Abstract
Tissue homeostasis relies on the fine regulation between stem and progenitor cell maintenance and lineage commitment. In the adult prostate, stem cells have been identified in both basal and luminal cell compartments. However, basal stem/progenitor cell homeostasis is still poorly understood. We show that basal stem/progenitor cell maintenance is regulated by a balance between BMP5 self-renewal signal and GATA3 dampening activity. Deleting Gata3 enhances adult prostate stem/progenitor cells self-renewal capacity in both organoid and allograft assays. This phenotype results from a local increase in BMP5 activity in basal cells as shown by the impaired self-renewal capacity of Bmp5-deficient stem/progenitor cells. Strikingly, Bmp5 gene inactivation or BMP signaling inhibition with a small molecule inhibitor are also sufficient to delay prostate and skin cancer initiation of Pten-deficient mice. Together, these results establish BMP5 as a key regulator of basal prostate stem cell homeostasis and identifies a potential therapeutic approach against Pten-deficient cancers.
Highlights
Maintaining homeostasis in adult tissues requires a fine balance between stem cell maintenance and differentiation (Morrison and Kimble, 2006)
This finding was confirmed by qRT-PCR analysis (Figure 1—figure supplement 1C) and by immunofluorescence staining of GATA3 in basal and luminal cells (Figure 1—figure supplement 1D)
We sought to determine whether GATA3 plays a role in prostate stem/progenitor cell homeostasis
Summary
Maintaining homeostasis in adult tissues requires a fine balance between stem cell maintenance and differentiation (Morrison and Kimble, 2006). Tissue homeostasis and regeneration of the prostate have been shown to rely on endogenous stem cell populations. Allograft assays and lineage-tracing experiments revealed the presence of stem cells in both the basal and luminal compartments (Choi et al, 2012; Goldstein et al, 2010; Wang et al, 2013). Adult stem cells are largely unipotent (Choi et al, 2012; Liu et al, 2011; Wang et al, 2013). Basal stem cells are constitutively multipotent in the developing prostate, where they populate the luminal cell layer through asymmetric cell divisions
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