PDGFRα-induced stromal maturation is required to restrain postnatal intestinal epithelial stemness and promote defense mechanisms

• DOI: 10.1016/j.stem.2022.04.005
• Publication Date: 2022-05-05T14:50:37Z
• Authors: Jean-Marie Jacob; Selene E. Di Carlo; Igor Stzepourginski; Anthony Lepelletier; Papa Diogop Ndiaye; Hugo Varet; Rachel Legendre; Etienne Kornobis; Adam Benabid; Giulia Nigro; Lucie Peduto
• Keywords: IESC; perivascular; stromal niches; 0303 health sciences; Receptor, Platelet-Derived Growth Factor alpha; rsubepithelial fibroblasts; [SDV]Life Sciences [q-bio]; Stem Cells; Cell Differentiation; epithelial differentiation; [SDV] Life Sciences [q-bio]; Intestines; Lymphotoxin beta receptor; intestinal barrier; intestinal repair; Mice; 03 medical and health sciences; inflammation; Lymphotoxin beta Receptor; postnatal intestinal maturation; Animals; Intestinal Mucosa; intestinal epithelial stem cells; Defense Mechanisms

After birth, the intestine undergoes major changes to shift from an immature proliferative state to a functional intestinal barrier. By combining inducible lineage tracing and transcriptomics in mouse models, we identify a prodifferentiation PDGFRαHigh intestinal stromal lineage originating from postnatal LTβR+ perivascular stromal progenitors. The genetic blockage of this lineage increased the intestinal stem cell pool while decreasing epithelial and immune maturation at weaning age, leading to reduced postnatal growth and dysregulated repair responses. Ablating PDGFRα in the LTBR stromal lineage demonstrates that PDGFRα has a major impact on the lineage fate and function, inducing a transcriptomic switch from prostemness genes, such as Rspo3 and Grem1, to prodifferentiation factors, including BMPs, retinoic acid, and laminins, and on spatial organization within the crypt-villus and repair responses. Our results show that the PDGFRα-induced transcriptomic switch in intestinal stromal cells is required in the first weeks after birth to coordinate postnatal intestinal maturation and function.