Localization of Islet-1–Positive Cells in the Healthy and Infarcted Adult Murine Heart

Abstract

Rationale The transcription factor Islet-1 is a marker of cardiovascular progenitors during embryogenesis. The isolation of Islet-1-positive (Islet-1+) cells from early postnatal hearts suggested that Islet-1 also marks cardiac progenitors in adult life. Objective We investigated the distribution and identity of Islet-1+ cells in adult murine heart and evaluated whether their number or distribution change with age or after myocardial infarction. Methods and Results Distribution of Islet-1+ cells in adult heart was investigated using gene targeted mice with nuclear β-galactosidase inserted into the Islet-1 locus. nLacZ-positive cells were only present in 3 regions of the adult heart: clusters in the interatrial septum and around the pulmonary veins, scattered within the wall of the great vessels, and a strictly delimited cluster between the right atrium and superior vena cava. Islet-1+ cells in the first type of clusters coexpressed markers for parasympathetic neurons. Positive cells in the great arteries coexpressed smooth muscle actin and myosin heavy chain, indicating a smooth muscle cell identity. Very few Islet-1+ cells within the outflow tract expressed the cardiomyocyte marker α-actinin. Islet-1+ cells in the right atrium coexpressed the sinoatrial node pacemaker cell marker HCN4. Cell number and localization remained unchanged between 1 to 18 months of age. Consistently Islet-1 mRNA was detected in human sinoatrial node. Islet-1+ cells could not be detected in the infarct zone 2 to 28 days after myocardial infarction, aside from 10 questionable cells in 1/13 hearts. Conclusions Our results identify Islet-1 as a novel marker of the adult sinoatrial node and do not provide evidence for Islet-1+ cells to serve as cardiac progenitors.

Developmental origin and lineage plasticity of endogenous cardiac stem cells

“…However, regardless of the species -mouse, rat or human -ISL1 + cells are rare in the adult, and in the mouse they are largely confined to the sinoatrial node (Fig. 4) (Weinberger et al, 2012).…”

“…Cells were marked by β-galactosidase staining (blue) from an Isl1-nuclear lacZ knock-in allele. Reproduced with permission (Weinberger et al, 2012). (B) The epicardium (shown in red, along with the coronary vessels within the myocardium) gives rise to perivascular cells and stromal fibroblasts in development, and in the adult this potential is retained, which is activated after injury.…”

Migration of Resident Cardiac Stem Cells in Myocardial Infarction

“…These Isl-1 þ cells were isolated from very young animals, do not express c-kit but harbor cardiomyogenic potential both in vitro and in vivo. After 4 weeks of age, the Isl-1 þ cardiac cells lost the capacity for differentiation (Weinberger et al, 2012). Thus, Isl-1 þ cells are a population of cells with cardiac progenitor potential, but only in young hearts.…”

“…Mouse and human c-kit þ , CD31 þ , CD34 þ c-kit, CXCR4 Messina et al, 2004;Davis et al, 2009;Smith et al, 2007;Tang et al, 2009 Isl Laugwitz et al, 2005;Weinberger et al, 2012 CSCs, cardiac stem cells; CSP, cardiac side population.…”

Endogenous Cardiac Stem Cell Therapy for Ischemic Heart Failure

“…For instance, the IGF-1/IGF-1 receptor (IGF-1R) system preserves the pool of endogenous CSCs through enhancing telomerase activity and delaying senescence by activating the PI3K-Akt pathway, indicating that IGF-1 may protect CSCs against adverse aging effects [122]. It has been shown that the IGF-1/ IGF-1R axis exists in cardiac stem cells in very old animals, but the IGF-1 synthesis and the IGF-1R expression are found to decrease in aging human CSCs [122,125,126]. In this regard, preconditioning of cultured resident CSCs in old age by over-expressing telomerase or up-regulation of favourable growth factor signalling may improve the regenerative capabilities of survival, growth and differentiation in vivo following transplantation [104,124,127].…”