My laboratory studies the regulatory mechanisms underlying stem cell self-renewal and differentiation.
Ongoing Work
Deriving therapeutic hematopoietic stem cells from embryonic stem cells.
ES cells are totipotent and capable of recapitulating all of the developmental events of embryogenesis. They are therefore theoretically the ideal source of cells for regenerative therapies. However, turning theory into practice is not straightforward, and very few successful models of such therapy exist. We have shown that in the case of the hematopoietic system, ES cells are programmed to undergo an embryonic mode of hematopoiesis, which produces a different array of cell types than the adult, and derives from a distinct, so called ?primitive? hematopoietic stem cell. The primitive hematopoietic stem cell is incapable of engrafting when transplanted into lethally irradiated adult recipients. To derive adult, definitive hematopoietic stem cells, a developmental maturation process must be induced. Our goal is to understand the molecular details of this process: what secreted factors specify definitive hematopoiesis, and what key differences distinguish the primitive and definitive hematopoietic stem cells.
The Hox code for hematopoietic stem cell self-renewal.
Gain of function studies with HoxB4 have shown that this Hox family member is involved in the regulation of self-renewal. Unfortunately, because other Hox genes cause leukemia when constitutively expressed, they have largely been ignored. By using conditional gene expression, we have shown that HoxB4 is neither unique in promoting hematopoietic stem cell self-renewal, nor most potent. We wish to understand how Hox genes control stem cell self-renewal, and are identifying regulatory circuits under Hox control.
Specification of Hematopoietic Mesoderm.
HoxB4 plays a role in the maturation of hematopoietic stem cells. We are also interested in factors that specify the origin of the hematopoietic stem cell in early mesoderm. Our ultimate goal is the synchronous generation of hematopoietic stem cells from ES cells. While therapeutically useful, it is also the gold standard by which we can judge our understanding of the process: if we can enforce with certainty a given lineage on the progeny of an ES cell, then we can be satisfied that we understand, at least at a basic level, the process of lineage selection.
Skeletal muscle stem cells and FSH muscular dystrophy.
Certain degenerative diseases may be the result of ineffective self-renewal or differentiation of lineage specific stem cells. We are particularly interested in Fascioscapulohumeral Muscular Dystrophy (FSHD), a dominant dystrophy associated with a contraction of 4q subtelomeric repeats. Although the condition is almost certainly caused by derepression of a gene in the viscinity of 4q, the protein products of candidate genes in this area can not be detected overexpressed in patient muscle samples. Because muscle stem cells (satellite cells) are rare, proteins overexpressed specifically in satellite cells are unlikely to be identified in patient biopsies. We are testing the hypothesis that a Hox gene embedded within the 4q repeats, DUX4, causes FSHD when derepressed in muscle satellite cells.
RESEARCH INTERESTS
Stem Cell Biology
Developmental Biology
Hematopoiesis
Muscle Development
RECENT PUBLICATIONS
Darabi R, Gehlbach K, Bachoo RM, Kamath S, Osawa M, Kamm KE, Kyba M, Perlingeiro RC., "Functional skeletal muscle regeneration from differentiating embryonic stem cells" Nature Medicine, in press 2008
Kyba, M., "Genesis of hematopoietic stem cells in vitro and in vivo: new insights into developmental maturation" Int. J. Hematol., 81:275-280, 2005
Kyba, M., Perlingeiro, R.C.R., Hoover, R.R., Lu, C.W., Pierce, J., Daley, G.Q., "Enhanced hematopoietic differentiation of embryonic stem cells conditionally expressing Stat5" Proc Natl Acad Sci USA, Suppl 1:11904-11910, 2003
Kyba, M., Daley, G.Q., "Hematopoiesis from ES cells: lessons from and for ontogeny" Exp. Hematol, 2003
Kyba, M., Perlingeiro, R.C.R., Daley, G.Q., "Development of hematopoietic repopulating cells from embryonic stem cells" Methods Enzymol 365, 2003
SIGNIFICANT PUBLICATIONS
Darabi R, Gehlbach K, Bachoo RM, Kamath S, Osawa M, Kamm KE, Kyba M, Perlingeiro RC., "Functional skeletal muscle regeneration from differentiating embryonic stem cells" Nature Medicine, in press 2008
Kyba, M, Perlingeiro, RCR, Daley, GQ, "HoxB4 Confers Definitive Lymphoid-Myeloid Engraftment Potential on Embryonic Stem Cell and Yolk Sac Hematopoietic Progenitors" Cell, 109:29-37, 2002
Rideout, WM*, Hochedlinger, K*, Kyba, M*, Daley, GQ, Jaenisch, R., "Correction of a Genetic Defect by Nuclear Transplantation and Combined Cell and Gene Therapy" Cell, 109:17-27, 2002
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