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Novel direct reprogramming technique for the generation of culture-expandable cardiac progenitor cells from fibroblasts.

Since the tremendous discovery of induce-pluripotent stem cells (iPSCs) in 2006 (1,2), investigators have been trying to induce somatic cell reprogramming into certain lineage cells following the basic method, in which lineagerelated critical genes are initially screened out of numerous candidates and several master genes are then selected by transduction of multiple genes with appropriate culture conditions in somatic cells confirming transdifferentiation of the transduced cells. The technique is called as “direct reprogramming” which can avoid generating iPSCs and previous studies have successfully demonstrated lineage reprogramming into a variety of differentiated cell types such as neuronal cells (3), hepatocytes (4), and cardiomyocytes (5). Despite of the achievement of direct lineage reprogramming, investigators next challenged the generation of progenitor cells rather than terminally differentiated cells by direct reprogramming, because progenitor cells are generally proliferative and have advantage of large scale expansion as a tool for regeneration therapy. Indeed, recent reports exhibited that reprogrammed progenitors of neuronal cells (3), hepatocytes (6), and cardiomyocytes (7) were capable of proliferation. Cardiac progenitor cells (CPCs) have been identified with a variety of markers (Table 1) including: (I) transcription factors of Mesp1, Ist1, and Nkx2.5 in embryonic stem cells, (II) cell surface proteins of CXCR4, PDGFR-a, Flk1/KDR, and SIRPA in pluripotent stem cells, and (III) cell surface proteins of Sca-1 and c-Kit in mammalian somatic stem cells. On the other hand, induced-CPCs including cardiomyocyte-like cells have also been attempted to generate from fibroblasts by direct reprogramming methods (Table 2). In the very recent study, Lalit et al. (7) reported that a combination of cardiac factors and signaling molecules reprogramed adult mouse fibroblasts into expandable induced cardiac progenitor cells (iCPCs). The iCPCs were multipotent and could differentiate into not only cardiomyocytes but also smooth muscle cells and endothelial cells that also could be sources of myocardium. Moreover, iCPCs generate myocardium when injected into the embryonic and adult post-MI mouse heart. First, the authors focused on 22 genes including 18 candidate genes that are critical during embryonic cardiovascular development and 4 iPSC factors, and finally selected 5 genes (Gata4, Mesp1, Tbx5, Nkx2.5, and Baf60c) for generating CPCs utilizing an Nkx2.5 cardiac reporter mouse model expressing enhanced yellow fluorescent protein (EYFP). The source of fibroblasts was chosen from adult but not neonatal fibroblasts for reprogramming in terms of clinical applicability. They next worked out optimizing culture conditions to let the generated CPCs to proliferate/expand with activating Wnt and JAK/ STAT signaling by chemical compounds. Intriguingly, the proliferating iCPCs exhibited neither protein expression for pluripotency of Oct4 nor cardiovascular lineage differentiation markers of α-actinin, smooth muscle-myosin Editorial