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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 pluripotency, which is the ability to produce all mature cell types of the body. Previous groundbreaking discoveries have shown that adult cells can be reprogrammed into pluripotent 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 allowed us to elucidate basic mechanisms that maintain cellular identity and prevent aberrant cell fate change. 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 due to the low efficiency of reprogramming and the heterogeneity of cell cultures. 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.
Sox2 functions as a tumor suppressor in the stomach by suppressing an alternative intestinal program and Wnt/b-catenin signaling. Depicted are gastric organoids from Apc/Sox2 deficient mice showing ectopic activation of an Olfm4-EGFP reporter (C. Sebastian & R. Mostoslavsky) that is normally confined to intestinal stem cells (green signal). (see Sarkar et al., Cell Reports, in press). Image: Abby Sarkar
We have identiﬁed biomarkers to track and prospectively isolate rare intermediate cell populations that are poised to become iPSCs, 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 originally been suggested. Nevertheless, we discovered that immature hematopoietic cells give rise to iPSCs more efficiently than any tested mature cell types, suggesting that the differentiation stage and therefore the epigenetic state of the starting cell has a profound effect on its potential to be reprogrammed. 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. Additionally, our lab has conducted unbiased shRNA screens for barriers to reprogramming, uncovering new mechanisms that safeguard somatic cell identity. For example, we identified the histone chaperone CAF-1 and the protein modifier Sumo2 as novel modulators of mammalian cell fate change and we are currently exploring the underlying mechanisms as well as their role in tissue homeostasis and cancer.
One major roadblock for the therapeutic use of iPSCs has been the fact that integrating viruses were initially 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 the first iPSCs devoid of any viral elements and thus any genetic manipulation. In addition to eliminating a potential roadblock to the therapeutic application of iPSC technology, this finding allowed us to compare unaltered iPSCs to genetically matched embryonic stem cells, which represent the gold standard for pluripotent 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 extended this study to human cells, demonstrating that isogenic, vector-free iPSCs are equivalent to human embryonic stem cells. These results indicated that genetic background and reprogramming method are major contributors of transcriptional and epigenetic variation in human pluripotent stem cell lines.
In a separate line of investigation, we are 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. 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. Unexpectedly, we discovered that Sox2 functions as a tumor suppressor in a mouse model of stomach cancer, which may have important therapeutic implications given its role as an oncogene in other tissues. Future work in the lab is aimed at further understanding the molecular and functional role of Sox2 and Sox2+ cells in stomach homeostasis and using mouse and human cells.
View a list of publications by researchers at the Hochedlinger Laboratory
Sarkar A, Huebner AJ, Sulahian R, Anselmo A, Xu X, Flattery K, Desai N, Sebastian C, Yram MA, Arnold K, Rivera, Mostoslavsky R, Bronson R, Bass A, Sadreyev R, Shivdasani RA, Hochedlinger K. Sox2 suppresses gastric tumorigenesis in mice. Cell Reports 2016 Aug 16;16(7):1929-41.
Borkent M, Bennett BD, Lackford B, Bar-Nur O, Brumbaugh J, Wang L, Du Y, Fargo DC, Apostolou E, Cheloufi S, Maherali N, Elledge SJ, Hu G, Hochedlinger K. A Serial shRNA Screen for Roadblocks to Reprogramming Identifies the Protein Modifier SUMO2. Stem Cell Reports. 2016 May 10;6(5):704-16.
Choi J, Lee S, Mallard W, Clement K, Tagliazucchi GM, Lim H, Choi IY, Ferrari F, Tsankov AM, Pop R, Lee G, Rinn JL, Meissner A, Park PJ, Hochedlinger K. A comparison of genetically matched cell lines reveals the equivalence of human iPSCs and ESCs. Nat Biotechnol. 2015 Nov;33(11):1173-81.
Cheloufi S, Elling U, Hopfgartner B, Jung YL, Murn J, Ninova M, Hubmann M, Badeaux AI, Euong Ang C, Tenen D, Wesche DJ, Abazova N, Hogue M, Tasdemir N, Brumbaugh J, Rathert P, Jude J, Ferrari F, Blanco A, Fellner M, Wenzel D, Zinner M, Vidal SE, Bell O, Stadtfeld M, Chang HY, Almouzni G, Lowe SW, Rinn J, Wernig M, Aravin A, Shi Y, Park PJ, Penninger JM, Zuber J, Hochedlinger K. The histone chaperone CAF-1 safeguards somatic cell identity. Nature. 2015 Dec 10;528(7581):218-24.
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.
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