High Runx1 Levels Promote a Reversible, More-Differentiated Cell State in Hair-Follicle Stem Cells during Quiescence

Abstract

Quiescent hair follicle (HF) bulge stem cells (SCs) differentiate to early progenitor (EP) hair germ (HG) cells, which divide to produce transit-amplifying (TA) matrix cells. EPs can revert to SCs upon injury, but whether this de-differentiation occurs in normal HF homeostasis (hair cycle), and the mechanisms regulating both differentiation and de-differentiation are unclear. Here we use lineage tracing, gain of function, transcriptional profiling, and functional assays to examine the role of observed endogenous Runx1 level changes in the hair cycle. We find that forced Runx1 expression induces hair degeneration (catagen) and simultaneously promotes changes in the quiescent bulge SC transcriptome towards a cell-state resembling the EP HG fate. This cell-state transition is functionally reversible. We propose that SC differentiation and de-differentiation are likely to occur during normal HF degeneration and niche restructuring in response to changes in endogenous Runx1 levels associated with SC location with respect to the niche.

Runx1 Role in Epithelial and Cancer Cell Proliferation Implicates Lipid Metabolism and Scd1 and Soat1 Activity

“…Runx1 Fl/Fl +TM and K14-CreERT2; Runx1 Fl/Fl +oil littermates served as control. For overexpression studies, we used pTRE-mycRunx1 crossed with Tet-on K14-rTA mice previously generated (29). These mice were fed with doxycycline (doxy) chow (1,000 mg/kg) at PD19 to induce Runx1 expression and sacrificed at PD20, as described before (29).…”

“…We implicated Runx1 in adult HFSC timely activation from quiescence and normal hair cycle progression (29) and in rates of self-renewal (25, 30). Runx1 is up-regulated in quiescent HFSCs migrating outside the niche (bulge), and promotes a reversible early progenitor (hair germ) cell-state prone for subsequent rapid activation and proliferation (29). We found Runx1 absolutely essential for keratinocyte proliferation and survival in cell culture and for skin and oral epithelial tumorigenesis in mice (30, 31).…”

“…To systematically investigate how Runx1 is accomplishing its role in epithelial cell proliferation and survival, we characterized the global gene expression changes induced by Runx1 elevation in quiescent HFSCs in vivo (29). Among thousands of genes that changed mRNA expression upon Runx1 induction, we found a distinct GEO set of elevated genes with known functions in lipid metabolism (Table 1).…”

Linking chromatin dynamics, cell fate plasticity, and tissue homeostasis in adult mouse hair follicle stem cells

“…1A). Stem cells positioned below the bulge in the hair germ (Hg) proliferate rapidly and differentiate without self-renewal to matrix progenitor cells at anagen (growth phase) onset, which further give rise to the terminally differentiated lineages on the hair follicle, including the inner root sheath and the hair shaft (7, 8). Subsequently, early anagen bulge stem cells replenish their own pool by symmetric stem cell population expansion within the bulge, without further cellular contribution to the differentiated compartment until the next catagen (5).…”

Precocious Phenotypic Transcription‐Factor Expression During Early Development

“…Multiple reports have detailed a role for RUNX1 in epithelial biology [Scheitz and Tumbar, 2013]. RUNX1 has been shown to modulate developmental activation and proliferation of hair follicle stem cells and inner olfactory nerve layer olfactory ensheathing cells [Hoi et al, 2010; Lee et al, 2014; Murthy et al, 2014; Osorio et al, 2008; Osorio et al, 2011]. RUNX1 is a key regulator of the differentiation of mammary epithelium stem cells from a state of ductal and lobular bipotency [Sokol et al, 2015].…”