R spondin 2 regulates regeneration of the hematopoietic stem cell niche

Hematopoietic stem cells (HSCs) depend upon paracrine signals from bone marrow endothelial cells (BM ECs) and perivascular stromal cells for their maintenance and regeneration. Chemotherapy and total body irradiation (TBI) utilized in the curative treatment of cancer cause profound damage to the BM vascular niche, which impedes hematopoietic reconstitution. The mechanisms controlling regeneration of the HSC vascular niche are not well understood. We discovered that conditional deletion of R spondin 2 (Rspo2) from BM endothelial cells (ECs) impaired HSC regeneration in mice following total body irradiation (TBI), in association with decreased HSC survival. Mice lacking EC - Rspo2 expression demonstrated delayed regeneration of the BM vascular niche following TBI and Rspo2 - deficient BM ECs displayed defective angiogenesis. Conversely, systemic administration of R spondin 2 caused early restoration of the BM sinusoidal vascular niche in irradiated mice and augmented BM EC angiogenesis. Concordantly, R spondin 2 - treated mice displayed accelerated regeneration of the HSC pool. These studies suggest that BM ECs regulate the regeneration of the BM sinusoidal vascular niche via secretion of R spondin 2.