Co-transplantation of Mesenchymal Stromal Cells and Induced Pluripotent Stem Cell-Derived Cardiomyocytes Improves Cardiac Function After Myocardial Damage.

Jürgen Hescheler,Klaus Neef,Tomo Šarić,Vera Lepperhof,Florian Drey,Yeong-Hoon Choi,Thorsten Wahlers

doi:10.3389/fcvm.2021.794690

Abstract

Induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) represent an attractive resource for cardiac regeneration. However, survival and functional integration of transplanted iPS-CM is poor and remains a major challenge for the development of effective therapies. We hypothesized that paracrine effects of co-transplanted mesenchymal stromal cells (MSCs) augment the retention and therapeutic efficacy of iPS-CM in a mouse model of myocardial infarction (MI). To test this, either iPS-CM, MSC, or both cell types were transplanted into the cryoinfarction border zone of syngeneic mice immediately after injury. Bioluminescence imaging (BLI) of iPS-CM did not confirm enhanced retention by co-application of MSC during the 28-day follow-up period. However, histological analyses of hearts 28 days after cell transplantation showed that MSC increased the fraction of animals with detectable iPS-CM by 2-fold. Cardiac MRI analyses showed that from day 14 after transplantation on, the animals that have received cells had a significantly higher left ventricular ejection fraction (LVEF) compared to the placebo group. There was no statistically significant difference in LVEF between animals transplanted only with iPS-CM or only with MSC. However, combined iPS-CM and MSC transplantation resulted in higher LVEF compared to transplantation of single-cell populations during the whole observation period. Histological analyses revealed that MSC increased the capillarization in the myocardium when transplanted alone or with iPS-CM and decreased the infarct scar area only when transplanted in combination with iPS-CM. These results indicate that co-transplantation of iPS-CM and MSC improves cardiac regeneration after cardiac damage, demonstrating the potential of combining multiple cell types for increasing the efficacy of future cardiac cell therapies.

Highlights

Ischemic cardiomyopathy is currently the most frequent global cause of death [1]
We have shown that mesenchymal stromal cells (MSCs) support the adhesion of induced pluripotent stem cells (iPSCs)-derived CM to non-contractile ventricular tissue slices and that factors secreted by MSCs improve electrical integration of Induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) into vital myocardial tissue in vitro [33] and counteract the effects of hypoxia on cultured iPS-CM [34]
The differentiation of murine iPSC line pUbC-FLuc-αPIG and puromycin selection generated a homogeneous population of spontaneously beating clusters, which contained more than 95% viable and enhanced green fluorescent protein (eGFP) expressing iPS-CM and yielded an average of 2.5 CM per iPSC initially used (Figures 1A,B)

Summary

Introduction

One of the main underlying pathophysiological issues in this disease is the limited intrinsic capacity of the human myocardium to regenerate after injury [2]. The recent progress in stem cell research has accelerated the field of regenerative medicine, often involving transplantation of cells to compensate for cell loss, rebuilding damaged tissue, and restoring the organ function [4,5,6]. Different cell types have been investigated as treatment options for ischemic heart disease leading to variable results with respect to the therapeutic benefit [7]. The cells that indirectly support the endogenous regenerative capacities after transplantation and, secondly, the cells that functionally integrate into the damaged myocardium and directly contribute to the restoration of its pump function. A likely reason is the inability of MSC to restore lost contractility necessary for proper electromechanical heart function

Methods

Results

Conclusion