Probes for INS

Thrombin is frequently increased in the CNS after injury yet little is known regarding its effects on neural stem cells. Here we show that the subventricular zone (SVZ) of adult mice lacking the high affinity receptor for thrombin, proteinase activated receptor 1 (PAR1), show increased numbers of Sox2+ and Ki-67+ self-renewing neural stem cells (NSCs) and Olig2+ oligodendrocyte progenitors. SVZ NSCs derived from PAR1-knockout mice, or treated with a PAR1 small molecule inhibitor (SCH79797), exhibited enhanced capacity for self-renewal in vitro, including increases in neurosphere formation and BrdU incorporation. PAR1-knockout SVZ monolayer cultures contained more Nestin, NG2+ and Olig2+ cells indicative of enhancements in expansion and differentiation towards the oligodendrocyte lineage. Cultures of NSCs lacking PAR1 also expressed higher levels of myelin basic protein, proteolipid protein and glial fibrillary acidic protein upon differentiation. Complementing these findings, the corpus callosum and anterior commissure of adult PAR1-knockout mice contained greater numbers of Olig2+ progenitors and CC1+ mature oligodendrocytes. Together these findings highlight PAR1 inhibition as a means to expand adult SVZ NSCs and to promote an increased number of mature myelinating oligodendrocytes in vivo that may be of particular benefit in the context of neural injury where PAR1 agonists such as thrombin are deregulated.

Long-term adult stem cells sustain tissue regeneration throughout the lifetime of an organism. They were hypothesized to originate from embryonic progenitor cells that acquire long-term self-renewal ability and multipotency at the end of organogenesis. The process through which this is achieved often remains unclear. Here, we discovered that long-term hair follicle stem cells arise from embryonic progenitor cells occupying a niche location that is defined by attenuated Wnt/β-catenin signaling. Hair follicle initiation is marked by placode formation, which depends on the activation of Wnt/β-catenin signaling. Soon afterwards, a region with attenuated Wnt/β-catenin signaling emerges in the upper follicle. Embryonic progenitor cells residing in this region gain expression of adult stem cell markers and become definitive long-term hair follicle stem cells at the end of organogenesis. Attenuation of Wnt/β-catenin signaling is a prerequisite for hair follicle stem cell specification because it suppresses Sox9, which is required for stem cell formation.

Alveoli, the lung's respiratory units, are tiny sacs where oxygen enters the bloodstream. They are lined by flat AT1 cells, which mediate gas exchange, and AT2 cells, which secret surfactant. Rare AT2s also function as alveolar stem cells. We show that AT2 lung stem cells display active Wnt signaling and many of them are near single, Wnt-expressing fibroblasts. Blocking Wnt secretion depletes these stem cells. Daughter cells leaving the Wnt niche transdifferentiate into AT1s: maintaining Wnt signaling prevents transdifferentiation whereas abrogating Wnt signaling promotes it. Injury induces AT2 autocrine Wnts, recruiting 'bulk' AT2s as progenitors. Thus, individual AT2 stem cells reside in single cell fibroblast niches providing juxtacrine Wnts that maintain them, whereas injury induces autocrine Wnts that transiently expand the progenitor pool. This simple niche maintains the gas exchange surface, and is coopted in cancer.