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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.
- 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.
- 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.
- 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.
- 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.
- 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
Venezia, TA, Merchant AA, Ramos CA, Whitehouse NL, Young AS, Shaw CA, Goodell MA (2004) Molecular signatures of proliferation and quiescence
in hematopoietic stem cells. PLoS Biology 2:e301.
Bowman TV, McCooey AJ, Merchant AA, Ramos CA, Fonseca P, Poindexter A, S. B. Bradfute SB, Oliveira DM, Green R, Zheng Y, Jackson KA, Chambers SM, McKinney-Freeman
SL, Norwood KG, Darlington G, Gunaratne PH, Steffen D, Goodell MA (2006) Differential mRNA processing in hematopoietic stem cells. Stem Cells 24:662-670.
Chambers SM, Shaw CA, Gatza C, Fisk CJ, Donehower LA, Goodell MA (2007) Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation.
PLoS Biology 5:e201.
Chambers SM, Boles NC, Lin KY, Tierney MP, Bowman TV, Bradfute SB, Chen AJ, Merchant AA, Sirin O, Weksberg DC, Merchant MG, Fisk CJ, Shaw CA, Goodell MA (2007)
Hematopoietic fingerprints: an expression database of stem cells and their progeny. Cell Stem Cell 1:578-591.
Souroullas GP, Salmon JM, Sablitzky F, Curtis DJ, Goodell MA (2009) Adult hematopoietic stem and progenitor cells require either Lyl1 or Scl for survival. Cell
Stem Cell 4:180-186.
Challen GA, Boles NC, Chambers SM, Goodell MA (2010) Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-beta1. Cell Stem Cell
6:265-278.
Baldridge MT, King KY, Boles NC, Weksberg DC, Goodell MA (2010) Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection.
Nature 465:793-797.
Sirin O, Lukov GL, Mao R, Conneely OM, Goodell MA (2010) The orphan nuclear receptor Nurr1 restricts the proliferation of haematopoietic stem cells. Nature Cell
Biology 12:1213-1219.
Contact Information
- Margaret A. Goodell, Ph.D.
- Center for Cell and Gene Therapy
- Baylor College of Medicine
- One Baylor Plaza N1030
- Houston, Texas 77030, U.S.A.
- Lab Website
- Tel: (713) 798-1265
- Fax: (713) 798-1230
- E-mail: goodell@bcm.edu
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