Single- cell resolution of intestinal regeneration in pythons without crypts illuminates conserved vertebrate regenerative mechanisms

• 成果类型: Article
• 署名作者: Westfall, Aundrea K.; Gopalan, Siddharth S.; Kay, Jarren C.; Tippetts, Trevor S.; Cervantes, Margaret B.; Lackey, Kimberly; Chowdhury, Saiful M.; Pellegrino, Mark W.; Castoe, Todd A.
• 署名单位: University of Texas System; University of Texas Arlington; University of Texas System; University of Texas Southwestern Medical Center; University of Alabama System; University of Alabama Tuscaloosa; University of Texas System; University of Texas Arlington
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12773
• DOI: 10.1073/pnas.2405463121
• 发表日期: 2024-10-22
• 关键词: burmese python; diabetes remission; gastric bypass; stem-cells; expression; responses; notch1; gene; dll4; metabolism

摘要

Canonical models of intestinal regeneration emphasize the critical role of the crypt stem cell niche to generate enterocytes that migrate to villus ends. Burmese pythons possess extreme intestinal regenerative capacity yet lack crypts, thus providing opportunities to identify noncanonical but potentially conserved mechanisms that expand our understanding of regenerative capacity in vertebrates, including humans. Here, we leverage single- nucleus RNA sequencing of fasted and postprandial python small intestine to identify the signaling pathways and cell-cell interactions underlying the python's regenerative response. We find that python intestinal regeneration entails the activation of multiple conserved mechanisms of growth and stress response, including core lipid metabolism pathways and the unfolded protein response in intestinal enterocytes. Our single- cell resolution highlights extensive heterogeneity in mesenchymal cell population signaling and intercellular communication that directs major tissue restructuring and the shift out of a dormant fasted state by activating both embryonic developmental and wound healing pathways. We also identify distinct roles of BEST4+ enterocytes in coordinating key regenerative transitions via NOTCH signaling. Python intestinal regeneration shares key signaling features and molecules with mammalian gastric bypass, indicating that conserved regenerative programs are common to both. Our findings provide different insights into cooperative and conserved regenerative programs and intercellular interactions in vertebrates independent of crypts which have been otherwise obscured in model species where temporal phases of generative growth are limited to embryonic development or recovery from injury.