IGF1R signaling in perinatal mesenchymal stem cells determines definitive hematopoiesis in bone marrow

During the transition from embryonic to adult life, the sites of hematopoiesis undergo dynamic shifts across various tissues. In adults, although bone marrow (BM) becomes the primary site for definitive hematopoiesis, the establishment of the BM niche for accommodating hematopoietic stem cells (HSCs) remains incompletely understood. Here, we reveal that perinatal BM mesenchymal stem cells (BMSCs) exhibit highly activated insulin-like growth factor 1 receptor (IGF1R) signaling compared with adult BMSCs (aBMSCs). Deletion of Igf1r in perinatal BMSCs (pBMSCs) hinders the transition of HSCs from the fetal liver to the BM in perinatal mice and disrupts hematopoiesis in adult individuals. Conversely, the deletion of Igf1r in aBMSCs, adipocytes, osteoblasts, or endothelial cells does not affect HSCs in the BM. Mechanistically, IGF1R signaling activates the transcription factor nuclear factor of activated T cells c1 in pBMSCs, which upregulates CXCL12 and other niche factors for HSC retention. Overall, IGF1R signaling in pBMSCs regulates the development of the BM niche for hematopoiesis.