Single cell RNA-seq and ATAC-seq analysis of cardiac progenitor cell transition states and lineage settlement

Nat Commun. 2018 Nov 19;9(1):4877. Doi: 10.1038/s41467-018-07307-6

Avant-garde technologies are intensively and extensively used to revisit specific biomedical research areas holding an intrinsic complexity. The early differentiation and segregation of cell lineages forming the heart have been previously studied. Obviously, researchers have aimed at both improving our understanding of these key biological phenomena as well as to collect information that could foster the development of new sustitutive therapies to ammend the diseased heart. However, after many years of research on the gene regulatory networks and epigenetic changes that control cell fate transitions during early cardiogenesis, this process is only partially understood.

In this report, mouse cardiac progenitor cells (CPCs), marked by the expression of the master transcriptional regulatos Nkx2-5 and Isl1 (E7.5 to E9.5), have been characterized combining single-cell RNA sequencing and transposase-accessible chromatin profiling (ATAC-seq). Through this approach, the authors have identified different previously unknown cardiac subpopulations, some of them temporarily displaying expresion of genes that had not been associated to cardiac development (e.g. posterior Hox genes like Hoxa7/9/10, Hoxb6, Hoxc8, and Hoxd8). In detail, the authors suggest that «multipotent Isl1+ CPC pass through an attractor state before separating into different developmental branches, whereas extended expression of Nkx2-5 commits CPC to an unidirectional cardiomyocyte fate». This conclusion results from the careful analysis of pairwise cell-to-cell distances : while distances between Nkx2-5+ CPCs do not seem vary significantly, cell-to-cell distances of Isl1+ CPCs in different clusters, built from a self-organizing map (SOM) analytical approach, are remarkable. It is also interesting to discover that Isl1 and Nkx2-5 co-expressing cells do not form a distinct group within the Nkx2-5+ CPC population, whereas Isl1 and Nkx2-5 coexpression is characteristic of one of the clusters of Isl1+ CPCs. Moreover, this work shows that CPC fate transitions are associated with distinct open chromatin states that strictly depend on on Isl1 and Nkx2-5 expression.

This interesting study underlines the transcriptional diversity of CPCs, providing crucial information on CPC cell dynamics by identifying an «attractor state» for early Isl1+ CPCs, just before they start to segregate and differentiate.