Paper: Differential stem-and progenitor-cell trafficking by prostaglandin E2. doi:10.1038/nature11929
PGE2: Your Bone Marrow’s Best Babysitter
Stem cells are un-programmed cells that can develop into and replace the existing cells in the body as they age. Production and circulation of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs), or stem cells that ultimately differentiate into blood cells, is known to be regulated by stem cell interactions with gatekeeping cells called niche cells that line the bone marrow (Butler and Rafii 2013). Hematopoietic stem cell transplantation (HSCT) is a therapy used to treat a variety of cancers, hematological conditions, and even Lysosomal Storage Disorders (LSDs) such as Krabbe Disease—in this treatment, the patient’s HSCs and HPCs are ablated and replaced with hematopoietic stem and progenitor cells from a donor (Jin et al. 2006). Despite the frequency with which HSCT is utilized clinically, very little is understood regarding the regulatory mechanisms that mobilize HPCs and HSCs into the blood for purposes such as ablation prior to transplant. Now, a study by Hoggatt et al. (Nature 2013, 495, published online March 13, DOI: doi:10.1038/nature11929) identifies prostaglandin E2 (PGE2) signaling through the E-prostanoid 4 (EP4) receptor as a major source of restricting HSCs to HPCs to the bone marrow and demonstrates how clinical disruption of this signaling mobilizes HPC and HSC migration.
By assessing serum levels of multiple kinds of naturally occurring HPCs and two distinct but common phenotypes of HSCs in mice before and after NSAID treatment, the authors demonstrate that NSAID therapy results in both HPC and HSC mobilization from the marrow into the bloodstream. Repeating these studies with non-cyclooxygenase (COX) specific anti-inflammatory agents such as lipoxygenase inhibitors fails to induce HPC/HSC migration, indicating that NSAID therapy is specifically acting to reduce PGE2 levels through the COX pathway and that PGE2 may be implicated in regulating HPC/HSC trafficking. This hypothesis is further strengthened by mobilization of HPCs and HSCs following NSAID therapy and combination therapy of NSAID treatment and clinical granulocyte mobilizing agent G-CSF consistently observed in baboons and in healthy human patients.
The authors begin to establish a molecular mechanism through which PGE2 regulates HSC/HPC mobility by repeating these assays in knockout mice for each one of the four E-prostanoid receptors that normally bind PGE2 and identifying PGE2-EP4 receptor signaling disruption (in conjunction with HSC/HPC mobility assays and HPC/HSC mobility studies with EP receptor agonists and antagonists) as necessary for HPC/HSC migration. Then, the authors connect their findings to previous knowledge of HSC/HPC niche cells to further elucidate a molecular mechanism for the relationship between PGE2/EP4 signaling and HSC/HPC mobility by assessing the morphology and immunohistochemistry of osteoblast cells lining the niche in EP4 knockout mice and osteopontin knockout mice (osteopontin promotes HPC/HSC retention within bone marrow). Both types of mice experience reduced numbers of osteoclasts and decreased levels of hematopoietic supportive proteins as compared to wild-type mice. These levels further decrease following NSAID therapy, suggestive of the downstream biochemical and physiological consequences of PGE2/EP4 signal disruption that ultimately lead to HPC/HSC release from the marrow. The authors further refine the PGE2/EP4 signaling pathway by demonstrating differential regulation of HPC/HSC retention in stromal niche cells (regulate HPC retention) and hematopoietic niche cells (regulate HSC retention) through studies in inducible EP4 knockout mice.
Better understanding of NSAID-mediated PGE2/EP4 signaling and resulting HPC/HSC release may facilitate modification of hematopoietic stem cell transplantation to improve the intervention’s efficacy (Hoggatt et al. 2013) and provide more insight into the molecular mechanisms behind clinically observed cardiovascular protective effects conferred by NSAIDs such as aspirin (Jin et al. 2006).