Self-renewal of progenitors of the bone and thymic epithelium is regulated by Wnt signaling [electronic resource]

Among the myriad of roles that Wnts play in biology, one of its most well-known functions is as a self-renewal signal for stem and progenitor cells. As we delve deeper into studying the mechanism(s) by which Wnt signaling effects a self-renewing outcome on the stem/progenitor cells, knowing where the Wnts come from becomes an imperative. In other words, what are the niche cells? It has been difficult to study the Wnt-producing niches as the Wnt family comprises of as many as 19 functionally redundant proteins, rendering loss-of-function experiments of individual Wnt genes liable to muted phenotypes, if any. The bone field is a prime example where sparingly little is known about the Wnt producers, even though there has been intensive studies on the Wnt responders and the functions of Wnt signaling in the osteolineage cells. Efforts to investigate how Wnts secreted by specific sources contribute to osteogenesis have just begun due to the recent availability of tools that allow for targeting of the post-translational processes necessary for Wnt secretion. Hence, we set out to identify the Wnt producers during bone development and their role in osteogenesis. Using a combination of in situ hybridization, lineage tracing and in vivo genetics, we found that osteolineage precursors direct their own self-renewal by producing their own Wnts and responding to them, thus setting up an autocrine Wnt signaling loop. This is interesting because Wnt signaling has generally been thought to promote osteogenic differentiation, and has not been associated with the maintenance of immature populations. More importantly, we are starting to unravel the molecular basis for how osteolineage precursors determine their own behavior. While Wnt signaling has been shown to regulate the stem/progenitor cells of numerous tissues, its involvement in many other tissues and cell types, the thymic epithelium for example, is still unclear. Hence, we postulated that Wnt signaling could regulate the self-renewal of the stem/progenitors of thymic epithelial cells (TECs). Indeed, through transplantation, we found that Wnt-responsiveness enriches for TEC progenitors that can create an ectopic thymus microenvironment capable of supporting T cell development, which is the first demonstration of a transplantable functional postnatal TEC population. Complementary to the transplantation study, we also performed lineage tracing to track the fates of Wnt-responsive TEC stem/progenitor cells. Unexpectedly, we found that the cortical lineage-restricted TEC (cTEC) progenitor is regulated by Wnt signaling, while other progenitors like the medullary lineage-restricted TEC progenitor are not. Hence, we have uncovered the first instance of differential regulation of the TEC progenitor populations. In addition, we also present the first conclusive evidence that cTEC progenitors exist, and in vivo proof that they contribute to cTEC maintenance over the long term. Hence, based on the status of Wnt signaling response, we can delineate cell fates and lineage potential of the various progenitor populations in the thymic epithelium. In summary, we have implicated Wnt signaling in the self-renewal of two populations whose self-renewal mechanisms were previously unclear -- the osteolineage precursors and cTEC progenitors. In the process, we discovered possible ways by which these cells maintain their identity, and more importantly, how Wn3t signaling specifically contributes to the maintenance of the bone and thymus. As the fields proceed to learn more about the how Wnt signaling promotes self-renewal, it is also important to take the knowledge to a broader perspective and ask, how does the tissue ensure which cells are able to respond to Wnt signaling and which are not, especially in contexts where Wnt signaling has multiple functions in one tissue. By following the basic principle of identifying the Wnt producers, Wnt responders, and possibly the Wnt inhibitors, we will achieve a more complete understanding of Wnt signaling's role at the tissue level, and eventually, at the level of the organism.

Keywords: Cancer Biology.
Advisor: Nusse Roel
Desai Tushar advisor. Thesis advisor
Fuller Margaret
Weinberg Kenneth (Pediatric oncologist) advisor. Thesis advisor
Wu Joy