Professor of Stem Cell & Regenerative Biology
4 South 0.66
Tel: +44 (0) 1225 386532
Current lab members:
- Heather Bone
- Christopher Brimson (joint with Dr Makoto Furutani-Seiki)
- Zoe Burke
- Ed Carter (joint with Professor Steve Ward)
- James Corbett
- Yu Chen
- Leonard Griffiths
- Barbara Rees
- Caroline Sangan
- Michael Storm
- Nelly Wung
Prof David Tosh
My lab is mainly interested in the general phenomenon of cellular reprogramming. Reprogramming is defined as the conversion of one cell type (including stem cells) to another.
We have developed a number of models for the reprogramming of pancreatic cells to liver cells and the reverse, liver to pancreas transformation and for the conversion of oesophagus to intestine (see selected publications).
Studying cellular reprogramming will help us to:
- Understand the normal developmental biology of the cells that interconvert.
- Identify transcription factors that could be used to differentiate stem cells for therapeutic transplantation and
- Gain insight into how certain cancers develop.
How does dissecting the cellular and molecular basis of reprogramming help with understanding normal embryonic development? The answer is that the gene (transcription factor) that induces reprogramming is also probably important in distinguishing the two tissues during development. We are currently developing this research to identify developmentally important genes.
Stem Cell Therapy
Stem cells are now entering an exciting phase of research and attention has recently focused on the ability to utilise stem cells as therapeutic modalities. If we can identify key transcription factors (which we call master switch genes) that will induce conversion of one cell type to another, we may be able to use these genes to induce the differentiation of stem cells.
We now know that in certain pathological conditions reprogramming may predispose to cancer. Perhaps one of the best known examples is Barrett’s metaplasia. In this condition intestinal epithelium appears in the oesophagus. Patients with Barrett’s metaplasia have a greater risk of developing oesophageal adenocarcinoma. In order to gain a better understanding of the disease, we wish to determine the steps leading from normal oesophageal epithelium to intestinal epithelium.
Chien, C. Y., Lee, H. S., Cho, C. H. H., Lin, K. I., Tosh, D., Wu, R. R., Mao, W. Y. and Shen, C. N., 2016. Forthcoming. Maternal vitamin A deficiency during pregnancy affects vascularized islet development. Journal of Nutritional Biochemistry, 36, pp. 51-59.
Kia, R., Kelly, L., Sison-Young, R. L. C., Zhang, F., Pridgeon, C. S., Heslop, J. A., Metcalfe, P., Kitteringham, N. R., Baxter, M., Harrison, S., Hanley, N. A., Burke, Z. D., Storm, M. P., Welham, M. J., Tosh, D., Küppers-Munther, B., Edsbagge, J., Starkey Lewis, P. J., Bonner, F., Harpur, E., Sidaway, J., Bowes, J., Fenwick, S. W., Malik, H., Goldring, C. E. P. and Kevin Park, B., 2015. MicroRNA-122:A novel hepatocyte-enriched in vitro marker of drug-induced cellular toxicity. Toxicological Sciences, 144 (1), pp. 173-185.
Sangan, C. B., Jover, R., Heimberg, H. and Tosh, D., 2015. In vitro reprogramming of pancreatic alpha cells towards a beta cell phenotype following ectopic HNF4α expression. Molecular and Cellular Endocrinology, 399, pp. 50-59.
Carter, E., Miron-Buchacra, G., Goldoni, S., Danahay, H., Westwick, J., Watson, M. L., Tosh, D. and Ward, S. G., 2014. Phosphoinositide 3-kinase alpha-dependent regulation of branching morphogenesis in murine embryonic lung:Evidence for a role in determining morphogenic properties of FGF7. PLoS ONE, 9 (12), e113555.
O'Neill, K.E., Thowfeequ, S., Li, W.-C., Eberhard, D., Dutton, J.R., Tosh, D. and Slack, J.M.W., 2014. Hepatocyte-ductal transdifferentiation is mediated by reciprocal repression of SOX9 and C/EBPα. Cellular Reprogramming, 16 (5), pp. 314-323.
Wung, N., Acott, S. M., Tosh, D. and Ellis, M. J., 2014. Hollow fibre membrane bioreactors for tissue engineering applications. Biotechnology Letters, 36 (12), pp. 2357-2366.
