Prostacyclin is an endosteal bone marrow niche component and its clinical analog iloprost protects hematopoietic stem cell potential during stress

Hematopoietic stem cells (HSCs) with superior reconstitution potential are reported to be enriched in the endosteal compared to central bone marrow (BM) region. To investigate whether specific factors at the endosteum may contribute to HSC potency, we screened for candidate HSC niche factors enriched in the endosteal compared to central BM regions. Together with key known HSC supporting factors Kitl and Cxcl12, we report that prostacyclin/prostaglandin I2 (PGI2) synthase (Ptgis) was one of the most highly enriched mRNAs (>10‐fold) in endosteal compared to central BM. As PGI2 signals through receptors distinct from prostaglandin E2 (PGE2), we investigated functional roles for PGI2 at the endosteal niche using therapeutic PGI2 analogs, iloprost, and cicaprost. We found PGI2 analogs strongly reduced HSC differentiation in vitro. Ex vivo iloprost pulse treatment also significantly boosted long‐term competitive repopulation (LT‐CR) potential of HSCs upon transplantation. This was associated with increased tyrosine‐phosphorylation of transducer and activator of transcription‐3 (STAT3) signaling in HSCs but not altered cell cycling. In vivo, iloprost administration protected BM HSC potential from radiation or granulocyte colony‐stimulating factor‐induced exhaustion, and restored HSC homing potential with increased Kitl and Cxcl12 transcription in the BM. In conclusion, we propose that PGI2 is a novel HSC regulator enriched in the endosteum that promotes HSC regenerative potential following stress. Prostacyclin/prostaglandin I2 (PGI2) is a novel hematopoietic stem cell (HSC) regulatory factor enriched at the endosteum. PGI2 is synthesized by prostacyclin syntase (PTGIS) expressed mainly by osteoblasts, mesenchymal stromal cells and endothelial cells. Ex vivo and in vivo treatment with PGI2 analogs enhance HSC long‐term competitive repopulation potential and protect reconstituting HSC from stress.