Secretome from Human Mesenchymal Stem Cells-Derived Endothelial Cells Promotes Wound Healing in a Type-2 Diabetes Mouse Model.

Valeska Ormazabal,Yanara Pavez,Felipe A Zúñiga,Estefanía Nova-Lampeti,Daniela Rojas,Carlos Escudero,Guillermo Cabrera-Vives,Katherine Oporto,Mabel Vidal,Alexa Moreno,Milly Yáñez,Camila Reyes,Claudio Aguayo,Paola Lagos

doi:10.3390/ijms23020941

Abstract

Tissue regeneration is often impaired in patients with metabolic disorders such as diabetes mellitus and obesity, exhibiting reduced wound repair and limited regeneration capacity. We and others have demonstrated that wound healing under normal metabolic conditions is potentiated by the secretome of human endothelial cell-differentiated mesenchymal stem cells (hMSC-EC). However, it is unknown whether this effect is sustained under hyperglycemic conditions. In this study, the wound healing effect of secretomes from undifferentiated human mesenchymal stem cells (hMSC) and hMSC-EC in a type-2 diabetes mouse model was analyzed. hMSC were isolated from human Wharton’s jelly and differentiated into hMSC-EC. hMSC and hMSC-EC secretomes were analyzed and their wound healing capacity in C57Bl/6J mice fed with control (CD) or high fat diet (HFD) was evaluated. Our results showed that hMSC-EC secretome enhanced endothelial cell proliferation and wound healing in vivo when compared with hMSC secretome. Five soluble proteins (angiopoietin-1, angiopoietin-2, Factor de crecimiento fibroblástico, Matrix metallopeptidase 9, and Vascular Endothelial Growth Factor) were enriched in hMSC-EC secretome in comparison to hMSC secretome. Thus, the five recombinant proteins were mixed, and their pro-healing property was evaluated in vitro and in vivo. Functional analysis demonstrated that a cocktail of these proteins enhanced the wound healing process similar to hMSC-EC secretome in HFD mice. Overall, our results show that hMSC-EC secretome or a combination of specific proteins enriched in the hMSC-EC secretome enhanced wound healing process under hyperglycemic conditions.

Highlights

In healthy individuals, wound healing involves multiple processes, including extracellular matrix remodeling, synthesis of pro-inflammatory mediators, and new vessel formation [1]
Our results demonstrate that human endothelial cell-differentiated mesenchymal stem cells (hMSC-EC) secretome or a combination of specific proteins enriched in the human mesenchymal stem cells (hMSC)-EC secretome enhanced wound healing under hyperglycemic conditions
Our results revealed that human endothelial cell-differentiated mesenchymal stem cells secretome improved wound healing in high fat diet (HFD) mice

Summary

Introduction

Wound healing involves multiple processes, including extracellular matrix remodeling, synthesis of pro-inflammatory mediators, and new vessel formation [1]. When the wounding healing response becomes abnormal, excessive healing or an ulcerative lesion (chronic wound) occurs. Chronic wounds are defined as tissue injuries that have not been repaired on time or in the correct sequential order to recover the anatomical and functional integrity of the damaged tissue [2]. Chronic wounds are generally associated with poor cellular responses, reduced endogenous prohealing growth factors, or impaired activity in the wounded microenvironment [3]. Diabetes mellitus (DM) is characterized by hyperglycemia and alterations in the metabolism of hydrates of carbon, fats, and proteins [4,5]. Poor glycemic control may occur, leading to metabolic and systemic complications, such as the development of foot ulcers (DFU). DFU is characterized by skin ulceration, an injury that affects the total thickness of the foot dermis

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