3028 – ENHANCING AGED HEMATOPOIETIC STEM CELL FUNCTION WITH PROSTAGLANDIN E2

Abstract

Aging of human hematopoiesis is associated with increased frequency and clonality of hematopoietic stem cells (HSC), along with functional compromise and myeloid bias, and donor age is a significant variable in survival after HSC transplantation. No clinical methods exist to enhance aged HSC function, and little is known regarding how aging affects molecular responses of HSC to biological stimuli. Exposure of young fish, mouse, nonhuman primate and human HSC to 16,16-dimethyl prostaglandin E2 (dmPGE2) can enhance transplantation, but the effect of dmPGE2 on aged HSC has not yet been tested. Bone marrow cells from young (3 mo) and aged (25 mo) C57BL/6J mice were pulsed ex vivo with dmPGE2 or vehicle prior to competitive transplantation. DmPGE2 enhanced long-term repopulation of aged grafts in primary and secondary transplantation, increasing final chimerism an average of 27%, similar to the average increase of 21% for young grafts (both p<0.05). RNA sequencing of highly purified HSC sorted after dmPGE2 pulse indicated CREB1, an established mediator of PGE2 signaling, remained the most activated regulator in both young and aged HSC, suggesting the major molecular responses to dmPGE2 are similar in young and old. A subset of genes differentially affected by dmPGE2 in young and old HSC included numerous phosphoproteins induced in young but already elevated with age. However, the highest-scoring cellular functions of dmPGE2-induced genes remained the same in young and aged HSC, including increased cell survival, homeostasis, synthesis of D-glucose, cell movement, self-renewal, differentiation, and decreased apoptosis. HSC expression of the PGE2 receptor EP4, implicated in HSC function, increased with age in both mRNA and surface protein. This work suggests that aging does not alter the major dmPGE2 response pathways in HSC, and dmPGE2 is able to enhance aged HSC function.