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 I-2 (PGI(2)) synthase (Ptgis) was one of the most highly enriched mRNAs (>10-fold) in endosteal compared to central BM. As PGI(2) signals through receptors distinct from prostaglandin E-2 (PGE(2)), we investigated functional roles for PGI(2) at the endosteal niche using therapeutic PGI(2) analogs, iloprost, and cicaprost. We found PGI(2) 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 PGI(2) is a novel HSC regulator enriched in the endosteum that promotes HSC regenerative potential following stress.

Automated summary

The study reveals that PGI(2) enriched in the endosteum is a novel regulator of HSCs that promotes regenerative potential by enhancing STAT3 signaling in HSCs, protecting HSC potential in vivo, and restoring HSC homing potential.