Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice

Stem Cell Research & Therapy

Victor Aliaga-Tobar¹  Vinicius Maracaja-Coutinho¹  Fernando Ezquer²  Diego Díaz²  David Contador²  Constanza Cárcamo²  Cristian De Gregorio²  Marcelo Ezquer²  Daniela Santapau²  Lorena Lobos-Gonzalez²  Mario Campero³  Daniel Carpio⁴  Cristian Acosta⁵  Caterina Gabriele⁶  Marco Gaspari⁶ 

[1] Advanced Center for Chronic Diseases-ACCDiS, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile;Center for Regenerative Medicine, School of Medicine Clínica Alemana-Universidad del Desarrollo;Department of Neurology & Neurosurgery, Hospital José Joaquín Aguirre, Universidad de Chile;Institute of Anatomy, Histology and Pathology, Universidad Austral de Chile;Institute of Histology and Embryology of Mendoza (IHEM-CONICET), School of Medicine, Universidad Nacional de Cuyo;Research Center for Advanced Biochemistry and Molecular Biology, Department of Experimental and Clinical Medicine, University of Catanzaro;

关键词: Diabetic polyneuropathy;    Diabetic foot ulcer;    Mesenchymal stem cells;    Conditioned medium;    Deferoxamine;   

DOI  :  10.1186/s13287-020-01680-0

来源: DOAJ

【 摘 要 】

Abstract Background Diabetic polyneuropathy (DPN) is the most common and early developing complication of diabetes mellitus, and the key contributor for foot ulcers development, with no specific therapies available. Different studies have shown that mesenchymal stem cell (MSC) administration is able to ameliorate DPN; however, limited cell survival and safety reasons hinder its transfer from bench to bedside. MSCs secrete a broad range of antioxidant, neuroprotective, angiogenic, and immunomodulatory factors (known as conditioned medium), which are all decreased in the peripheral nerves of diabetic patients. Furthermore, the abundance of these factors can be boosted in vitro by incubating MSCs with a preconditioning stimulus, enhancing their therapeutic efficacy. We hypothesize that systemic administration of conditioned medium derived from preconditioned MSCs could reverse DPN and prevent foot ulcer formation in a mouse model of type II diabetes mellitus. Methods Diabetic BKS db/db mice were treated with systemic administration of conditioned medium derived from preconditioned human MSCs; conditioned medium derived from non-preconditioned MSCs or vehicle after behavioral signs of DPN was already present. Conditioned medium or vehicle administration was repeated every 2 weeks for a total of four administrations, and several functional and structural parameters characteristic of DPN were evaluated. Finally, a wound was made in the dorsal surface of both feet, and the kinetics of wound closure, re-epithelialization, angiogenesis, and cell proliferation were evaluated. Results Our molecular, electrophysiological, and histological analysis demonstrated that the administration of conditioned medium derived from non-preconditioned MSCs or from preconditioned MSCs to diabetic BKS db/db mice strongly reverts the established DPN, improving thermal and mechanical sensitivity, restoring intraepidermal nerve fiber density, reducing neuron and Schwann cell apoptosis, improving angiogenesis, and reducing chronic inflammation of peripheral nerves. Furthermore, DPN reversion induced by conditioned medium administration enhances the wound healing process by accelerating wound closure, improving the re-epithelialization of the injured skin and increasing blood vessels in the wound bed in a skin injury model that mimics a foot ulcer. Conclusions Studies conducted indicate that MSC-conditioned medium administration could be a novel cell-free therapeutic approach to reverse the initial stages of DPN, avoiding the risk of lower limb amputation triggered by foot ulcer formation and accelerating the wound healing process in case it occurs.

【 授权许可】

Unknown