Stem cell niches in the adult mouse heart

Abstract

Cardiac stem cells (CSCs) have been identified in the adult heart, but the microenvironment that protects the slow-cycling, undifferentiated, and self-renewing CSCs remains to be determined. We report that the myocardium possesses interstitial structures with the architectural organization of stem cell niches that harbor long-term BrdU-retaining cells. The recognition of long-term labelretaining cells provides functional evidence of resident CSCs in the myocardium, indicating that the heart is an organ regulated by a stem cell compartment. Cardiac niches contain CSCs and lineagecommitted cells, which are connected to supporting cells represented by myocytes and fibroblasts. Connexins and cadherins form gap and adherens junctions at the interface of CSCs-lineagecommitted cells and supporting cells. The undifferentiated state of CSCs is coupled with the expression of ␣4-integrin, which colocalizes with the ␣2-chain of laminin and fibronectin. CSCs divide symmetrically and asymmetrically, but asymmetric division predominates, and the replicating CSC gives rise to one daughter CSC and one daughter committed cell. By this mechanism of growth kinetics, the pool of primitive CSCs is preserved, and a myocyte progeny is generated together with endothelial and smooth muscle cells. Thus, CSCs regulate myocyte turnover that is heterogeneous across the heart, faster at the apex and atria, and slower at the base-midregion of the ventricle.

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

“…However, few passages after enriching the c-kit pos cell fraction from 15%-20%-90%, the original c-kit pos /Sca-1 pos ratio was restored. 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].…”

“…Conversely, the present findings demonstrated that the healthy myocardium is characterized by a constitutive cell cupidity, very likely, directed to collect as many fit cardiomyocytes as possible to guarantee the best myocardial function in all conditions. This continued demand is not self-restricted, but is independently regulated by the limited release of new cardiomyocytes from the two marginally located (atria and apex) sites hosting quiescent cardiac progenitor cells [20]. The conceivable finality of this mechanism could be the preservation of an optimal cardiac structure and function avoiding a disproportionate thickness of the ventricular walls.…”

“…Stem cells grown in monolayer, treated or not with 5 lM H 2 O 2 , were used as controls, as described elsewhere [20]. The experiment was repeated three times.…”

Niche regulation of corneal epithelial stem cells at the limbus

“…One common method to identify limbal epithelial SCs is to label them according to their slow cell cycle [6]. Using this method, epidermal [71] and cardiac [72] niches have been identified. No study has been conducted in the same manner to identify the cellular components of the limbal niche.…”

Stem cells in the heart: What's the buzz all about?—Part 1: Preclinical considerations

“…This evidence suggestive of a c-Kit + resident cardiac stem cell population was explicitly reinforced shortly thereafter in a study of adult rat hearts. 7 Analogous c-Kit + cardiac stem cell populations have been identified in the adult dog 8 and mouse, 9 in which the majority were found to coexpress c-Kit, MDR-1, and Sca-1, suggesting an overlap in what some have described as distinct cardiac stem cell populations. The rat study first described clusters of cKit + cells, many of which expressed early cardiac-specific transcription factors (Nkx2.5), characterized these cells as blood lineage negative (CD34 − , CD45 − , CD20 − , CD45RO − , CD8 − ), and demonstrated that single cardiac c-Kit + cells were self-renewing and clonogenic (expanded in culture after plating one cell per well) as well as multipotent (generating cardiomyocytes, smooth muscle cells, and endothelial cells when placed in differentiation medium containing dexamethasone).…”