To optimize the regenerative proficiency of stem cells, a cardiopoietic
protein-based cocktail consisting of multiple
growth factors has been developed and advanced into clinical trials for treatment of ischemic
heart failure. Streamlining the inductors of cardiopoiesis would address the resource intensive nature of the current stem cell enhancement protocol. To this end, the microencapsulated-modified-
mRNA (M3
RNA) technique was here applied to introduce early cardiogenic genes into human adipose-derived mesenchymal stem cells (AMSCs). A single mesodermal
transcription factor,
Brachyury, was sufficient to trigger high expression of cardiopoietic markers, Nkx2.5 and Mef2c. Engineered cardiopoietic stem cells (eCP) featured a transcriptome profile distinct from pre-engineered AMSCs. In vitro, eCP demonstrated protective
antioxidant capacity with enhanced
superoxide dismutase expression and activity; a vasculogenic secretome driving angiogenic tube formation; and macrophage polarizing immunomodulatory properties. In vivo, in a murine model of
myocardial infarction, intramyocardial delivery of eCP (600 000 cells per heart) improved cardiac performance and protected against decompensated
heart failure. Thus, heart repair competent stem cells, armed with
antioxidant, vasculogenic, and immunomodulatory traits, are here engineered through a
protein-independent single gene manipulation, expanding the available regenerative toolkit.