Title: Intestinal stem cells in the upper crypt are marked by ATAD2 and regulated by a neural niche
Abstract: Intestinal epithelial homeostasis is sustained by stem cells, yet the identity and regulation of long-lived isthmus stem cells remain incompletely understood. The current intestinal epithelial model proposes that Lgr5_ crypt-base columnar (CBC) cells represent the sole intestinal stem cell compartment. We have utilized an unbiased bioinformatic to analyze single cell profiles of intestinal crypt cells and found that stemness potential exists largely in the isthmus region, not in the CBC. This analysis also led to the identification of a new intestinal stem cell gene signature. Using intersection lineage tracing, we identify Ki67+/SOX9+ and LGR4+/SOX9+ cells as long-lived isthmus stem cells in the small intestine. We have validated one of the new signature ISC gene markers, ATAD2, and though lineage tracing demonstrated durable multilineage differentiation in homeostasis, and regeneration capacity following injury, including after radiation and LGR5+ cell ablation. ATAD2 contributes to more open chromatin in these upper crypt stem cells and activation of downstream MYC/E2F target genes. They are also regulated by a neural niche that activates CGRP-dependent signaling through RAMP1. Inhibition of the CGRP/RAMP1 axis impairs intestinal regeneration. Together, these findings identify a neural niche-regulated isthmus stem cell population that drives intestinal homeostasis and regeneration.
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