A Transcriptional Basis for Neonatal Heart Regeneration at Single Cell Resolution

The adult mammalian heart has limited capacity for regeneration following injury, whereas the neonatal heart can readily regenerate within a short period after birth. Deciphering the molecular underpinnings of neonatal heart regeneration and the blockade to regeneration in later life may provide novel insights for heart repair. Neonatal heart regeneration is orchestrated by multiple cell types including cardiac resident cells and immune cells that infiltrate the heart after injury. To systematically elucidate the transcriptional response after injury at cellular level during heart regeneration, we performed single cell RNA-sequencing on hearts at various time points post P1 or P8 myocardial infarction injury, and coupled that with bulk tissue RNA-sequencing data collected at the same time points. This integrated approach provides detailed transcriptome landscape and dynamics during heart regeneration at single cell resolution. We further depict a ligand-receptor interaction network that potentially reveal cellular signaling and cell-cell cross-talks during heart regeneration in cell autonomous and non-autonomous manners. Furthermore, to uncover the transcriptional dynamics in a single cardiomyocyte (CM), which was technically challenging due to incompatibility of CM diameter with Drop-Seq platforms, we performed single nucleus RNA-sequencing for CM population, and identified a subset of CMs in the regenerative hearts with unique molecular properties. Taken together, our data provide , and suggest numerous inroads that might be therapeutically manipulated to enhance cardiac function in response to injury.