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      Autophagy of umbilical cord mesenchymal stem cells induced by rapamycin conduces to pro-angiogenic function of the conditioned medium

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          Abstract

          Angiogenesis is critical for wound healing and tissue repair. Umbilical cord mesenchymal stem cells (UCMSCs)-conditioned medium has certain actions to promote angiogenesis, and is expected for wound healing and tissue repair. However, recent studies showed that the pro-angiogenic efficacy of unprocessed MSCs-conditioned medium is low, and insufficient for tissue repair. Autophagy is a process for protein recycling and a contributor for cell exocrine, which may enhance pro-angiogenic efficacy of the conditioned medium by stimulating cytokine release from UCMSCs. Therefore, in this study we attempted to obtain enhanced autophagy in UCMSCs using different concentrations of rapamycin and compared pro-angiogenic functions of the conditioned media. The in vitro data showed that although 100 nM-10 μM rapamycin all could induce autophagy in UCMSCs, 100 nM was the best dose to optimize the angiogenic effect of the conditioned medium. The in vivo data also showed that pro-angiogenic effect of the optimized conditioned medium was more obvious than that of the control conditioned medium (0 nM group) in the injected matrigel plaques. Further, the expressions of VEGF, FGF-2, MMP-9, PDGF-α and PDGF-β were markedly increased in UCMSCs treated with 100 nM rapamycin. In conclusion, appropriately enhancing autophagy of UCMSC can improve pro-angiogenic efficacy of the conditioned medium, which may optimize therapeutic applications of UCMSCs-conditioned medium in wound healing and tissue repair.

          Highlights

          • •

            The conditional medium derived from umbilical cord mesenchymal stem cells (UCMSCs) has been used in regeneration medicine including enhancing angiogenesis, but its effect is unsatisfactory.

          • •

            Autophagy has been reported to enhance exocrine functions of stem cells.

          • •

            We found that inducing autophagy of UCMSCs could enhance a pro-angiogenic efficacy of the conditioned medium.

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          Most cited references31

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          Autophagy maintains the metabolism and function of young and old (hematopoietic) stem cells

          Theodore Ho, Matthew Warr, Emmalee Adelman … (2017)
          With age, hematopoietic stem cells (HSCs) lose their ability to regenerate the blood system, and promote disease development. Autophagy is associated with health and longevity, and is critical for protecting HSCs from metabolic stress. Here, we show that loss of autophagy in HSCs causes accumulation of mitochondria and an activated metabolic state, which drives accelerated myeloid differentiation mainly through epigenetic deregulations, and impairs HSC self-renewal activity and regenerative potential. Strikingly, the majority of HSCs in aged mice share these altered metabolic and functional features. However, ~ 1/3 of aged HSCs exhibit high autophagy levels and maintain a low metabolic state with robust long-term regeneration potential similar to healthy young HSCs. Our results demonstrate that autophagy actively suppresses HSC metabolism by clearing active, healthy mitochondria to maintain quiescence and stemness, and becomes increasingly necessary with age to preserve the regenerative capacity of old HSCs.
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            Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine

            Matthew B Murphy, Kathryn Moncivais, Arnold I. Caplan (2013)
            Mesenchymal stem cells (MSCs) are partially defined by their ability to differentiate into tissues including bone, cartilage and adipose in vitro, but it is their trophic, paracrine and immunomodulatory functions that may have the greatest therapeutic impact in vivo. Unlike pharmaceutical treatments that deliver a single agent at a specific dose, MSCs are site regulated and secrete bioactive factors and signals at variable concentrations in response to local microenvironmental cues. Significant progress has been made in understanding the biochemical and metabolic mechanisms and feedback associated with MSC response. The anti-inflammatory and immunomodulatory capacity of MSC may be paramount in the restoration of localized or systemic conditions for normal healing and tissue regeneration. Allogeneic MSC treatments, categorized as a drug by regulatory agencies, have been widely pursued, but new studies demonstrate the efficacy of autologous MSC therapies, even for individuals affected by a disease state. Safety and regulatory concerns surrounding allogeneic cell preparations make autologous and minimally manipulated cell therapies an attractive option for many regenerative, anti-inflammatory and autoimmune applications.
            Article 0 comments Cited 183 times – based on 0 reviews     Review now
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              Human umbilical cord mesenchymal stem cells: a new era for stem cell therapy.

              Dah-Ching Ding, Yu-Hsun Chang, Woei-Cherng Shyu … (2015)
              The human umbilical cord is a promising source of mesenchymal stem cells (HUCMSCs). Unlike bone marrow stem cells, HUCMSCs have a painless collection procedure and faster self-renewal properties. Different derivation protocols may provide different amounts and populations of stem cells. Stem cell populations have also been reported in other compartments of the umbilical cord, such as the cord lining, perivascular tissue, and Wharton's jelly. HUCMSCs are noncontroversial sources compared to embryonic stem cells. They can differentiate into the three germ layers that promote tissue repair and modulate immune responses and anticancer properties. Thus, they are attractive autologous or allogenic agents for the treatment of malignant and nonmalignant solid and soft cancers. HUCMCs also can be the feeder layer for embryonic stem cells or other pluripotent stem cells. Regarding their therapeutic value, storage banking system and protocols should be established immediately. This review critically evaluates their therapeutic value, challenges, and future directions for their clinical applications.
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                Author and article information

                Contributors
                Wenjie Ren
                Xianwei Wang
                Journal
                Journal ID (nlm-ta): Biochem Biophys Rep
                Journal ID (iso-abbrev): Biochem Biophys Rep
                Title: Biochemistry and Biophysics Reports
                Publisher: Elsevier
                ISSN (Electronic): 2405-5808
                Publication date PMC-release: 18 November 2023
                Publication date Collection: December 2023
                Publication date (Electronic): 18 November 2023
                Volume: 36
                Electronic Location Identifier: 101583
                Affiliations
                [a ]Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
                [b ]Clinical Medical Center of Tissue Engineering and Regeneration, Xinxiang Medical University, Xinxiang, China
                Author notes
                [∗ ]Corresponding author. Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, China. wangxianwei1116@ 123456126.com
                [∗∗ ]Corresponding author. Clinical Medical Center of Tissue Engineering and Regeneration, Xinxiang Medical University, China. wjren1966@ 123456163.com
                Article
                Publisher Item ID: S2405-5808(23)00164-4 Publisher ID: 101583
                DOI: 10.1016/j.bbrep.2023.101583
                PMC ID: 10694647
                PubMed ID: 38053620
                SO-VID: 3dadfb1f-e022-463f-b2f2-0abef689b7e7
                Copyright © © 2023 The Authors
                License:

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

                History
                Date received : 10 August 2023
                Date revision received : 26 October 2023
                Date accepted : 13 November 2023
                Categories
                Subject: Short Communication

                Keywords: autophagy,umbilical cord mesenchymal stem cells,conditioned medium,angiogenesis
                Data availability:
                Keywords: autophagy, umbilical cord mesenchymal stem cells, conditioned medium, angiogenesis

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