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Protecting Haematopoietic Stem Cells from Radiation



Original article from STEM CELLS

"Prostaglandin E2 Increases Hematopoietic Stem Cell Survival and Accelerates Hematopoietic Recovery After Radiation Injury"

Modulation of the bone marrow microenvironment to allow the expansion and engraftment of hematopoietic stem and progenitor cells (HSPCs) following transplantation has shown some success (Adams et al, Bormberg et al, Calvi et al and Mendez-Ferrer et al).   Prostaglandin E2 (PGE2) has recently been shown to improve HSPC repopulating ability through the activation of EP2 and EP4 receptors (Goessling et al, Hoggatt et al and North et al) but little is known of the distinct mechanisms behind this action (Frisch et al).   In a recent study published in Stem Cells, researchers from the laboratory of Laura M. Calvi at the University of Rochester School of Medicine, New York have shown that PGE2 treatment in naïve mice inhibits apoptosis of HSPCs without changing their proliferation rate and decreased the loss of functional HSPCs following radiation injury, as demonstrated both phenotypically and by their increased reconstitution capacity (Porter et al).
Initial apoptosis assays found that PGE2 treatment of bone marrow HSPCs in naïve mice inhibited apoptosis, compared to vehicle-treated HPSCs (control), in both the short-term-hematopoietic stem cell/multipotent progenitor (ST-HSC/MPP) populations of cells and the phenotypic long-term hematopoietic stem cells (LT-HSCs).   Next, bone marrow mononuclear cells (BMMCs) were treated ex vivo either with vehicle or PGE2, followed by cytarabine (Ara-C) to induce cell death, which found that PGE2 treatment decreased the rate of apoptosis in lineage Sca-1+ c-Kit+ (LSK) cells.   In vivo analysis using a sublethal total body irradiation (TBI) murine model and the more stable PGE2 analog 16,16-dimethyl-PGE2 (dmPGE2) found that 24 hours post irradiation,  dmPGE2-treated mice had significantly more LSK cells than controls across various radiation doses, and surviving HSPCs were deemed functional by competitive repopulation assays.   Additionally, although BMMC engraftment following transplantation was low, dmPGE2-treated mice had a superior BMMC repopulating ability.

The cellular makeup of the bone marrow was then assessed, which found that while in vivo dmPGE2 treatment did not significantly change the total number of bone marrow cells, after TBI, in vivo dmPGE2 treatment increased the number of immature progenitors with significant repopulatingpotential (HPP-CFCs) at 24 and 72 hours and increased mature lineage-restricted myeloid progenitors (LPP-CFC) at 72 hours, with no effect on myeloid progenitor/precursors at 24 or 72 hours observed.   At 14 days, no detrimental effect of dmPGE2 treatment was observed on HPP or LPP numbers, although myeloid colonies were increased, perhaps suggesting that dmPGE2 may have a microenvironmental effect on HSPCs.   Peripheral blood counts, indicative of the production of mature blood cells, were similar between control and treated mice at 24 days, suggesting that the antiapoptotic effect of dmPGE2 is likely limited to immature hematopoietic cells.  However, there was an accelerated recovery of platelets, neutrophil counts and haemoglobin levels in dmPGE2-treated mice compared with vehicle-treated controls.

Assessment of the release of PGE2 from the bone marrow in response to TBI found that endogenous PGE2 was significantly elevated at 8-hours post-TBI and this was sustained long after the time of injury, which was supported by the increased expression of cyclo-oxygenase 2 (Cox2), a critical inducible enzyme that regulates PGE2 synthesis.   Isolation and analysis of both CD45+ hematopoietic and CD45− non-haematopoietic cells enriched for osteolineage cells (Frisch et al) found that after TBI Cox2 expression was significantly increased in CD45− microenvironmental cells and remained unchanged in CD45+ hematopoietic cells, while Cox2 protein was detected on cells lining the endosteal or trabecular bone surfaces in the marrow of irradiated mice.   PGE2 treatment itself also increased Cox2+ cells in the bone marrow compared with vehicle-treated controls, specifically in the CD45+ cell fraction, which was perhaps a non- microenvironmental effect.   Finally, macrophages, known to be relatively radioresistant and which express Cox2 and produce PGE2 (Fournier et al), were found to increase and persist in the bone marrow post-TBI in both vehicle and dmPGE2-treated mice, while the total number of macrophages in the bone marrow was similar.
Overall, this study shows that PGE2 appears to promote HSPC expansion through the inhibition of apoptosis, and increases the survival of the pool of functional immature hematopoietic cells in the bone marrow after radiation injury, allowing accelerated recovery of peripheral blood cell counts.   Additionally, PGE2 was also shown to have initiate microenvironmental changes in specific subpopulations of macrophages in the bone marrow leading to increased HSPC survival and hematopoietic recovery following radiation injury.   In a therapeutic setting, this study suggests that PGE2 agonists may represent an approach to accelerate recovery of peripheral blood counts in patients following myelosuppressive treatments or injuries.



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Study originally appeared in Stem Cells.

STEM CELLS correspondent Stuart P Atkinson reports on those studies appearing in current journals that are destined to make an impact on stem cell research and clinical studies.