth factors (VEGFs) currently includes VEGF-A, -B, -C, -D, -E, and placenta growth factor (PlGF). Several of these factors, notably VEGF-A, exist as different isoforms, which appear to have unique biological functions. The VEGF family proteins bind in a distinct pattern to three structurally related receptor tyrosine kinases, denoted VEGF receptor-1, -2, and -3. Neuropilins, heparan-sulfated proteoglycans, cadherins, and integrin alphavbeta3 serve as coreceptors for certain but not all VEGF proteins. Moreover, the angiogenic response to VEGF varies between different organs and is dependent on the genetic background of the animal. Inactivation of the genes for VEGF-A and VEGF receptor-2 leads to embryonal death due to the lack of endothelial cells. Inactivation of the gene encoding VEGF receptor-1 leads to an increased number of endothelial cells, which obstruct the vessel lumen. Inactivation of VEGF receptor-3 leads to abnormally organized vessels and cardiac failure. Although VEGF receptor-3 normally is expressed only on lymphatic endothelial cells, it is up-regulated on vascular as well as nonvascular tumors and appears to be involved in the regulation of angiogenesis. A large body of data, such as those on gene inactivation, indicate that VEGF receptor-1 exerts a negative regulatory effect on VEGF receptor-2, at least during embryogenesis. Recent data imply a positive regulatory role for VEGF receptor-1 in pathological angiogenesis. The VEGF proteins are in general poor mitogens, but binding of VEGF-A to VEGF receptor-2 leads to survival, migration, and differentiation of endothelial cells and mediation of vascular permeability. This review outlines the current knowledge about the signal transduction properties of VEGF receptors, with focus on VEGF receptor-2.
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              Atg5 and Ambra1 differentially modulate neurogenesis in neural stem cells.

              Francesco Cecconi, Ana Arroba, Francisco Núñez de Cáceres González … (2012)
              Neuroepithelial cells undergoing differentiation efficiently remodel their cytoskeleton and shape in an energy-consuming process. The capacity of autophagy to recycle cellular components and provide energy could fulfill these requirements, thus supporting differentiation. However, little is known regarding the role of basal autophagy in neural differentiation. Here we report an increase in the expression of the autophagy genes Atg7, Becn1, Ambra1 and LC3 in vivo in the mouse embryonic olfactory bulb (OB) during the initial period of neuronal differentiation at E15.5, along with a parallel increase in neuronal markers. In addition, we observed an increase in LC3 lipidation and autophagic flux during neuronal differentiation in cultured OB-derived stem/progenitor cells. Pharmacological inhibition of autophagy with 3-MA or wortmannin markedly decreased neurogenesis. These observations were supported by similar findings in two autophagy-deficient genetic models. In Ambra1 loss-of-function homozygous mice (gt/gt) the expression of several neural markers was decreased in the OB at E13.5 in vivo. In vitro, Ambra1 haploinsufficient cells developed as small neurospheres with an impaired capacity for neuronal generation. The addition of methylpyruvate during stem/progenitor cell differentiation in culture largely reversed the inhibition of neurogenesis induced by either 3-MA or Ambra1 haploinsufficiency, suggesting that neural stem/progenitor cells activate autophagy to fulfill their high energy demands. Further supporting the role of autophagy for neuronal differentiation Atg5-null OB cells differentiating in culture displayed decreased TuJ1 levels and lower number of cells with neurites. These results reveal new roles for autophagy-related molecules Atg5 and Ambra1 during early neuronal differentiation of stem/progenitor cells.
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                Author and article information

                Contributors
                Q. T. Wang: yznmbk@fmmu.edu.cn
                Y. Jin: yanjinfmmu@139.com , yanjin@fmmu.edu.cn
                Journal
                Journal ID (nlm-ta): Cell Death Dis
                Journal ID (iso-abbrev): Cell Death Dis
                Title: Cell Death & Disease
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2041-4889
                Publication date (Electronic): 19 January 2018
                Publication date PMC-release: 19 January 2018
                Publication date Collection: February 2018
                Volume: 9
                Issue: 2
                Electronic Location Identifier: 58
                Affiliations
                [1 ]ISNI 0000 0004 1761 4404, GRID grid.233520.5, State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, , The Fourth Military Medical University, ; Xi’an, Shaanxi 710032 China
                [2 ]ISNI 0000 0004 1761 4404, GRID grid.233520.5, State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, , The Fourth Military Medical University, ; Xi’an, Shaanxi 710032 China
                [3 ]Xi’an Institute of Tissue Engineering and Regenerative Medicine, Xi’an, Shaanxi 710032 China
                [4 ]ISNI 0000 0004 1761 8894, GRID grid.414252.4, Institute of Stomatology, , Chinese PLA General Hospital, ; Beijing, 100853 China
                [5 ]Department of Stomatology, PLA Xizang Military Region General Hospital, Lhasa, Tibet 850007 China
                Author information
                http://orcid.org/0000-0002-8429-416X
                Article
                Publisher ID: 82
                DOI: 10.1038/s41419-017-0082-8
                PMC ID: 5833357
                PubMed ID: 29352190
                SO-VID: 0f24ff93-ebdc-4f9d-936a-ddc51a162186
                Copyright © © The Author(s) 2018
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 1 August 2017
                Date revision received : 19 September 2017
                Date accepted : 29 September 2017
                Categories
                Subject: Article
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                issue-copyright-statement © The Author(s) 2018

                ScienceOpen disciplines: Cell biology
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                ScienceOpen disciplines: Cell biology

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