IGF-1-Overexpressing Mesenchymal Stem/Stromal Cells Promote Immunomodulatory and Proregenerative Effects in Chronic Experimental Chagas Disease.

Daniela N Silva,Ricardo Ribeiro-Dos-Santos,Paloma G De Jesus,Gisele B Carvalho,Milena B P Soares,Cassio S Meira,Bruno S F Souza,Malena S Feitoza,Carine M Azevedo,Bruno Raphael Cavalcante,Juliana F Vasconcelos

doi:10.1155/2018/9108681

Abstract

Mesenchymal stem/stromal cells (MSCs) have been investigated for the treatment of diseases that affect the cardiovascular system, including Chagas disease. MSCs are able to promote their beneficial actions through the secretion of proregenerative and immunomodulatory factors, including insulin-like growth factor-1 (IGF-1), which has proregenerative actions in the heart and skeletal muscle. Here, we evaluated the therapeutic potential of IGF-1-overexpressing MSCs (MSC_IGF-1) in a mouse model of chronic Chagas disease. C57BL/6 mice were infected with Colombian strain Trypanosoma cruzi and treated with MSCs, MSC_IGF-1, or vehicle (saline) six months after infection. RT-qPCR analysis confirmed the presence of transplanted cells in both the heart and skeletal muscle tissues. Transplantation of either MSCs or MSC_IGF-1 reduced the number of inflammatory cells in the heart when compared to saline controls. Moreover, treatment with MSCs or MSC_IGF-1 significantly reduced TNF-α, but only MSC treatment reduced IFN-γ production compared to the saline group. Skeletal muscle sections of both MSC- and MSC_IGF-1-treated mice showed a reduction in fibrosis compared to saline controls. Importantly, the myofiber area was reduced in T. cruzi-infected mice, and this was recovered after treatment with MSC_IGF-1. Gene expression analysis in the skeletal muscle showed a higher expression of pro- and anti-inflammatory molecules in MSC_IGF-1-treated mice compared to MSCs alone, which significantly reduced the expression of TNF-α and IL-1β. In conclusion, our results indicate the therapeutic potential of MSC_IGF-1, with combined immunomodulatory and proregenerative actions to the cardiac and skeletal muscles.

Highlights

In the field of regenerative medicine, mesenchymal stem/ stromal cells (MSCs) are promising tools for the development of novel advanced therapy medicinal products to treat chronic inflammatory diseases [1]
We evaluated whether insulin-like growth factor-1 (IGF-1) overexpression can increase the immunomodulatory and/or regenerative actions of MSCs in the context of experimental Chagas disease cardiomyopathy
We found that transplantation of MSC_IGF-1 reduced cardiac inflammation and fibrosis, in a similar magnitude to the effect observed in MSC-treated mice

Summary

Introduction

In the field of regenerative medicine, mesenchymal stem/ stromal cells (MSCs) are promising tools for the development of novel advanced therapy medicinal products to treat chronic inflammatory diseases [1]. The release of trophic paracrine factors by MSCs has been associated with many of the proregenerative and immunomodulatory effects observed in the context of MSC-based therapies [2]. One of such growth factors is insulin-like growth factor-1 (IGF-1), which has been shown to exert proregenerative actions in skeletal muscle, promoting muscle cell proliferation and differentiation, histological recovery of muscle fiber type and size, and functional improvements [6, 7]. IGF-1 induces myocyte hypertrophy and satellite cell activation and increases protein synthesis

Methods

Results

Conclusion