Pituitary stem cells produce paracrine WNT signals to control the expansion of their descendant progenitor cells

Abstract

In response to physiological demand, the pituitary gland generates new hormone-secreting cells from committed progenitor cells throughout life. It remains unclear to what extent pituitary stem cells (PSCs), which uniquely express SOX2, contribute to pituitary growth and renewal. Moreover, neither the signals that drive proliferation nor their sources have been elucidated. We have used genetic approaches in the mouse, showing that the WNT pathway is essential for proliferation of all lineages in the gland. We reveal that SOX2+ stem cells are a key source of WNT ligands. By blocking secretion of WNTs from SOX2+ PSCs in vivo, we demonstrate that proliferation of neighbouring committed progenitor cells declines, demonstrating that progenitor multiplication depends on the paracrine WNT secretion from SOX2+ PSCs. Our results indicate that stem cells can hold additional roles in tissue expansion and homeostasis, acting as paracrine signalling centres to coordinate the proliferation of neighbouring cells.

Decoding the activated stem cell phenotype of the vividly maturing neonatal pituitary

“…Integrating our neonatal mouse AP scRNA-seq dataset with the recently published data of fetal human pituitary (Zhang et al, 2020) revealed considerable overlap, including an analogous WNT landscape. A pronounced WNT profile has recently also been reported in the early-postnatal (2- weeks-old) mouse pituitary (Russell et al, 2021). Interestingly, this study showed a paracrine- regulatory role of these stem cells, stimulating neighboring committed progenitor cells (as well as stem cells) to proliferate and expand.…”

“…Very recently, it has been reported that stem cells in early-postnatal (PD14) pituitary can function as autocrine and paracrine signaling center, among others stimulating proliferation within the own stem cell compartment (Russell et al, 2021). Interestingly, when co-cultured, neonatal (PD7) AP organoids (as developed from WT mice) elevate the outgrowth of organoids from adult AP (as established from ubiquitously tdTomato(tdT)-expressing R26 mT/mG mice) (Figure 2D), coinciding with increased proliferation of the adult AP organoid-constituting stem cells, showing a Ki67 + index reaching the one of neonatal AP-derived organoids (Figure 2D).…”

Single nucleus transcriptome and chromatin accessibility of postmortem human pituitaries reveal diverse stem cell regulatory mechanisms

“…Cell clusters were annotated manually using differential RNA expression of established pituitary marker genes. Key cell type markers included FSHB, LHB , and GNRHR for gonadotropes; GH1 for somatotropes; POMC for corticotropes; DIO2 for thyrotropes ( Cheung et al, 2018 ; Zhang et al, 2020 ); PRL for lactotropes; and SOX9 ( Rizzoti et al, 2013 ), LGR4 ( Russell et al, 2021 ), and RBPMS ( Cheung et al, 2018 ) for PSCs. A list of established markers used for the assignment of each cell type as well as markers identified in our datasets ( IQCJ-SCHIP1, NTNG1, EBF1, BNC2, ADGRA3 for PSCs) are listed in Table S2 .…”

“…Interestingly, expression of JUN and JUND , which have been implicated in the regulation of stemness in other tissues ( Pagin et al, 2021 ; Semba et al, 2020 ), was heterogeneous, with the highest expression associated with uncommitted clusters consisting mostly of male cells ( Figures 3B and 3C ). JUN has not been proposed as a PSC marker but was recently reported to be enriched in SOX2-positive cells through bulk RNA-seq in mice ( Russell et al, 2021 ). We therefore examined whether Jun showed co-expression with the stem cell marker Sox2 by mRNA in situ hybridization in male neonatal, juvenile, and adult mouse pituitaries.…”

Dynamic Expression of Imprinted Genes in the Developing and Postnatal Pituitary Gland

“…This population has the ability to self-renew and to give rise to terminally differentiated pituitary cells, in vitro and in vivo [63,81,82,84], and in response to injury [85]. Additionally, they secrete paracrine signalling factors, including WNT ligands, which promote the generation of new endocrine cells from more committed neighbouring progenitors [86]. Thus, adult progenitor/stem cells appear to contribute to the plasticity of the pituitary gland both directly and indirectly, enabling adaptation and generation of new endocrine cells in response to physiological events or injuries.…”