Understanding the foundations of mammalian cellular diversity
Comprehending how mammalian cells with apparently identical genetic background acquire their extraordinarily specific, stable and yet
extremely diverse phenotypes poses one of the most daunting challenges of modern biomedical research. Until the molecular principles that govern branching and maintenance of
the basic cellular lineages in the embryo and in the mature organism become clear, it will not be possible to fully address persistent questions in developmental
biology, regenerative medicine, cancer biology, and the pathophysiology of degenerative diseases.
Embryonic stem (ES) and ES-like cells (induced pluripotent stem cells, iPS) afford ideal model systems for unraveling the complex molecular
networks that give rise to cellular identity. They are relatively easy to generate and maintain in culture and are amenable to manipulation with the growing repertoire of
molecular research tools now in the hands of cell biologists. More importantly, they have the property of pluripotency, meaning that they can differentiate to many
cell types in the body, even to germ cells. Several groups believe that a small core set of regulatory factors, including Pou5f1 (encoding the Oct4 protein), Sox2 and Nanog,
maintain ES cells in the pluripotent state by acting on a limited number of target genes. This fundamental concept has generated enormous excitement in the biomedical
community, leading to successful reprogramming of somatic cells to an ES-like state. Yet, recent discoveries in our laboratory suggest that the complement of factors needed
to direct ES cell pluripotency is considerably larger than originally thought.
We plan to generate a comprehensive list of pluripotency factors that would serve as foundation for identifying alternative networks of key factors involved in the
maintenance of pluripotency. This quest will include candidate proteins we have already identified (e.g., Ronin) as well as others known to be associated with
stem cell self-renewal and differentiation function. The most obvious question raised by the discovery of novel pluripotency factors is whether they could be used, either
alone or in combination to reprogram somatic cells to an ES cell-like state (iPS cells). Such studies are under way in our lab, and early indications are that such manipulation is not only
feasible, but will add significantly to the body of knowledge on stem cell regulation. Most exciting, perhaps, is the possibility that some of these factors are not specific
for a particular cellular state but rather open up the epigenome to other factors that can effectively change the epigenetic landscape towards a different cell type. Thus,
cellular reprogramming may not be limited to iPS cells but may also allow differentiation from one somatic cell type to another assuming
that the appropriate core set of regulation genes is found.
Selected Publications
Zwaka TP, Thomson JA (2003) Homologous recombination in human embryonic stem cells. Nature Biotechnology 21:319-321.
Zwaka TP, Thomson JA (2005) A germ cell origin of embryonic stem cells? Development 132:227-233.
Zwaka TP, Thomson JA (2005) Differentiation of human embryonic stem cells occurs through symmetric cell division. Stem Cells 23:146-149.
Zwaka TP (2006) Breathing chromatin in pluripotent stem cells. Developmental Cell 10:1-2.
Zwaka TP (2006) Keeping the noise down in ES cells. Cell 127:1301-1302.
Zwaka TP (2008) What comes after iPS? Nature Reports: Stem Cells, doi:10.1038/stemcells.2008.54.
Fujita J, Crane AM, Souza MK, Dejosez M, Kyba M, Flavell RA, Thomson JA, Zwaka TP (2008) Caspase activity mediates the differentiation of
embryonic stem cells. Cell Stem Cell 2:595-601.
Dejosez M, Krumenacker JS, Zitur LJ, Passeri M, Chu LF, Songyang Z, Thomson JA, Zwaka TP (2008) Ronin is essential for embryogenesis and the
pluripotency of mouse embryonic stem cells. Cell 133:1162-1174.
Contact Information
- Thomas P. Zwaka, M.D., Ph.D.
- Center for Cell and Gene Therapy
- Baylor College of Medicine
- One Baylor Plaza N1030
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-1272
- Fax: (713) 798-1230
- E-mail: tpzwaka@bcm.edu
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