Although a small number of cardiomyocytes may reenter the cell cycle after injury, the adult mammalian heart is incapable of a robust cardiomyocyte proliferation. A function for periostin as a regulator of cardiomyocyte proliferation has been proposed but remains controversial. Periostin is highly expressed in the developing heart. While barely detectable in adult healthy myocardium, periostin becomes re-expressed in damaged hearts. Alternative splicing of the human periostin gene results in seven isoforms lacking sequences between exons 17 and 21. We previously reported that exosomes (Exo) secreted by human cardiac explant-derived progenitor cells (CPC) express periostin. Here, we investigate whether these vesicles stimulate cardiomyocyte cycling. By proteomic analysis we found that exosome carry a short periostin isoform. Furthermore, periostin expression in CPC-secreted Exo was detected using an antibody raised against aa 537-836, but not using an antibody raised against amino acids mapping at exon 17 of human periostin. CPC-secreted Exo induced the proliferation of neonatal rat cardiomyocytes in vitro and in vivo, and adult cardiomyocytes after myocardial infarction. Exo promoted phosphorylation of focal adhesion kinase (FAK), actin polymerization, and nuclear translocation of Yes-associated protein (YAP) in cardiomyocytes. Knocking down of periostin or YAP, or PF-573228–mediated blockade of FAK phosphorylation nullified Exo-induced proliferation. In conclusion here we showed, for the first time, that CPC-secreted Exo promote cardiomyocyte cell cycle-reentry through a short periostin isoform, while the full-length periostin was inert. Finally, these data are the first step to understand the isoform-specific mechanisms of periostin role in myocardial regeneration.