Professor Oregon Health & Science Univ, Oregon, United States
Abstract: Intestinal epithelial development and homeostasis critically relies upon balanced stem cell proliferation, involving slow-cycling/label-retaining, and active-cycling/canonical Wnt-dependent intestinal stem cell (ISC) subtypes. However, how different subpopulations may be regulated to maintain homeostasis is not completely understood. Further, ISC regulation during development remains poorly understood but has important implications for establishing key mechanisms governing tissue maintenance. The developing intestine provides a less complex paradigm to investigate ISC subpopulations, their contribution to the tissue and pathways that regulate their proliferative status. We definitively identified Bmi1+ cells as functional stem cells in early murine intestinal development and determine that they are established prior to the existence of Lgr5-expressing ISCs. Lineage-tracing and single cell RNA-sequencing analyses reveal that Bmi1+ ISC can trace to Lgr5+ ISCs and other differentiated lineages in the developing epithelia. Initially highly proliferative Bmi1+ ISCs transition to slow-cycling states as Lgr5+ ISCs emerge. Omics analyses followed by in vitro functional validation established the non-canonical Wnt signaling pathway as a key regulator of the proliferative Bmi1+ cell state. These novel findings highlight the dynamic interplay between stem cell populations and the opposing Wnt pathways that govern intestinal stem cell proliferation during development. Our findings have implications not only for tissue development, but also for tissue homeostasis, regeneration and tumorigenesis, where these fundamental developmental mechanisms are re-expressed to underlie epithelial proliferation.
