Cell Sheet Comprised of Mesenchymal Stromal Cells Overexpressing Stem Cell Factor Promotes Epicardium Activation and Heart Function Improvement in a Rat Model of Myocardium Infarction

Abstract

Cell therapy of the post-infarcted myocardium is still far from clinical use. Poor survival of transplanted cells, insufficient regeneration, and replacement of the damaged tissue limit the potential of currently available cell-based techniques. In this study, we generated a multilayered construct from adipose-derived mesenchymal stromal cells (MSCs) modified to secrete stem cell factor, SCF. In a rat model of myocardium infarction, we show that transplantation of SCF producing cell sheet induced activation of the epicardium and promoted the accumulation of c-kit positive cells in ischemic muscle. Morphometry showed the reduction of infarct size (16%) and a left ventricle expansion index (0.12) in the treatment group compared to controls (24–28%; 0.17–0.32). The ratio of viable myocardium was more than 1.5-fold higher, reaching 49% compared to the control (28%) or unmodified cell sheet group (30%). Finally, by day 30 after myocardium infarction, SCF-producing cell sheet transplantation increased left ventricle ejection fraction from 37% in the control sham-operated group to 53%. Our results suggest that, combining the genetic modification of MSCs and their assembly into a multilayered construct, we can provide prolonged pleiotropic effects to the damaged heart, induce endogenous regenerative processes, and improve cardiac function.

Analysis of MicroRNA Profile Alterations in Extracellular Vesicles From Mesenchymal Stromal Cells Overexpressing Stem Cell Factor

“…Previously, we examined changes in protein content by mass spectrometry ( Zubkova et al, 2019 ; Dergilev et al, 2020 ) to determine if rAAV infection could induced alteration in MSC EV cargoes and did not find significant differences between EVs from intact or transduced MSC (less than 5% of unique proteins). In the present study, we focused on microRNA content of EVs.…”

Autophagy, Mesenchymal Stem Cell Differentiation, and Secretion

“…Improvement of the methods for the clinical application of MSCs can be associated with the preconditioning of cell cultures in a controlled microenvironment [ 34 , 35 ], the creation of structures (“cell sheets”) of high cell density [ 36 , 37 ], the use of extracellular vesicles of MSCs as a source of trophic factors, cytokines, etc. [ 38 , 39 ], and a number of other approaches.…”

“…In this regard, the great interest represent studies performed by group of A. Betancourt [ 35 , 36 ]. These authors have shown that MSC preconditioning with proinflammatory factors/cytokines (LPS, TNFalpha, INFgamma) acquire a proinflammatory phenotype, i.e., a capability to express and secrete proinflammatory factors.…”

Possible Treatment of Myocardial Infarct Based on Tissue Engineering Using a Cellularized Solid Collagen Scaffold Functionalized with Arg-Glyc-Asp (RGD) Peptide

“…Optimization of the recognition of key integrins may be a way for the control of cell retention and differentiation as well as a means of enhancing cell survival in a hypoxic and damaged myocardium and of decreasing secondary migration [34]. Application of stem cells as an epicardial patch after MI may be also a way for controlling cells' microenvironment and preserve their immune functionality after implantation [54,[174][175][176], and thereby possibly a new approach for improving the results of cell therapy after MI.…”