- Center for Cell and Gene Therapy Baylor College of Medicine One Baylor Plaza N1030 Houston, Texas 77030 United States
- 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
- Regulation of hematopoietic stem cells
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.
- Luo M1, Jeong M1, Sun D2, Park HJ2, Rodriguez BA2, Xia Z2, Yang L1, Zhang X1, Sheng K1, Darlington GJ3, Li W4, Goodell MA5.. "Long non-coding RNAs control hematopoietic stem cell function.." Cell Stem Cell.. 2015 April 2;16(4):426-38. Pubmed PMID: 25772072
- Yang L1, Rau R2, Goodell MA3.. "DNMT3A in haematological malignancies.." Nat Rev Cancer.. 2015 March:152-65. Pubmed PMID: 25693834
- Challen GA1, Sun D2, Mayle A3, Jeong M4, Luo M5, Rodriguez B2, Mallaney C6, Celik H6, Yang L4, Xia Z2, Cullen S4, Berg J4, Zheng Y4, Darlington GJ7, Li W2, Goodell MA8.. "Dnmt3a and Dnmt3b have Overlapping and Distinct Functions in Hematopoietic Stem Cells." Cell Stem Cell.. 2014 September 4;15(3):350-64. Pubmed PMID: 25130491
- Sun D1, Luo M2, Jeong M2, Rodriguez B1, Xia Z1, Hannah R3, Wang H4, Le T5, Faull KF5, Chen R4, Gu H6, Bock C7, Meissner A6, Göttgens B3, Darlington GJ8, Li W9, Goodell MA10.. "Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal.." Cell Stem Cell.. 2015 May 1;14(5):673-88. Pubmed PMID: 24792119
- Jeong M1, Sun D2, Luo M1, Huang Y3, Challen GA1, Rodriguez B4, Zhang X5, Chavez L3, Wang H6, Hannah R7, Kim SB8, Yang L5, Ko M3, Chen R6, Göttgens B7, Lee JS8, Gunaratne P9, Godley LA10, Darlington GJ11, Rao A3, Li W2, Goodell MA1.. "Large conserved domains of low DNA methylation maintained by Dnmt3a.." Nat Genet.. 2014 January;46(1):17-23. Pubmed PMID: 24270360
- Zohren F1, Souroullas GP, Luo M, Gerdemann U, Imperato MR, Wilson NK, Göttgens B, Lukov GL, Goodell MA.. "Lymphoblastic Leukemia 1 (Lyl1) Regulates Lymphoid Specification and Maintenance of Early T Lineage Progenitors.." Nat Immunol.. 2012 July 8;13(8):761-9. Pubmed PMID: 22772404
- Challen GA, Sun D, Jeong M, Luo M, Jelinek J, Berg JS, Bock C, Vasanthakumar A, Gu H, Xi Y, Liang S, Lu Y, Darlington GJ, Meissner A, Issa JP, Godley LA, Li W, Goodell MA. "Dnmt3a is essential for hematopoietic stem cell differentiation.." Nat. Genet.. 2011;44(1):23-31. Pubmed PMID: 22138693