A symbiotic relationship between epithelial and stromal stem cells

Most adult tissues contain a pool of tissue-specific stem cells responsible for maintaining homeostasis. Adult stem cells are generally responsible for replacing lost cells over time and mediating tissue-regeneration after injury. An important component in maintaining epithelial stem cells is an environment rich in inductive growth factors secreted from the neighboring stromal cells (1). 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. These unique findings suggest that epithelial and stromal stem cells in the mouse prostate exhibit reciprocal signaling and maintain a symbiotic relationship.

The epithelium of the prostate is comprised primarily of a layer of basal cells, which reside against the basement membrane, and a layer of luminal cells that rest on top of the basal cells. Neuroendocrine cells represent a third epithelial cell-type that is found infrequently in the prostate with variable localization. Each epithelial cell-type can be distinguished based on expression of well-characterized markers (3). Epithelial stem cells in the prostate have gained considerable interest over the past several decades as new methods have been described for their isolation and characterization to better understand their behavior. A variety of in vivo experimental model systems have been used to identify prostate epithelial stem cells, in both the basal and luminal layers, capable of prostate regeneration. Importantly, either stem cell can respond to oncogenic transformation to initiate malignancy in the mouse (4–7), but basal stem cells can initiate human prostate cancer (8). In vitro model systems have been developed to determine cell-intrinsic mechanisms that regulate epithelial progenitor activity, making use of Matrigel, rich in basement membrane proteins and growth factors, to mimic the growth-stimulating effects of the stromal compartment on the epithelium (9, 10).

Several studies have determined that stromal-derived factors, including ligands in the Wnt, FGF, and TGF-β family, contribute to prostate epithelial homeostasis, regeneration, and transformation (11–13). 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. These findings bring up several important questions. Are all stromal layers maintained by a single stem cell? Are individual stromal cell layers maintained by restricted progenitor cells? Do nonstromal cells provide factors to promote stromal stem cell maintenance in a reciprocal fashion?

In 2012, Choi et al. (6) performed lineage tracing studies to determine that basal and luminal epithelial cells are largely self-sustained lineages in the postpubertal normal adult mouse prostate. These findings suggest that epithelial progenitor cells predominantly act in a unipotent manner to replace lost cells in their native environment, even though isolated stem cells are capable of generating all lineages upon transplantation. In PNAS, Peng et al. (2) perform lineage tracing in the stroma to address the same issue. The authors determine that Sma⁺ smooth muscle cells are replaced by Sma⁺ smooth muscle cells after castration-induced involution and androgen-mediated regeneration. These findings suggest a similar model to the epithelium, whereby each layer is likely maintained by its own unipotent progenitor. It remains to be seen whether there is a mouse prostate stromal stem cell at the top of the hierarchy that could generate all four layers in a transplantation assay.

One of the best-studied developmental regulators is Shh, which binds to receptors (Patched) on neighboring cells, resulting in downstream signaling through the Gli-1 transcription factor (15). Although previous studies have demonstrated that Shh inhibition can prevent mouse prostate regeneration (16), the role of specific cell-types in this effect remains unclear. Peng et al. (2) now determine that basal cells express Shh and stromal cells express the Shh-responsive target Gli-1. When combined with previous findings that stromal cells signal to basal cells via several growth factors, these data indicate that basal cells and stromal cells signal in both directions (Fig. 1). Future studies will be necessary to determine the precise role that Shh plays in maintaining the overall survival of the stroma and whether Shh signaling alters production of specific growth factors sent back to the mouse prostate epithelium to mediate regeneration. For example, Shh expressed in bladder epithelial stem cells signals to the mesenchyme to increase Wnt ligands, promoting both stromal and epithelial proliferation and tissue regeneration (17). In contrast, Shh signaling from epithelium to stroma in the rat prostate causes reduced mesenchymal expression of FGF10 and an inhibition of epithelial branching (18).

Fig. 1.

Reciprocal signaling between mouse prostate epithelial and stromal progenitor cells. Mouse prostate stromal cells signal to epithelium through Wnt ligands, fibroblast growth factors (FGFs), and transforming growth factor-β (TGF-β). Mouse prostate basal cells signal to a number of stromal cell-types through Sonic hedgehog.

The notion that epithelial stem cells signal to stromal stem cells to maintain a supportive growth environment has important implications for disease. Cancer cells regularly use normal stem cell mechanisms to promote their survival, suggesting that metastatic cancer cells and stromal cells likely exhibit reciprocal signaling to maintain a more supportive environment for malignant growth. In fact, the SDF-1/CXCR4 signaling axis is used both by limbal epithelial progenitor cells to attract supportive stromal cells (19), and by bone marrow stromal cells to attract metastatic prostate cancer cells (20). Continuing to define the reciprocal relationship between epithelial and stromal cells will lead to a better understanding of how cells maintain their survival and growth and may provide insights into treating metastatic disease.