Hematopoietic stem cell niche generation and maintenance are distinguishable by an epitranscriptomic program

The niche is typically considered as a pre-established structure sustaining stem cells. Therefore, the regulation of its formation remains largely unexplored. It is unknown whether distinct molecular mechanisms control the establishment versus maintenance of a stem cell niche. To address this, we compared perinatal with adult bone marrow mesenchymal stromal cells (MSCs), a key component of the hematopoietic stem cell (HSC) niche. MSCs exhibited an enrichment in genes mediating m6A mRNA methylation regulation at the perinatal stage and downregulated the expression of Mettl3, the m6A methyltransferase, shortly after birth. Deletion of Mettl3 from developing MSCs led to excessive osteogenic differentiation and a severe HSC niche formation defect, which was rescued by deletion of Klf2, a target of m6A. In contrast, deletion of Mettl3 from MSCs postnatally did not affect HSC niche or hematopoiesis. Stem cell niche generation and maintenance thus depend on divergent molecular mechanisms, which may be exploited for regenerative medicine. Overall design: We performed scRNA-seq on non-hematopoietic cells in the limb bone marrow of two-week-old control and Prx1-cre;Mettl3-fl/fl mice