Hematopoietic stem cells (HSCs) maintain the stem cell pool and constantly provide mature blood cells to the organism throughout its lifespan. The hematopoietic system is exquisitely sensitive to injury and bone marrow failure leads to serious clinical consequences. Further, HSCs are routinely used therapeutically, so a greater understanding of potential mechanisms regulating and protecting this critical population could be useful for restoring normal hematopoiesis after bone marrow injury. Regulation of HSCs occurs at least in part by the bone marrow microenvironment, or HSC niche. Prostaglandin E2 (PGE2) is a local mediator of injury with protective effects on many cell types, and could be important for microenvironmental control of HSCs. Our data demonstrate that 1) systemic PGE2 administration expands HSCs in vivo, 2) PGE2 levels increase in the bone marrow after myelosuppressive injury, and that 3) in vitro PGE2 protects primitive hematopoietic cells from death by cytotoxic chemotherapeutic agents. Based on these data, we hypothesize that PGE2 produced during myelosuppressive injury protects primitive hematopoietic cells by activating anti-apoptotic mechanisms. In order to verify this hypothesis, we propose the following specific aims:
Aim 1 : To determine if PGE2 protects primitive hematopoietic cells from injury Aim 2: To determine if PGE2 decreases apoptotic rates in primitive hematopoietic cells HSCs are widely used in humans for treatment of hematologic malignancies and bone marrow failure. Therefore, mechanisms to protect HSCs or regulate their cell fate choices to cause better engraftment and reconstitution would greatly increase their efficacy. Clinical trials investigating ex vivo PGE2 treatment of human cord blood stem cells prior to transplantation are currently underway and a greater understanding of the mechanisms underlying the effect of PGE2 would allow us to more specifically modulate HSCs for clinical use. Further, novel methods to protect the critically important HSC population from environmental or iatrogenic injury would be greatly beneficial. As it is already approved for clinical use in patients, PGE2 may be a useful treatment before, during or after chemotherapeutic or radiation treatments. In addition, we plan to determine the mechanisms that mediate the PGE2 effects, allowing for more specific targeting of these pathways and avoiding adverse effects of systemic PGE2 treatment.
Our long-term goal is to develop new therapeutic strategies to protect the critically important hematopoietic stem cell (HSC) population in the setting of bone marrow injury. We are investigating the protective role of prostaglandin E2, which is produced by the local HSC microenvironment in response to injury.
