Sonic hedgehog signals to multiple prostate stromal stem cells that replenish distinct stromal subtypes during regeneration

Abstract

Significance Sonic hedgehog (SHH) signaling regulates adult stem cells in many self-renewing organs. However, whether SHH also regulates adult stem cells in tissues like the prostate is unclear. Improving therapy for prostate diseases, including benign prostatic hyperplasia and prostate cancer, will require a better understanding of the key signaling pathways that regulate prostate homeostasis and regeneration. We show that SHH signals from basal epithelial cells to the surrounding stroma in the adult prostate. Moreover, SHH responding cells repopulate the stroma and exhibit long-term self-renewal capacity during multiple rounds of involution and regeneration. Furthermore, we identified four stromal subtypes and present evidence for a model in which the three ductal stromal subtypes are maintained largely by distinct unipotent stem/progenitor cells.

Roles for Hedgehog signaling in adult organ homeostasis and repair

“…However, the experiment has not been repeated and the cell type that responded to HH was not identified. SHH was recently found to be secreted by basal cells within the epithelial compartment of the prostate, which are likely to be the main source of HH within the prostate ducts (Peng et al, 2013). In the same study, Gli1 was shown to be expressed in four subtypes of stromal cells, each possibly maintained by a distinct unipotent progenitor.…”

“…In the same study, Gli1 was shown to be expressed in four subtypes of stromal cells, each possibly maintained by a distinct unipotent progenitor. Following multiple rounds of involution and regeneration, GLI1+ stromal cells were shown to continuously self-renew (Peng et al, 2013), indicating that epithelial SHH signals to bona fide stem cells in the prostate stroma in a paracrine fashion, much like during prostate development (Shaw and Bushman, 2007). Determining the identity of SHH-responding stem cells in the prostate is a priority, as SHH signaling has been implicated in prostate cancer , and overexpression of SHH ligand in the adult prostate is sufficient to induce neoplasia (Chang et al, 2011).…”

“…In the adult, HH continues to signal to discrete populations of stem and progenitor cells within various organs, including the brain (Ahn and Joyner, 2005;Ihrie et al, 2011;Machold et al, 2003), skin (Brownell et al, 2011), prostate (Peng et al, 2013) and bladder (Shin et al, 2011), among others. Whether HH signaling in the adult functions to control proliferation, specification and/or plasticity, and the mechanism by which this occurs, remain unclear.…”

A symbiotic relationship between epithelial and stromal stem cells

“…Although it is to the benefit of the epithelial stem cell to ensure the survival of the stroma, little is known about how stromal cells are maintained long-term. In PNAS, Peng et al (2) suggest that prostate stromal cell heterogeneity is maintained not by a single stem cell but by several distinct stromal stem cells. The authors describe a process whereby epithelial stem cells signal back toward stromal stem cells via Sonic hedgehog (Shh) signaling.…”

“…Although nonepithelial cell-types of the prostate are considered an important component in maintaining epithelial stem cells, the degree of heterogeneity has not been well characterized. Based on differential expression of CD34 and smooth muscle actin (SMA), Peng et al (2) identify four distinct layers of stromal cells in the proximal region of the mouse prostate, the area closest to the urethra where the majority of epithelial progenitor cells reside (14). The authors label these layers subepithelial fibroblasts, smooth muscle cells, wrapping cells, and interstitial fibroblasts.…”