YFP+ and YFP– stromal cells isolated from intestinal ulcers of indomethacin treated LTBRYFP mice

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 pro-differentiation PDGFRaHigh intestinal stromal lineage originating from postnatal LTßR+ perivascular stromal progenitors. Genetic blockage of this lineage increased the intestinal stem cells pool while decreasing epithelial and immune maturation at weaning age, leading to reduced postnatal growth and dysregulated repair responses. Ablating PDGFRa in the LTßR stromal lineage demonstrates that PDGFRa has a major impact on the lineage fate and function, inducing a transcriptomic switch from pro-stemness genes such as Rspo3 and Grem1 to pro-differentiation factors including BMPs, retinoic acid and laminins, and on spatial organization within the crypt-villus and repair responses. Our results show that PDGFRa-induced transcriptomic switch in intestinal stromal cells is required in the first weeks after birth to coordinate postnatal intestinal maturation and function. Overall design: CD45-CD31- stromal cells expressing YFP (YFP+) or not (YFP-) were isolated by FACS from the intestinal ulcers of indomethacin treated LTßRYFP mice to perform RNA sequencing