DE GREGORIO CONCHA, CRISTIAN ALEJANDRO
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DE GREGORIO CONCHA, CRISTIAN ALEJANDRO
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crdegregorio@udd.cl
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57193329776

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2020 2020 2019 2019 2018 2018 0.0 0.0 0.2 0.2 0.4 0.4 0.6 0.6 0.8 0.8 1.0 1.0

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Administration of secretome derived from human mesenchymal stem cells prevents diabetic neuropathy progression in an animal model of type 2 diabetes

2019 , EZQUER, EDUARDO FERNANDO , DE GREGORIO CONCHA, CRISTIAN ALEJANDRO , CONTADOR MARTINEZ, DAVID ERNESTO , Campero, M. , Santapau, D , EZQUER, EDUARDO MARCELO

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

2020 , DE GREGORIO CONCHA, CRISTIAN ALEJANDRO , CONTADOR MARTINEZ, DAVID ERNESTO , Cristian Acosta , Diego Díaz , Constanza Cárcamo , Daniela Santapau , Lorena Lobos-Gonzalez , Mario Campero , Daniel Carpio , Caterina Gabriele , Marco Gaspari , Victor Aliaga-Tobar , Vinicius Maracaja-Coutinho , EZQUER, EDUARDO MARCELO , EZQUER, EDUARDO FERNANDO

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.

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Characterization of diabetic neuropathy progression in a mouse model of type 2 diabetes mellitus

2018 , DE GREGORIO CONCHA, CRISTIAN ALEJANDRO , CONTADOR MARTINEZ, DAVID ERNESTO , Mario Campero , EZQUER, EDUARDO MARCELO , EZQUER, EDUARDO FERNANDO

Diabetes mellitus (DM) is one of most frequent chronic diseases with an increasing incidence in most countries. Diabetic neuropathy (DN) is one of the earliest and main complications of diabetic patients, which is characterized by progressive, distal-to-proximal degeneration of peripheral nerves. The cellular and molecular mechanisms that trigger DN are highly complex, heterogeneous and not completely known. Animal models have constituted a valuable tool for understanding diabetes pathophysiology; however, the temporal course of DN progression in animal models of type 2 diabetes (T2DM) is not completely understood. In this work, we characterized the onset and progression of DN in BKS db/db mice, including the main functional and histological features observed in the human disease. We demonstrated that diabetic animals display a progressive sensory loss and electrophysiological impairments in early-to-mid phases of disease. Furthermore, we detected an early decrease in intraepidermal nerve fibers (IENF) density in 18-week-old diabetic mice, which is highly associated with sensory loss and constitutes a reliable marker of DN. Other common histological parameters of DN, like Schwann cells apoptosis and infiltration of CD3+ cells in the sciatic nerve, were altered in mid-to-late phases of disease. Our results support the general consensus that DN evolves from initial functional to late structural changes. This work aimed to characterize the progression of DN in a reliable animal model sharing the main human disease features, which is necessary to assess new therapies for this complex disease. Finally, we also aimed to identify an effective temporal window where these potential treatments could be successfully applied.

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