Lymphatics and fibroblasts support intestinal stem cells in homeostasis and injury

• Published in: Cell stem cell Vol. 29; no. 8; pp. 1246 - 1261.e6
• Main Authors: Goto, Norihiro, Goto, Saori, Imada, Shinya, Hosseini, Sahar, Deshpande, Vikram, Yilmaz, Ömer H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.08.2022
• Subjects: Endothelial Cells; fibroblast; Fibroblasts; Homeostasis; Intestinal Mucosa - metabolism; intestinal stem cell; Intestines; Lgr5; lymphatic endothelial cell; RSPO3; Stem Cells - metabolism; RSPO3; lymphatic endothelial cell; Lgr5; intestinal stem cell; fibroblast
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2022.06.013

Lgr5+ intestinal stem cells (ISCs) depend on niche factors for their proper function. However, the source of these ISC niche factors and how they support ISCs in vivo remain controversial. Here, we report that ISCs depend on lymphatic endothelial cells (LECs) and RSPO3+GREM1+ fibroblasts (RGFs). In the intestine and colon, LECs are surrounded by RGFs and are located near ISCs at the crypt base. Both LECs and RGFs provide the critical ISC niche factor RSPO3 to support ISCs, where RSPO3 loss in both cell types drastically compromises ISC numbers, villi length, and repair after injury. In response to injury, LEC and RGF numbers expand and produce greater amounts of RSPO3 and other growth/angiocrine factors to foster intestinal repair. We propose that LECs represent a novel niche component for ISCs, which together with RGFs serve as the major in vivo RSPO3 source for ISCs in homeostasis and injury-mediated regeneration. [Display omitted] •LECs and RGFs are the major sources of mucosal RSPO3 in the small intestine and colon•RGFs reside close to ISCs and surround LECs•LECs and RGFs support ISCs and post-injury regeneration in vivo•LECs and RGFs expand to facilitate epithelial regeneration after injury Goto and colleagues identify lymphatic endothelial cells (LECs) and RSPO3+GREM1+ fibroblasts (RGFs) as stromal niche components of intestinal stem cells (ISCs). LECs and RGFs sustain ISCs through the production of RSPO3 and GREM1 in homeostasis. In injury, LECs and RGFs expand in number and produce growth/lymphangiocrine factors to orchestrate ISC-mediated repair.