Stromal Gli2 activity coordinates a niche signaling program for mammary epithelial stem cells

Abstract

The stem cell niche is a complex local signaling microenvironment that sustains stem cell activity during organ maintenance and regeneration. The mammary gland niche must support its associated stem cells while also responding to systemic hormonal regulation that triggers pubertal changes. We find that , the major Hedgehog pathway transcriptional effector, acts within mouse mammary stromal cells to direct a hormone-responsive niche signaling program by activating expression of factors that regulate epithelial stem cells as well as receptors for the mammatrophic hormones estrogen and growth hormone. Whereas prior studies implicate stem cell defects in human disease, this work shows that niche dysfunction may also cause disease, with possible relevance for human disorders and in particular the breast growth pathogenesis associated with combined pituitary hormone deficiency.

The Stromal Niche for Epithelial Stem Cells: A Template for Regeneration and a Brake on Malignancy

“…Recent work, however, has shown that in the pubertal and adult mammary gland Hedgehog activity mediated by the transcriptional effector Gli2 is required to specify a stromal cell niche signaling program involving expression of both paracrine factors and hormone receptors. The Gli2-specified niche supports mammary epithelial stem cells in pubertal and virgin adult mice (Zhao et al, 2017). In the mammary gland, Gli2 expression is initially induced by crosstalk with TGFβ1 produced by adjacent epithelial cells.…”

“…The mammary ductal defects in Gli2 ΔS mice thus are not rescued by growth hormone, but are rescued by local supplementation with the stromally-expressed paracrine factors induced by growth hormone (Igf1 and Wnt2b) (Zhao et al, 2017). This type of niche failure may explain the pathogenesis of certain human diseases sometimes associated with GLI2 mutation, including the deficient breast development and hormonal insensitivity associated with the human disorder combined pituitary hormone deficiency, (Darendeliler et al, 2011; Maghnie et al, 2006).…”

“…One emerging theme is that the Hedgehog (Hh) signaling pathway is active in stromal niches and specifies the expression of secreted niche signals. We discuss the stromal niche signaling programs specified by Hedgehog response in both the urinary bladder (Shin et al, 2011; Shin et al, 2014) and the mammary gland (Zhao et al, 2017), two organs of very distinct developmental origin but with the best defined adult epithelial stem cells and corresponding stromal niches. For bladder, we review evidence that niche-derived differentiation factors play an important role in restraining bladder cancer progression (Shin et al, 2014).…”

New paradigms for the Hedgehog signaling network in mammary gland development and breast Cancer

“…Recently, the tissue compartment specific roles of Gli2 have been further defined using Fsp-Cre;Gli2 conditional ablation animals [69]. This animal displays reduced proliferation, reduced stroma adjacent to mammary epithelium, hypoplasia, and reduced collagen deposition [69].…”

Identity of Gli1+ cells in the bone marrow

“…Differences in the biological activities of GLI1 and GLI2 are evident, since GLI1 knockout mice have no obvious phenotype [46], in contrast to GLI2 knockout mice which die at birth [47, 48]. Gli2 is important for several physiological functions [49], and possibly is expressed in a different subset of bone marrow cells than Gli1. Consequently, blocking Gli2 may cause several undesired side effects in the patients with myelofibrosis.…”