Dr. Muller-Sieburg's research focuses on understanding the cellular and molecular mechanisms that regulate hematopoietic stem cells.
Dr. Muller-Sieburg received her Dr. rer. nat., (Ph.D.) in genetics and immunology from the Universität Köln.
View All Publications
Predicting clonal self-renewal and extinction of hematopoietic stem cells.
Sieburg HB, Rezner BD, Muller-Sieburg CE
Proc Natl Acad Sci U S A. 2011 Mar 15;108(11):4370-5
A new mechanism for the aging of hematopoietic stem cells: aging changes the clonal composition of the stem cell compartment but not individual stem cells.
Cho RH, Sieburg HB, Muller-Sieburg CE
Blood. 2008 Jun 15;111(12):5553-61
Myeloid-biased hematopoietic stem cells have extensive self-renewal capacity but generate diminished lymphoid progeny with impaired IL-7 responsiveness.
Muller-Sieburg CE, Cho RH, Karlsson L, Huang JF, Sieburg HB
Blood. 2004 Jun 1;103(11):4111-8
Functional heterogeneity of the hematopoietic microenvironment: rare stromal elements maintain long-term repopulating stem cells.
Wineman J, Moore K, Lemischka I, Müller-Sieburg C
Blood. 1996 May 15;87(10):4082-90
Genetic control of the frequency of hematopoietic stem cells in mice: mapping of a candidate locus to chromosome 1.
Müller-Sieburg CE, Riblet R
J Exp Med. 1996 Mar 1;183(3):1141-50
Separation of pluripotent stem cells and early B lymphocyte precursors with antibody Fall-3.
J Exp Med. 1991 Jul 1;174(1):161-8
Isolation of two early B lymphocyte progenitors from mouse marrow: a committed pre-pre-B cell and a clonogenic Thy-1-lo hematopoietic stem cell.
Muller-Sieburg CE, Whitlock CA, Weissman IL
Cell. 1986 Feb 28;44(4):653-62
Christa Muller-Sieburg's Research Focus
Aging-Related Diseases, Leukemia/Lymphoma, Radiation Damage
Christa Muller-Sieburg's Research Report
Genetic, Epigenetic, and Environmental Regulation of Hematopoietic Stem Cells
We have a long-standing interest in the cellular and molecular switches that determine how hematopoietic stem cells (HSC) decide whether to differentiate or to self-renew. To this end we use a combination of rigorous functional approaches (long-term transplantation assays), molecular approaches to modulate the gene program of stem cells, and mathematical and computer modeling. The defining features of all stem cells are self-renewal and differentiation capacity. These features make HSC ideally suited for replacement therapy and HSC are an important model for tissue specification and regeneration. The recent demonstration that neuronal stem cells can give rise to tumors emphasize the importance of understanding the growth and regenerative potential of adult tissue specific stem cells. Decisions about self-renewal and commitment are made on the level of a single HSC, and thus require examination on the clonal level. So far, we have build a database of over 200 individual, clonal HSC, each followed in vivo in long-term transplantation experiments. These data allowed us to show that HSC are heterogeneous in their self-renewal and differentiation capacity. However, mathematical modeling showed that this heterogeneity is limited. Mathematical modeling shows that the stem cell compartment consist of only a few types of HSC that can be distinguished by their self-renewal capacity. Remarkably, the composition of HSC changes during development and aging. The HSC compartment in the young contains predominantly HSC that rapidly and efficiently generate lymphocytes. In contrast, the aged HSC is enriched for HSC that generate more myeloid than lymphoid cells. In the human population, lymphoid leukemia are more frequent in the young and myeloid leukemia’s more frequently in the aged. Thus, it is tempting to speculate that that humans experience a similar shift of HSC during aging. Restoring the lymphopoietic ability of aged HSC is one of the aims of our group. This may aid in boosting the attenuated immune response of the aged. A diminished immune response contributes to many of the pathologies and morbidity that are associated with aging. We have shown that the differences in these types of HSC are epigenetically fixed and HSC in different classes have distinctive molecular signatures. Consequently, the behavior of individual HSC is very predictable- consistent with a deterministic model of stem cell behavior. This has important implications for using HSC in clinical settings. Traditionally, HSC were thought to be malleable and easily changed. Our data now show that HSC have largely predetermined behaviors. Therefore, it will be important to select the correct type of HSC for applications such as the treatment of leukopenias or as target cells for gene therapy.
Specifically, we are interested in:
- A major emphasis in the laboratory is to define the developmental onset and the mechanism of the epigenetic regulation that lead to the different types of HSC. Recent data define the onset of epigenetic specification during embryonic development.
- We identified a number of candidate genes that are differentially expressed between HSC of the different classes. We are working to regulate expression of the genes in the different types of HSC and to understand how these genes are epigenetically regulated. This could aid in resetting the epigenetic restriction of HSC particularly in the aged.
- Amongst the candidate genes are members of the Hox genes and their co-factors. Using a combination of computer simulation and genetic models, we are exploring whether different Hox genes regulate self-renewal of normal HSC vs. abnormal Leukemic stem cells.
- In humans, lymphoid leukemia are more prevalent in the young and myeloid leukemia is found preferentially in the aged. We are exploring whether the epigenetic make-up of the different types of normal HSC predispose them to become myeloid or lymphoid leukemia.
- We are seeking to define phenotypes for the different types of HSC to allow their prospective isolation from young and aged donors.
- A genetic model of aging is allowing us to study HSC in short- and long-lived mice. Preliminary data demonstrate that the generation of lymphocytes is regulated by genetic mechanisms in old and young mice.
- Another area of interest is the role of the embryonic and aged microenvironment on the regulation of HSC.
- We have a longstanding interest in mathematical and computational approaches to understand HSC as a dynamical system. Aided by our database of the in vivo behavior of HSC clones we are working on defining algorithms that predict the life span of HSC.
About Christa Muller-Sieburg
Christa Muller-Sieburg received her Dr. rer. nat., (Ph.D.) in genetics and immunology from the Universität Köln. Under a postdoctoral fellowship from the Deutsche Forschungsgemeinschaft, she worked with Irv Weissman at Stanford University. During this time, she developed the first antigenic profile of HSC and performed the first purification of HSC. Thereafter, she worked as a postdoctoral fellow at Eli Lilly Research Laboratory, La Jolla. In 1989, she was appointed Assistant Member at the Medical Biology Institute. At that time, she became a Leukemia Society Scholar and in 1992 won the Stohlman Memorial Scholar Award. In 1993, she was promoted to Associate Member. She joined the Sidney Kimmel Cancer Center in 1998 as Professor and in 2009 the Sanford-Burnham Institute for Medical Research.