Professor and Director, Stem Cells and Regenerative Medicine Center (STaR)
Baylor College of Medicine
Vivian L. Smith Chair in Regenerative Medicine
Baylor College of Medicine
Houston, Texas, United States


BS from Imperial College, United Kingdom
PhD from University Of Cambridge
Post-Doctoral Fellowship at Whitehead Institute, Massachusetts Institute of Technology
Post-Doctoral Fellowship at Harvard Medical School

Professional Interests

  • Regulation of hematopoietic stem cells

Professional Statement

Interest in stem cells has intensified over the past ~5 years due to many new discoveries regarding the isolation of human embryonic stem cells, induced pluripotent stem cells, and stem cells derived from adults. The best studied of adult stem cells is the hematopoietic (blood-forming) stem cell (HSC) that resides in the bone marrow. Despite decades of work, little is known about the factors or mechanisms that regulate them. We are using the HSC as a paradigm to understand the general mechanisms governing adult stem cells.

1. Regulation of HSC self-renewal and activation

The HSC reside in a primarily quiescent state in the bone marrow, but they are rapidly activated to divide and differentiate into component cells of the blood when needed. One of the important questions is what controls the decision of stem cells to self-renew or differentiate. If we can understand how stem cells are maintained, we could potentially expand HSC ex vivo, thereby allowing improved bone marrow transplantation and cancer treatments.

Our approach to this problem has been to identify genes that are candidates for regulating the stem cell by examining gene expression patterns while stem cells are undergoing a decision process. We have determined the expression patterns of genes in quiescent or activated stem cells over a standardized time-course of activation, triggered by the anti-mitotic agent 5FU. Thus, we have identified several classes of genes that are preferentially upregulated during quiescence vs. activation or vice versa. Many of these genes are under study now in our lab, giving insight into the regulation of HSCs.

2. Regulation of HSC during stress

A number of the genes identified by the above approach turned out to be regulated by interferons, leading us to investigate a previously unexplored link between the immune response and HSC activation. We examined the impact of bacterial infection on HSCs, and found that during chronic infection, HSCs are rapidly activated to start regenerating the downstream components of peripheral blood. This process is dependent on an intact interferon response. We are now investigating 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.

3. Regulation of HSC during aging

With age, HSC regenerative potential diminishes. We have noted a number of similarities between the stress of aging and that of inflammatory conditions. By delineating the mechanisms of aging in HSCs at the molecular level and understanding how stem cells interact with the aging niche, we hope to gain insights that will enable us to enhance the regenerative properties of aged stem cells.

4. HSC growth control and malignancy

We observed that many of the HSC candidate regulatory genes were oncogenes or tumor suppressors in different circumstances. This has led us to investigate the mechanisms by which oncogenes regulate HSCs, and, when aberrantly expressed, how they may lead to malignancies. One particular oncogene, Lyl1, has become our focus since it is little-studied yet involved in one of the most aggressive forms of T-cell acute lymphoid leukemia. We have shown that this gene plays an important role in lymphoid development as well as HSC regulation.

5. Epigenetic regulation of HSC

Some of the data emerging from these projects has led to study of the mechanisms of epigenetic regulation of HSC. Our primary focus is on DNA methylation in stem cells. We are studying the role of DNA methyltransferases in regulating stem cell growth. We are determining which genes are regulated by DNA methylation and how aberrant DNA methylation may contribute to hematopoietic malignancies.

Selected Publications