Mesenchymal Stromal Cells regulate human Hematopoietic Stem Cell survival, engraftment and regeneration via PGE2/cAMP signaling pathway

Abstract

Ionizing radiation (IR) and chemotherapies severely impair hematopoietic stem and progenitor cell (HSPC) function, causing bone marrow failure and secondary malignancies. Mesenchymal stromal cells (MSCs) within the hematopoietic niche support HSPC survival and regeneration, but the underlying pro-survival mechanisms remain incompletely understood. Here, we show that MSCs suppress IR-induced apoptosis in human HSPCs and preserve their regenerative capacity. Transcriptomic analyses identified a robust induction of CREB target genes in HSPCs upon MSC contact, driven by MSC-secreted prostaglandin E2 (PGE2) via cAMP signaling. While MSC-derived PGE2 predominantly protected quiescent HSPCs from IR-induced apoptosis, direct pharmacological elevation of cAMP with Forskolin/IBMX (FSKN/IBMX) effectively shielded both quiescent and cycling HSPCs, significantly enhancing their engraftment and self-renewal. Mechanistically, cAMP pathway activation reduced pro-apoptotic ASPP1 and PUMA expression, elevated p21, and stabilized anti-apoptotic MCL1 and BCL-XL proteins. Collectively, our study uncovers an MSC-driven PGE2/CREB signaling pathway critical for human HSPC regeneration, highlighting pharmacological modulation of this axis as a promising strategy to mitigate DNA damage-induced myelosuppression and improve transplantation outcomes.