Cell Cycle Regulation, Apoptosis, Survival,
and Homing of Hematopoietic Stem Cells -
Old Players with New Roles

If you want to spend part of your Sunday afternoon learning about cell cycle regulation and apoptosis and their effects on hematopoiesis in general, one of the simultaneous oral sessions at 4:30 p.m. offers you just that opportunity.

Running in parallel will be another session focusing on stem cell homing and engraftment, and both sessions have an excellent collection of presentations. How Slug protects hematopoietic progenitors from radiation, how Cdc42 regulates erythropoiesis, why Fanconi anemia cells are hypersensitive to oxidative stress, and how heat shock cognate protein 70 regulates mRNA stability are some of the topics that will be discussed in the apoptosis/cell cycle regulation session. Dr. Wen-Shu Wu, from the Dana-Farber Cancer Institute, will explain how Slug plays an antiapoptotic role in radioprotecting myeloid progenitors, but not stem cells, most likely through a downstream antagonizing effect on p53 which leads to the inhibition of the radiation-activated mitochondria- dependent apoptotic pathway. Work from the laboratory of Dr. Xiaoling Zheng in Cincinnati utilizing conditional knockout mice will highlight the broad effect Cdc42 has on the survival, cytoskeleton regulation, and homing of HSC, and on erythropoiesis in particular.

The next two presentations in this session will focus on how Fanconi anemia stem cells handle oxidative stress. In the first, Dr. Grover Bagby (Oregon Health and Sciences University) outlines the role of STAT signaling in oxidative stress and maintains that FA-D2 in a FA-C dependent fashion promotes survival through maintenance of proper STAT signaling in response to oxidative stress. In the second, Dr. Zhang from the Cincinnati Children’s Hospital demonstrates that oxidative stress resulting from reoxygenation induces premature senescence in Fancc-/- BM through ATM signaling to p53.

Molecules that have a previously established role in hematopoiesis are finding new involvements in homing and trafficking of hematopoietic stem cells to and from the bone marrow. The Stem Cell Homing and Engraftment Simultaneous Session at 4:30 p.m. will discuss the roles of Rac1 and Rac2 Rho GTPases, RhoH, Plasmin, plasminogen activator, the alpha-4 integrin, CD45 phosphatase, and CXCR4 in homing, survival and adhesion, and self-renewal of stem cells. Work from the laboratory of Dr. David Williams in Cincinnati with Rac1 and Rac2 knockout mice revealed that engraftment and mobilization of stem cells are not mirror image processes and have distinct regulatory elements whereby, for example, Rac1 is more involved in engraftment. A newly identified Rho GTPase, RhoH was found to be a negative regulator of proliferation, survival, migration, and engraftment of stem cells. Plasminogen activators can now be added to the short list of molecules capable of retaining stem cells in the bone marrow while plasmin was found to augment the mobilization activity of G-CSF. Studies from the laboratory of Dr. Papayannopoulou add yet another function to the alpha4 molecule on stem cells. These studies demonstrate that alpha4-/- cells are deficient in maintaining hematopoiesis either because they cannot settle in niches supporting hematopoiesis or because they fail to respond to stem cell maintenance signals from the microenvironment. Dr. Lapidot adds another player to homing and mobilization of stem cells, namely CD45, and proposes that CD45 acts as a negative regulator of signaling pathways affecting adhesion properties of stem cells; in doing so, it strikes a balance between anchorage and release of these cells. This session ends with a study promoting a role for CXCR4 in the retention of stem cells in the marrow rather than directed homing. With multiple new roles for new and old players, this session will undoubtedly create some passionate discussions and you will leave the room wondering, “Why didn’t I think of that?”