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Konrad Hochedlinger, PhDProfessor of Medicine and Regenerative MedicineDepartment of Molecular Biology, Center for Regenerative Medicine, MGH Cancer Center, Harvard Medical School
The Hochedlinger laboratory explores the molecular mechanisms underlying cellular reprogramming. Recent groundbreaking discoveries have shown that adult cells can be reprogrammed into cells resembling embryonic stem cells by activating a handful of embryonic genes. The resultant cells, called induced pluripotent stem cells (iPSCs), have tremendous therapeutic potential; they can be derived from any patient’s skin or blood cells. In the laboratory, iPSCs can be coaxed into many specialized cell types. Our lab has contributed to a better understanding of the process of cellular reprogramming, which remains elusive. These ﬁndings allowed us and other labs to generate iPSCs in safer, better and more efficient ways. Our ultimate goal is to utilize these mechanistic insights for the development of new strategies to treat cancer and other complex diseases.
Konrad Hochedlinger, PhDPrincipal Investigator
The Hochedlinger lab is studying the mechanisms of cellular reprogramming using transcription-factor-mediated conversion of somatic cells into induced pluripotent stem (iPSCs). iPSCs are typically derived by retroviral transduction of the embryonic transcription factors Oct4, Sox2, c-Myc and Klf4, which reset the differentiation state of an adult cell into that of a pluripotent cell. The underlying transcriptional and epigenetic changes remain largely elusive. Importantly, iPSCs have been derived from different species—including human patients—and therefore provide a unique platform to model degenerative disorders such as Alzheimer’s disease, Parkinson’s disease and diabetes. Moreover, iPSCs could be ultimately used in regenerative medicine to replace damaged cells and tissues with genetically matched cells.
We have identiﬁed biomarkers to track and prospectively isolate intermediate cell populations during the reprogramming process, and we are currently using these populations to understand the transcriptional, epigenetic and proteomic changes in cells undergoing reprogramming. In addition, we have shown that terminally differentiated beta cells and lymphocytes can be reprogrammed into iPSCs, thus demonstrating that induced pluripotency is not limited to rare adult stem cells as has been suggested. Interestingly, however, we discovered that immature hematopoietic cells give rise to iPSCs more efficiently than any tested mature cell types, suggesting that the differentiation stage of the starting cell can inﬂuence the efficiency of reprogramming. At the molecular level, we have identiﬁed the p53 and p16/p19 tumor suppressor pathways as well as the Tgf-beta signaling cascade as roadblocks during the reprogramming process, pointing out striking similarities between pluripotent cells and cancer cells.
One major roadblock for the therapeutic use of iPSCs is the fact that integrating viruses are used to deliver the reprogramming genes to cells, resulting in genetically altered iPSCs. By using adenoviruses expressing the reprogramming factors transiently in cells, we were able to produce iPSCs devoid of any viral elements and thus any genetic manipulation. More recently, we have developed a reprogrammable mouse carrying a single doxycycline-inducible cassette with the four reprogramming genes in all tissues. We are employing this system to perform genetic and chemical screens to identify molecules important during the reprogramming process as well as for comparative studies between iPSCs and embryonic stem cells. For example, we discovered that the Dlk1- Dio3 imprinted gene cluster is aberrantly silenced by hypermethylation in many iPSC lines, which correlates with their impaired developmental potential. We recently showed that ascorbic acid treatment prevents aberrant silencing, thus providing the ﬁrst small compound that improves the quality of iPSCs. Furthermore, our lab is investigating the role of three-dimensional chromatin structure in pluripotency and reprogramming by using circular chromosome conformation capture (4C)-sequencing. This work revealed an unexpectedly complex interaction network of the Nanog locus with rest of the genome, which is critical for the maintenance and establishment of pluripotency (see also caption image).
In addition, we are interested in studying the role of Sox2 in adult tissues. While Sox2 has been mostly interrogated in the context of pluripotent stem cells and cellular reprogramming, recent data suggest that it may play important functions in adult tissues as well. For example, Sox2 is essential for neural stem cell maintenance, and its coding region is ampliﬁed in lung and esophageal cancer, thus implicating Sox2 in adult tissue regeneration and tumorigenesis. Intriguingly, we have identiﬁed Sox2-expressing cells in several adult tissues where it has not previously been characterized, including squamous epithelia lining the stomach, anus and cervix as well as in testes, lens and glandular stomach. Future work in the lab is aimed at understanding the role of Sox2 and Sox2+ cells in tissue homeostasis and cancer by utilizing conditional knockout, lineage tracing and cell ablation mouse models.
View a list of publications by researchers at the Hochedlinger Laboratory
Bar-Nur O, Verheul C, Sommer AG, Brumbaugh J, Schwarz BA, Lipchina I, Huebner AJ, Mostoslavsky G, Hochedlinger K. Lineage conversion induced by pluripotency factors involves transient passage through an iPSC stage. Nat Biotechnol. 2015 Jul;33(7):761-8.
Bar-Nur O, Brumbaugh J, Verheul C, Apostolou E, Pruteanu-Malinici I, Walsh RM, Ramaswamy S, Hochedlinger K. Small molecules facilitate rapid and synchronous iPSC generation. Nat Methods. 2014 Nov;11(11):1170-6.
Apostolou E, Ferrari F, Walsh RM, Bar-Nur O, Stadtfeld M, Chelouﬁ S, Stuart HT, Polo JM, Ohsumi TK, Borowsky ML, Kharchenko PV, Park PJ, Hochedlinger K. Genome-wide Chromatin Interactions of the Nanog Locus in Pluripotency, Differentiation, and Reprogramming. Cell Stem Cell. 2013 Jun 6;12(6):699-712.
Polo JM, Anderssen E, Walsh RM, Schwarz BA, Nefzger CM, Lim SM, Borkent M, Apostolou E, Alaei S, Cloutier J, Bar-Nur O, Chelouﬁ S, Stadtfeld M, Figueroa ME, Robinton D, Natesan S, Melnick A, Zhu J, Ramaswamy S, Hochedlinger K. A molecular roadmap of reprogramming somatic cells into iPS cells. Cell. 2012 Dec 21;151(7):1617-32.
Stadtfeld M, Apostolou E, Ferrari F, Choi J, Walsh RM, Chen T, Ooi SS, Kim SY, Bestor TH, Shioda T, Park PJ, Hochedlinger K. Ascorbic acid prevents loss of Dlk1-Dio3 imprinting and facilitates generation of all-iPS cell mice from terminally differentiated B cells. Nat Genet. 2012 Mar 4;44(4):398-405, S1-2.
Arnold K, Sarkar A, Yram MA, Polo JM, Bronson R, Sengupta S, Seandel M, Geijsen N, Hochedlinger K. Sox2(+) adult stem and progenitor cells are important for tissue regeneration and survival of mice. Cell Stem Cell. 2011 Oct 4;9(4):317-29.
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