Abstract
Aging of hematopoiesis is associated with increased frequency and clonality of hematopoietic stem cells (HSCs), along with functional compromise and myeloid bias, with donor age being a significant variable in survival after HSC transplantation. No clinical methods currently exist to enhance aged HSC function, and little is known regarding how aging affects molecular responses of HSCs to biological stimuli. Exposure of HSCs from young fish, mice, nonhuman primates, and humans to 16,16-dimethyl prostaglandin E2 (dmPGE2) enhances transplantation, but the effect of dmPGE2 on aged HSCs is unknown. Here we show that ex vivo pulse of bone marrow cells from young adult (3 mo) and aged (25 mo) mice with dmPGE2 prior to serial competitive transplantation significantly enhanced long-term repopulation from aged grafts in primary and secondary transplantation (27 % increase in chimerism) to a similar degree as young grafts (21 % increase in chimerism; both p < 0.05). RNA sequencing of phenotypically-isolated HSCs indicated that the molecular responses to dmPGE2 are similar in young and old, including CREB1 activation and increased cell survival and homeostasis. Common genes within these pathways identified likely key mediators of HSC enhancement by dmPGE2 and age-related signaling differences. 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 HSCs which mediate enhancement of both young and old HSC function, with significant implications for expanding the therapeutic potential of elderly HSC transplantation.
Highlights
Hematopoietic stem cells (HSCs) are responsible for continual replacement of all blood cell types, and hematopoietic stem cells (HSCs) transplantation (HSCT) is a life-saving option for many patients with hematologic diseases
While many factors are thought to contribute to HSC aging, including cell-intrinsic and nichemediated[2,12,13], specific molecular pathways functionally linked to aged HSC defects are not well characterized, and no treatment exists to enhance aging hematopoiesis or augment the transplantation potential of these cells
We have previously shown that pulse exposure to dimethyl prostaglandin E2 (dmPGE2) enhances homing, survival, and proliferation for both young (2–3 mo) mouse bone marrow (BM) and human cord blood derived CD34 + cells, which was associated with increased CXCR4 and Survivin expression, decreased apoptosis, and increased HSC proliferation[19,20]
Summary
Hematopoietic stem cells (HSCs) are responsible for continual replacement of all blood cell types, and HSC transplantation (HSCT) is a life-saving option for many patients with hematologic diseases. HSC function and engraftment capacity drastically decrease with age[1,2,3,4,5,6,7]. We have previously shown that pulse exposure to dmPGE2 enhances homing, survival, and proliferation for both young (2–3 mo) mouse BM and human cord blood derived CD34 + cells, which was associated with increased CXCR4 and Survivin expression, decreased apoptosis, and increased HSC proliferation[19,20]. DmPGE2 pulse exposure augmented competitiveness of human cord blood grafts in a Phase I clinical trial with double cord blood transplantation[21], and has been used clinically to enhance engraftment of gene modified HSCs22. DmPGE2 is known to enhance HSC function and has potential for clinical translation
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