Clonally amplified cardiac stem cells are regulated by Sca-1 signaling for efficient cardiovascular regeneration

Abstract

Recent studies have shown that cardiac stem cells (CSCs) from the adult mammalian heart can give rise to functional cardiomyocytes; however, the definite surface markers to identify a definitive single entity of CSCs and the molecular mechanisms regulating their growth are so far unknown. Here, we demonstrate a single-cell deposition analysis to isolate individually selected CSCs from adult murine hearts and investigate the signals required for their proliferation and survival. Clonally proliferated CSCs express stem cell antigen-1 (Sca-1) with embryonic stem (ES) cell-like and mesenchymal cell-like characteristics and are associated with telomerase reverse transcriptase (TERT). Using a transgene that expresses a GFP reporter under the control of the TERT promoter, we demonstrated that TERTGFP-positive fractions from the heart were enriched for cells expressing Sca-1. Knockdown of Sca-1 transcripts in CSCs led to retarded ex vivo expansion and apoptosis through Akt inactivation. We also show that ongoing CSC proliferation and survival after direct cell-grafting into ischemic myocardium require Sca-1 to upregulate the secreted paracrine effectors that augment neoangiogenesis and limit cardiac apoptosis. Thus, Sca-1 might be an essential component to promote CSC proliferation and survival to directly facilitate early engraftment, and might indirectly exert the effects on late cardiovascular differentiation after CSC transplantation.

Human Cardiac Progenitor Cell Grafts as Unrestricted Source of Supernumerary Cardiac Cells in Healthy Murine Hearts

“…This could imply that c-kit pos and Sca-1 pos progenitor cells, so far considered rather different cell population with overlapping figures [27] could represent two phenotypic stages of the same original population, in which c-kit expression could mark the more immature, slowly dividing progenitor cell pool, identified also in niches in vivo [20], while a more mature, actively growing and potentially cardiogenic progenitor cell population (a transit-amplifying population?) can be identified by the Sca-1 expression, as already demonstrated both in vitro and in vivo [13,14,25,28]. The hCPC phenotype was homogeneous in all preparations from the 13 donor cardiac patients and stable also in long-term conventional cultures (Sca-1 pos cells are able to uphold their phenotype for more than 50 passages).…”

Cell Therapy for Cardiovascular Regeneration

“…Instead of these cells, CSC/CPC isolated from host heart is now being focused on as one of candidates of cell sources of cardiac regeneration therapy. [20][21][22][23] Among somatic stem cells, CSC/CPC have a high potential to differentiate into cardiomyocytes. These cells have been confirmed to differentiate into cardiomyocytes in the ischemic heart through not only cell fusion with host cardiomyocytes but also effects on limb ischemia cannot be obtained.…”

Stem cell antigen-1 enhances tumorigenicity by disruption of growth differentiation factor-10 (GDF10)–dependent TGF-β signaling

“…Discussion Sca-1 is generally considered to be a stem cell marker of normal tissues, where Sca-1-positive cells have been shown to have a regenerative capacity (3,(20)(21)(22)(23)(24)(25)(26), despite the fact that its function is poorly described. In this study, we have defined a role for Sca-1 in tumor progression based on three key findings.…”