Generation of a prostate from a single adult stem cell

Abstract

The existence of prostate stem cells (PSCs) was first postulated from the observation that normal prostate regeneration can occur after repeated cycles of androgen deprivation and replacement in rodents. Given the critical role of PSCs in maintaining prostate tissue integrity and their potential involvement in prostate tumorigenesis, it is important to define specific markers for normal PSCs. Several cell-surface markers have been reported to identify candidate PSCs, including stem cell antigen-1 (Sca-1, also known as Ly6a), CD133 (Prom1) and CD44 (refs 3-10). However, many non-PSCs in the mouse prostate also express these markers and thus identification of a more defined PSC population remains elusive. Here we identify CD117 (c-kit, stem cell factor receptor) as a new marker of a rare adult mouse PSC population, and demonstrate that a single stem cell defined by the phenotype Lin(-)Sca-1(+)CD133(+)CD44(+)CD117(+) can generate a prostate after transplantation in vivo. CD117 expression is predominantly localized to the region of the mouse prostate proximal to the urethra and is upregulated after castration-induced prostate involution-two characteristics consistent with that of a PSC marker. CD117(+) PSCs can generate functional, secretion-producing prostates when transplanted in vivo. Moreover, CD117(+) PSCs have long-term self-renewal capacity, as evidenced by serial isolation and transplantation in vivo. Our data establish that single cells in the adult mouse prostate with multipotent, self-renewal capacity are defined by a Lin(-)Sca-1(+)CD133(+)CD44(+)CD117(+) phenotype.

Attributes of adult stem cells

“…Bipotential cells have also been isolated based on p63 expression [139]. Remarkably, single murine prostatic cells can form complete functional acini when transplanted under the renal capsule, these cells expressing CD117, CD44, CD133 and Sca-1 [140].…”

Understanding cancer stem cell heterogeneity and plasticity

“…Immunostaining shows that the CD117 + (c-Kit, stem cell factor receptor) population is enriched proximal to the urethra, predominantly in the basal layer (~3% of total basal cells). Fractionated CD117 + cells combined with rat UGSM (urogenital sinus mesenchyme) and transplanted under the kidney capsules can regenerate prostate-like structures comprising cells of the basal (K14 + ), luminal (K18 + ), and, for the first time, neuroendocrine (synaptophysin + ) lineages, thereby demonstrating tripotency [17]. Single cell-reconstitution assays achieved successful engraftments in 14 of 97 single cell transplantations (along with rat UGSM).…”

“…Again, the regenerated tubules are of clonal origin and contain both basal (e.g., K5 + , p63 + ) and luminal (K8 + ) cells providing evidence for the existence (and identity) of bipotential normal mouse prostatic basal stem cells. Further purification using the Lin -Sca-1 + CD133 + CD44 + CD117 + marker profile reveals multipotent prostate stem cells in the basal compartment [17]. Immunostaining shows that the CD117 + (c-Kit, stem cell factor receptor) population is enriched proximal to the urethra, predominantly in the basal layer (~3% of total basal cells).…”

“…Single cell-reconstitution assays achieved successful engraftments in 14 of 97 single cell transplantations (along with rat UGSM). The single cell-derived outgrowths also contain all three principal prostate cell types (basal, luminal, and neuroendocrine), with luminal cells expressing the critical differentiation-related homeobox protein, Nkx3-1, and the terminal differentiation marker, probasin, suggesting that the reconstituted tubules possessed functional secretory activities [17].…”

The stem cell factor (SCF)/c-KIT signalling in testis and prostate cancer

“…These cancer stem cells seem to be associated with the basal layer of prostate epithelium; a region reported to have high expression levels of c-KIT (Ceder et al 2017;Leong et al 2008). Moreover, it was demonstrated that tumorigenesis induced by prostate cancer stem cells is accompanied by the increased expression of c-KIT (Peng et al 2015).…”