Cargando…

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

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 amel...

Descripción completa

Detalles Bibliográficos
Autores principales: De Gregorio, Cristian, Contador, David, Díaz, Diego, Cárcamo, Constanza, Santapau, Daniela, Lobos-Gonzalez, Lorena, Acosta, Cristian, Campero, Mario, Carpio, Daniel, Gabriele, Caterina, Gaspari, Marco, Aliaga-Tobar, Victor, Maracaja-Coutinho, Vinicius, Ezquer, Marcelo, Ezquer, Fernando
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195803/
https://www.ncbi.nlm.nih.gov/pubmed/32357914
http://dx.doi.org/10.1186/s13287-020-01680-0
_version_ 1783528613764661248
author De Gregorio, Cristian
Contador, David
Díaz, Diego
Cárcamo, Constanza
Santapau, Daniela
Lobos-Gonzalez, Lorena
Acosta, Cristian
Campero, Mario
Carpio, Daniel
Gabriele, Caterina
Gaspari, Marco
Aliaga-Tobar, Victor
Maracaja-Coutinho, Vinicius
Ezquer, Marcelo
Ezquer, Fernando
author_facet De Gregorio, Cristian
Contador, David
Díaz, Diego
Cárcamo, Constanza
Santapau, Daniela
Lobos-Gonzalez, Lorena
Acosta, Cristian
Campero, Mario
Carpio, Daniel
Gabriele, Caterina
Gaspari, Marco
Aliaga-Tobar, Victor
Maracaja-Coutinho, Vinicius
Ezquer, Marcelo
Ezquer, Fernando
author_sort De Gregorio, Cristian
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7195803
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-71958032020-05-06 Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice De Gregorio, Cristian Contador, David Díaz, Diego Cárcamo, Constanza Santapau, Daniela Lobos-Gonzalez, Lorena Acosta, Cristian Campero, Mario Carpio, Daniel Gabriele, Caterina Gaspari, Marco Aliaga-Tobar, Victor Maracaja-Coutinho, Vinicius Ezquer, Marcelo Ezquer, Fernando Stem Cell Res Ther Research 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. BioMed Central 2020-05-01 /pmc/articles/PMC7195803/ /pubmed/32357914 http://dx.doi.org/10.1186/s13287-020-01680-0 Text en © The Author(s) 2020 Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.
spellingShingle Research
De Gregorio, Cristian
Contador, David
Díaz, Diego
Cárcamo, Constanza
Santapau, Daniela
Lobos-Gonzalez, Lorena
Acosta, Cristian
Campero, Mario
Carpio, Daniel
Gabriele, Caterina
Gaspari, Marco
Aliaga-Tobar, Victor
Maracaja-Coutinho, Vinicius
Ezquer, Marcelo
Ezquer, Fernando
Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice
title Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice
title_full Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice
title_fullStr Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice
title_full_unstemmed Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice
title_short Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice
title_sort human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic bks db/db mice
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195803/
https://www.ncbi.nlm.nih.gov/pubmed/32357914
http://dx.doi.org/10.1186/s13287-020-01680-0
work_keys_str_mv AT degregoriocristian humanadiposederivedmesenchymalstemcellconditionedmediumamelioratespolyneuropathyandfootulcerationindiabeticbksdbdbmice
AT contadordavid humanadiposederivedmesenchymalstemcellconditionedmediumamelioratespolyneuropathyandfootulcerationindiabeticbksdbdbmice
AT diazdiego humanadiposederivedmesenchymalstemcellconditionedmediumamelioratespolyneuropathyandfootulcerationindiabeticbksdbdbmice
AT carcamoconstanza humanadiposederivedmesenchymalstemcellconditionedmediumamelioratespolyneuropathyandfootulcerationindiabeticbksdbdbmice
AT santapaudaniela humanadiposederivedmesenchymalstemcellconditionedmediumamelioratespolyneuropathyandfootulcerationindiabeticbksdbdbmice
AT lobosgonzalezlorena humanadiposederivedmesenchymalstemcellconditionedmediumamelioratespolyneuropathyandfootulcerationindiabeticbksdbdbmice
AT acostacristian humanadiposederivedmesenchymalstemcellconditionedmediumamelioratespolyneuropathyandfootulcerationindiabeticbksdbdbmice
AT camperomario humanadiposederivedmesenchymalstemcellconditionedmediumamelioratespolyneuropathyandfootulcerationindiabeticbksdbdbmice
AT carpiodaniel humanadiposederivedmesenchymalstemcellconditionedmediumamelioratespolyneuropathyandfootulcerationindiabeticbksdbdbmice
AT gabrielecaterina humanadiposederivedmesenchymalstemcellconditionedmediumamelioratespolyneuropathyandfootulcerationindiabeticbksdbdbmice
AT gasparimarco humanadiposederivedmesenchymalstemcellconditionedmediumamelioratespolyneuropathyandfootulcerationindiabeticbksdbdbmice
AT aliagatobarvictor humanadiposederivedmesenchymalstemcellconditionedmediumamelioratespolyneuropathyandfootulcerationindiabeticbksdbdbmice
AT maracajacoutinhovinicius humanadiposederivedmesenchymalstemcellconditionedmediumamelioratespolyneuropathyandfootulcerationindiabeticbksdbdbmice
AT ezquermarcelo humanadiposederivedmesenchymalstemcellconditionedmediumamelioratespolyneuropathyandfootulcerationindiabeticbksdbdbmice
AT ezquerfernando humanadiposederivedmesenchymalstemcellconditionedmediumamelioratespolyneuropathyandfootulcerationindiabeticbksdbdbmice