The mammary microenvironment alters the differentiation repertoire of neural stem cells

Abstract

transplantation ͉ niche ͉ plasticity ͉ trans-differentiation ͉ regeneration S omatic stem cells are defined by how they function physiologically in the presence of heterologous cells, that is, the microenvironment or stem cell niche that balances protecting stem cells from exhaustion and protecting the host from unregulated stem cell growth. The dominance of the niche over the stem cell's autonomous phenotype has been demonstrated in several reports involving cells crossing lineage ''boundaries'' to regenerate ''foreign'' tissues. We previously demonstrated that cells isolated from the seminiferous tubules of the mature testis, when mixed together with normal mammary epithelial cells (MECs), would cooperate with these cells and contribute robust numbers of epithelial progeny to normally growing mammary glands in transplanted mammary fat pads (1). In these experiments, the testicular cells included Ϸ10% germinal stem cells (spermatogonia ␣ and ␤), Ϸ20% Sertoli cells, and the remainder primary and secondary spermatocytes and other cells at various stages of spermatogenic cell differentiation. Interstitial and vascular tissue was separated from the seminiferous tubules before dissociation. In these experiments, we were unable to distinguish whether all or just a subpopulation of the isolated seminiferous cells contributed progeny to the mammary epithelial outgrowths.In the present study, to more directly demonstrate the activity of multipotent cells (i.e., cells with the capacity to differentiate into multiple cell types) in this experimental model, we opted to begin with carefully characterized and stable multipotent stem cell populations that could be maintained indefinitely in vitro and could differentiate into multiple cell types in culture after the addition of serum factors and the removal of culture components responsible for stem cell maintenance. Toward this end, neural stem cells (NSCs) from fetal and adult WAP-Cre/Rosa26R mice were isolated and propagated in serum-free medium. Subsequently, these NSCs were mixed with equal numbers of MECs and inoculated immediately into epithelium-divested mammary fat pads of prepubertal female mice. Both fetal and adult NSCs were shown to interact with MECs on transplantation and to robustly contribute mammary epithelial-specific progeny to normal mammary outgrowths.

Lineage Enforcement by Inductive Mesenchyme on Adult Epithelial Stem Cells across Developmental Germ Layers

“…Androgen receptor and Nkx3.1 are two of the earliest markers of prostatic differentiation that are expressed at low/undetectable levels in mammary gland epithelium. Foxa1 interacts with AR and multiple prostatic enhancers to control androgen-induced activation of both human and rodent prostate-specific genes [18]. Foxa1 binding is also essential for ER--chromatin interactions and subsequent expression of estrogen target genes [27].…”

SPRY1 regulates mammary epithelial morphogenesis by modulating EGFR-dependent stromal paracrine signaling and ECM remodeling

“…The importance of mesenchyme, as the embryonic niche, in determining organ identity and fate of the epithelium was demonstrated long ago by classic embryological studies (2,3). More recent studies have shown, however, that postnatal stroma, a derivative of embryonic mesenchyme, is essential for maintenance of cell fate and differentiation status in adult life (4,5). Indeed, abnormal stroma can lead to the formation of a cancer microenvironment, and it plays a causative role during tumor onset and progression (1,6).…”

À la recherche d’une définition moléculaire plus que descriptive pour les cellules souches

“…Aucun marqueur moléculaire à l'heure actuelle ne permet de définir avec certitude un état pluripotent, espérons que l'analyse « épigénétique » sera en mesure de nous proposer cette définition moléculaire qui nous fait tant défaut aujourd'hui. ‡ Un processus de transdifférenciation de cellules issues d'autres tissus que la moelle osseuse a aussi été décrit, et dans certains cas, l'environnement -par exemple celui de la glande mammaire -aurait une action inductive sur ce processus [31].…”