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Macrophage Precursor Cells from the Left Atrial Appendage of the Adult Heart Spontaneously Reprogram into a C-kit+/CD45- Stem Cell-Like Phenotype [RNA-Seq]

ABSTRACT: The developmental origin of the c-kit expressing progenitor cell pool in the adult heart has remained elusive. Recently, it has been discovered that the injured heart is enriched with c-kit+ cells, which also express the hematopoietic marker CD45. In this study, we characterize the phenotype and transcriptome of the c-kit+/CD45+ cell population, originating from the left atrial appendage. These cells are defined as cardiac macrophage progenitors. We also demonstrate that the c-kit+/CD45+ progenitor cell population activates heart development, neural crest and pluripotency associated pathways in vitro, in conjunction with CD45 down-regulation, and acquire a c-kit+/lin- phenotype. This spontaneous reprogramming progresses further to a highly proliferative, partially myogenic phenotype. Our data suggests that c-kit+/lin- cells and cardiac macrophages have a common lineage origin possibly resolving some current conundrums in the field of cardiac regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE57125 | GEO | 2016/01/01

SECONDARY ACCESSION(S): PRJNA245514

REPOSITORIES: GEO

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Project description:Multipotent adult resident cardiac stem cells (CSCs) originally were identified by the expression of c-kit, the stem cell factor receptor. However, in the adult myocardium c-kit alone distinguish CSCs from other c-kit-expressing cardiac cells because the adult heart contains a heterogeneous mixture of c-kitpos cells, mainly composed of mast and endothelial/progenitor cells. This heterogeneity of cardiac c-kitpos cells has not been considered in recent c-kit-expressing cell fate mapping publications, which have equated the contribution of the whole heterogeneous c-kitpos population to cardiomyocyte generation in adulthood, which is minimal, to that of the CSCs, a result at odds with previous publications. To shed light on this issue, we have assessed the identity, abundancy and myogenic potential of true multipotent CSCs within the total c-kitpos cardiac cell cohort. Blood lineage-committed c-kitpos cells were removed by CD45 negative sorting to obtain a CD45negc-kitpos cell population (<10% of the total c-kitpos cells), which is enriched for cells that express c-kit at low levels and possess all properties of multipotent stem/progenitor cells in vitro. These characteristics are absent from the c-kitneg and the lineage-committed c-kitpos cardiac cells. Single Linnegc-kitpos cell-derived CSC clones, representing 1-2% of total c-kitpos cells, when instructed by TGF-b/Wnt molecules, acquire full transcriptome expression, sarcomere organization, spontaneous contraction and electrophysiological properties of differentiated cardiomyocytes. Significantly, clonogenic CSCs have a potent cardio-regenerative/repair capacity in vivo after acute myocardial infarction. CSC myogenic regenerative capacity is dependent on cardiomyocyte commitment through activation of the SMAD2 pathway. Such regeneration was not apparent when freshly-isolated total c-kitpos cardiac cells were administered. In conclusion, only a very small fraction of cardiac c-kitpos cells (~1-2%) have the characteristics of multipotent CSCs but these exhibit robust myogenic properties.  

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Macrophage Precursor Cells from the Left Atrial Appendage of the Adult Heart Spontaneously Reprogram into a C-kit+/CD45- Stem Cell-Like Phenotype [RNA-Seq]

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