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

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.

Development of composite functional tissue sheets using hiPSC-CMs and hADSCs to improve the cardiac function after myocardial infarction

“…Additionally, we attempted to enhance the function of tissue sheets and their therapeutic effects in vivo through several methods, such as physical stimulation [ 20 ], utilization of pharmaceutical agents [ 18 ], and stacking multiple fibers [ 16 ]. However, despite improvements in engraft retention achieved through the above approaches, there are still remaining issues in therapeutic efficacy because of the limited paracrine functions of exogenous hiPSC-CMs [ 16 , 18 , 20 , 35 ]. MSCs are considered a promising approach for repairing damaged myocardium after MI, improving LV function and remodeling, and enhancing neovascularization via various paracrine cytokines [ 36 ].…”

TRPA1 promotes the maturation of embryonic stem cell-derived cardiomyocytes by regulating mitochondrial biogenesis and dynamics

“…This study is the first study to reveal the positive role of TRPA1 channels in regulating the maturation of PSC-CMs. The generation of CMs from PSCs has provided huge promise for new therapeutic strategies to treat congenital and non-congenital heart diseases [ 33 – 35 ]. However, the incomplete morphological and functional maturation of PSC-CMs represents a crucial bottleneck in their utility [ 36 ].…”

Engineered Tissue for Cardiac Regeneration: Current Status and Future Perspectives

“…The MSCs have been reported to have profound immunomodulatory properties for their expression of anti-inflammatory cytokines, such as IL-10 and TGFβ [ 110 ]. The co-transplantation of iPSC-CM and MSC could reduce the immune rejection [ 111 ] and improve the heart function [ 112 ] more advantageously than in the iPSC-CM-only group. However, 4 weeks after surgery, only very few transplanted cells survived in the host myocardium, indicating that the immunomodulatory effect of MSC is still limited.…”