Background: Fibroblasts constitute nearly 50% of the cell mass of the normal heart,
though these cells do not contribute to contractility. Fibroblasts are generally considered
terminally differentiated cells incapable of further differentiation into
another cell type.
Methods/Results: Microarray analysis was used to identify genes present in rat neonatal
cardiac cells, and high-throughput screens identified 3 genes (Gata4, Mef2c,
and Tbx5; GMT) capable of inducing expression of cardiomyocyte-specific
target genes. When isolated transgenic
rat fibroblasts expressing a GFP expression vector were then exposed to GMT,
they were able to express GFP and target genes (including the troponin cTnT,
ryanodine receptor Ryr2, and connexin Gja1) present in normal adult cardiomyocytes
but not adult fibroblasts. Importantly,
genes present in embryonic myocytes were not induced in fibroblasts, suggesting
that it was not necessary for these cells to revert back to pluripotent stems
for differentiation. Mechanistic
expression analysis showed that the GMT combination induced transcription by a
demethylation. To confirm that the
mechanism was conversion of existing fibroblasts and not activation of rare
cardiac stem cells, the authors induced identical changes in dermal
fibroblasts. Finally, fibroblasts
induced by GMT were also shown to be spontaneously contractile. When GMT was infused in vivo into rat
hearts, fibroblasts in heart tissue were shown to develop the induced
cardiomyocyte phenotype.
Implications: Evidence exists that damaged myocardium may be
replaced when infusion of stem cells.
These data suggest that endogenous cells may instead by activated to
replace tissue by infusion of GMT. Additional
advantages is avoidance of tumor formation seen with direct stem cell
infusions. Large amounts of fibroblasts
can be easily cultured from endocardial biopsy by routine cell culture
techniques, and reprogrammed cells can infused back into the heart without
concern for donor mismatch. The presence
of abundant fibroblasts in cardiac tissue ensures a large reservoir of
potential progenitor cells.
Further
Leave a comment