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Konrad Hochedlinger, PhDProfessor of Medicine, Harvard Medical SchoolAssistant Professor of Stem Cell and Regenerative Biology, Harvard Universitykhochedlinger@helix.mgh.harvard.edu
Stem cells have the dual potential to self-renew and give rise to differentiated cells. They play key roles in normal development, during tissue homeostasis and following injury in the adult. Moreover, stem cells have been experimentally shown to be the cells of origin in certain types of cancer. To understand the biology of stem cells and to exploit their use for therapy, it is critical to identify and characterize the factors that control the decision between their self-renewal and differentiation under normal physiological conditions and in disease.
We are particularly interested in the biology of embryonic stem (ES) cells which are the only cell type that retains pluripotentiality. The pluripotent state of ES cells is maintained by a set of transcription factors including Oct4, Sox2 and Nanog. Genetic studies have shown that Oct4 and Nanog keep ES cells undifferentiated by inhibiting their differentiation into trophectoderm and endoderm, respectively. Interestingly, some of these factors appear to be important also in other cell types such as neural stem cells as well as in different biological processes, such as nuclear reprogramming. We have recently generated pluripotent cells from fibroblasts by ectopic expression of the transcription factors Oct4, Sox2, c-myc and Klf4. These cells show global epigenetic remodeling, reactivation of a silenced X chromosome and broad contribution to chimeric animals including female germ cells.
We are using in vitro and in vivo model systems to further characterize the role of pluripotency genes in stem cell self-renewal, reprogramming and cancer. Specifically, future projects will include (i) the screening for novel genes involved in the self-renewal of stem cells and (ii) their analysis in normal development and cancer by establishing novel mouse models, and (iii) nuclear reprogramming of mouse and human cells by defined factors.
Research FellowsOri Bar-Nur, Ph.D.Justin Brumbaugh, Ph.D.Sihem Cheloufi, Ph.D.Aaron Huebner, Ph.D.Inna Lipchina, Ph.D.
Clinical FellowBen Schwartz, M.D.
Ph.D. StudentsJiho Choi (Harvard University)Abby Sarkar (Harvard University)Ryan Walsh (Harvard University)
Undergraduate StudentKyle Flattery (Harvard University)
Stadtfeld et al., (2008), Induced Pluripotent stem cells generated without viral integration, Science, Sept 25; 10.1126/science.1162494.
Maherali et al., (2008), A high efficiency system for the generation and study of human iPS cells, Cell Stem Cell 3(3):340-345.
Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, Lensch MW, Cowan C, Hochedlinger K, Daley GQ (2008), Disease-specific induced pluripotent stem cells. Cell 134:877-86.
Maherali et al., (2007), Directly reprogrammed fibroblasts show global epigenetic reprogramming and widespread tissue contribution, Cell Stem Cell 1: 55-70.
Hochedlinger and Jaenisch (2006), Nuclear reprogramming and pluripotency, Nature 441;1061-1067.
Hochedlinger et al., Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues, (2005), Cell 121(3):465-77.
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