Reactivation of the Nkx2.5 cardiac enhancer after myocardial infarction does not presage myogenesis.

Aims: The contribution of resident stem or progenitor cells to cardiomyocyte renewal after injury in adult mammalian hearts remains a matter of considerable debate. We evaluated a cell population in the adult mouse heart induced by myocardial infarction (MI) and characterized by an activated Nkx2.5 enhancer element that is specific for multipotent cardiac progenitor cells (CPCs) during embryonic development. We hypothesized that these MI-induced cells (MICs) harbour cardiomyogenic properties similar to their embryonic counterparts.

Methods and results: MICs reside in the heart and mainly localize to the infarction area and border zone. Interestingly, gene expression profiling of purified MICs 1 week after infarction revealed increased expression of stem cell markers and embryonic cardiac transcription factors (TFs) in these cells as compared to the non-mycoyte cell fraction of adult hearts. A subsequent global transcriptome comparison with embryonic CPCs and fibroblasts and in vitro culture of MICs unveiled that (myo-)fibroblastic features predominated and that cardiac TFs were only expressed at background levels.

Conclusions: Adult injury-induced reactivation of a cardiac-specific Nkx2.5 enhancer element known to specifically mark myocardial progenitor cells during embryonic development does not reflect hypothesized embryonic cardiomyogenic properties. Our data suggest a decreasing plasticity of cardiac progenitor (-like) cell populations with increasing age. A re-expression of embryonic, stem or progenitor cell features in the adult heart must be interpreted very carefully with respect to the definition of cardiac resident progenitor cells. Albeit, the abundance of scar formation after cardiac injury suggests a potential to target predestinated activated profibrotic cells to push them towards cardiomyogenic differentiation to improve regeneration.