Fate of undifferentiated mouse embryonic stem cells within the rat heart: role of myocardial infarction and immune suppression

Abstract

It has recently been suggested that the infarcted rat heart microenvironment could direct pluripotent mouse embryonic stem cells to differentiate into cardiomyocytes through an in situ paracrine action. To investigate whether the heart can function as a cardiogenic niche and confer an immune privilege to embryonic stem cells, we assessed the cardiac differentiation potential of undifferentiated mouse embryonic stem cells (mESC) injected into normal, acutely or chronically infarcted rat hearts. We found that mESC survival depended on immunosuppression both in normal and infarcted hearts. However, upon Cyclosporin A treatment, both normal and infarcted rat hearts failed to induce selective cardiac differentiation of implanted mESC. Instead, teratomas developed in normal and infarcted rat hearts 1 week and 4 weeks (50% and 100%, respectively) after cell injection. Tight control of ESC commitment into a specific cardiac lineage is mandatory to avoid the risk of uncontrolled growth and tumourigenesis following transplantation of highly plastic cells into a diseased myocardium.

Mending a Faltering Heart

“…81,82 Lineage conversion has the obvious advantage of avoiding the risk of teratoma in the heart that may originate from the chance carryover of pluripotent cells. 83 It may also offer a shorter timeframe from biopsy to transplantable cells compared with iPSC generation followed by directed differentiation. Ieda et al 84 first reported that 3 cardiac-specific transcription factors, Gata4, Mef2c, and Tbx5 (collectively referred to as GMT), were sufficient to induce a cardiomyocyte-like phenotype from mouse postnatal cardiac or dermal fibroblasts.…”

Stem Cell Therapy for Chronic Myocardial Infarction

“…It is possible that once again, the inflammatory microenvironment played a role in cell disappearance, but other factors as the high dose employed (over 200 times the usual dose for mice) could have contributed to injected cell necrosis. On the other hand, they were unable to find any difference either in cardiac contraction (where cells induced no benefit) or cardiac muscle differentiation in rats transplanted with undifferentiated mouse ESC 1 or 4 weeks after MI [26]. Their results showed that ESC survival was dependent on immunosuppression, but resulted in teratoma development.…”

“…Again, in spite of an intense investigation being developed in the acute setting [10,32], only few reports have delved in the effects of ESC transplantation for chronic MI. As discussed below, He et al [26] found that ESC injection after MI resulted in no functional benefit, whereas the work of Dr. Menasché [67] showed that co-transplantation of ESC with MSC provided a better functional outcome than any of the single cell treatment.…”

Cardiac Regeneration with Stem Cells

“…This partial remuscularization was accompanied by beneficial effects on regional and global cardiac function [153,154], and the co-transplantation of ESC with MSC provides a better functional outcome than any of the single cell treatments [157]. However, some researchers have questioned whether these effects are sustained at later time points [158], because no functional benefit has been found by other groups [159]. Therefore, the mechanisms underlying the observed improvements in contractile function remain unclear.…”