Normal hematopoietic stem cell biology
A major focus of Dr. Goodell’s laboratory is the molecular regulation of hematopoietic stem cells (HSC). Her laboratory has sought to identify the genes that are responsible for maintaining the quiescent state of HSC, as well as their self renewal. A single injection of the chemotherapeutic agent 5-Fluoruracil (5FU) kills rapidly dividing progenitors in the bone marrow, and activates HSC, causing some to differentiate, regenerating the hematopoietic system, and others to self-renew. Using microarrays to examine gene expression changes over a time-course of activation, the laboratory has identified cohorts of genes that appear to be involved in activating self-renewal of the HSC (Venezia 2004, PubMed). The laboratory is now examining the role of specific genes in the self-renewal and activation cycle.
A long-term goal of these studies is to elucidate the genes required for HSC self-renewal, with the goal of determining conditions that would allow HSC to be expanded in vitro without differentiation, a long-sought goal of hematological research that could have enormous impact on the practice of bone marrow transplantation. A second major goal is to broadly understand growth regulation of normal stem cells, with the expectation that insights into regulation of normal stem cells would also apply to regulation of quiescence and activation of putative tumor stem cells.
Regulation of HSCs during stress
A number of the genes identified by the above approach turned out to be interferon-regulated genes, leading the lab to investigate a previously unexplored link between the immune response and HSC activation. In a murine model of chronic bacterial infection, HSCs are rapidly activated to start regenerating the downstream components of peripheral blood. This process is dependent on an intact interferon response. Further work will delineate potential interactions between other components of the IFN signaling pathway, as well as the response of HSC to different kinds of infectious, as well as non-infectious stress.
Hematopoietic stem cells in aging
Stem cells replenish the cells of aging tissues, and can thus act as a barrier against some of the affects of age. However, hematopoietic stem cells from older mice have been shown to have diminished function, suggesting that they themselves may age. The Goodell laboratory is examining the molecular changes in hematopoietic stem cells that may account for these functional changes, by profiling gene expression in purified stem cells over a time-course of aged mice. Many broad changes are observed, including some seen in other aging systems. Current efforts will are directed to identifying genes that are regulate the aging process, as opposed to those that are simple markers of aging.
HSC growth control and malignancy
Many candidate HSC regulatory genes are oncogenes or tumor suppressors in different circumstances. Thus the Goodell lab is investigating the mechanisms by which oncogenes regulate HSCs, and, when aberrantly expressed, how they may lead to malignancies. One particular oncogene, Lyl1, has become a focus since it is little-studied yet involved in one of the most aggressive forms of T-cell acute lymphoid leukemia. This gene plays an important role in lymphoid development as well as HSC regulation.
Epigenetic regulation of HSCs
Some of the data emerging from these projects have led to a study of the mechanisms of epigenetic regulation of HSCs. A primary focus is on DNA methylation in stem cells. Techniques such as bisulfite sequencing and inhibition of DNA methyltransferases will lead to insights into how DNA methylation normally contributes to HSC reulation and how aberrant DNA methylation may contribute to hematopoietic malignancies.
Many of our research protocols are publicly available by clicking here.