Ali Khan, M., Wood, P. J., Lamb-Guhren, N. M., Caggiano, L., Kociok-Köhn, G., Tosh, D. and Lewis, S. E., 2014. The enone motif of (+)-grandifloracin is not essential for 'anti-austerity' antiproliferative activity. Bioorganic & Medicinal Chemistry Letters, 24 (13), pp. 2815-2819.
Corbett, J.L. and Tosh, D., 2014. Conversion of one cell type into another:Implications for understanding organ development, pathogenesis of cancer and generating cells for therapy. Biochemical Society Transactions, 42 (3), pp. 609-616.
Storm, M.P., Kumpfmueller, B., Bone, H.K., Buchholz, M., Sanchez Ripoll, Y., Chaudhuri, J.B., Niwa, H., Tosh, D. and Welham, M.J., 2014. Zscan4 is regulated by PI3-kinase and DNA-damaging agents and directly interacts with the transcriptional repressors LSD1 and CtBP2 in mouse embryonic stem cells. PLoS ONE, 9 (3).
Gibson, M. K., Dhaliwal, A. S., Clemons, N. J., Phillips, W. A., Dvorak, K., Tong, D., Law, S., Pirchi, E. D., Rasanen, J., Krasna, M. J., Parikh, K., Krishnadath, K. K., Griffiths, L., Colleypriest, B. J., Farrant, J. M., Tosh, D., Das, K. M. and Bajpai, M., 2013. Barrett's esophagus:Cancer and molecular biology. Annals of the New York Academy of Sciences, 1300 (1), pp. 296-314.
Carter, E., Lau, C. Y., Tosh, D., Ward, S. G. and Mrsny, R. J., 2013. Cell penetrating peptides fail to induce an innate immune response in epithelial cells in vitro:Implications for continued therapeutic use. European Journal of Pharmaceutics and Biopharmaceutics, 85 (1), pp. 12-19.
Perán, M., Marchal, J. A., García, M. A., Kenyon, J. and Tosh, D., 2013. In vitro treatment of carcinoma cell lines with pancreatic (pro)enzymes suppresses the EMT programme and promotes cell differentiation. Cellular Oncology, 36 (4), pp. 289-301.
Burke, Z. D. and Tosh, D., 2012. Barrett's metaplasia as a paradigm for understanding the development of cancer. Current Opinion in Genetics & Development, 22 (5), pp. 494-499.
Bone, H. K., Nelson, A. S., Goldring, C. E., Tosh, D. and Welham, M. J., 2011. A novel chemically directed route for the generation of definitive endoderm from human embryonic stem cells based on inhibition of GSK-3. Journal of Cell Science, 124 (12), pp. 1992-2000.
Peran, M., Sanchez-Ferrero, A., Tosh, D., Marchal, J. A., Lopez, E., Alvarez, P., Boulaiz, H., Rodriguez-Serrano, F. and Aranega, A., 2011. Ultrastructural and molecular analyzes of insulin-producing cells induced from human hepatoma cells. Cytotherapy, 13 (2), pp. 193-200.
Al-Adsani, A., Burke, Z. D., Eberhard, D., Lawrence, K. L., Shen, C. N., Rustgi, A. K., Sakaue, H., Farrant, J. M. and Tosh, D., 2010. Dexamethasone treatment induces the reprogramming of pancreatic acinar cells to hepatocytes and ductal cells. PLoS ONE, 5 (10), e13650.
Sangan, C. B. and Tosh, D., 2010. A new paradigm in cell therapy for diabetes: Turning pancreatic alpha-cells into beta-cells. Bioessays, 32 (10), pp. 881-884.
Wu, S. Y., Hsieh, C. C., Wu, R. R., Susanto, J., Liu, T. T., Shen, C. R., Chen, Y., Su, C. C., Chang, F. P., Chang, H. M., Tosh, D. and Shen, C. N., 2010. Differentiation of pancreatic acinar cells to hepatocytes requires an intermediate cell type. Gastroenterology, 138 (7), pp. 2519-2530.
Peran, M., Marchal, J. A., Lopez, E., Jimenez-Navarro, M., Boulaiz, H., Rodriguez-Serrano, F., Carrillo, E., Sanchez-Espin, G., De Teresa, E., Tosh, D. and Aranega, A., 2010. Human cardiac tissue induces transdifferentiation of adult stem cells towards cardiomyocytes. Cytotherapy, 12 (3), pp. 332-337.
Slack, J. M. W., Colleypriest, B. J., Quinlan, J. M., Yu, W. Y., Farrant, J. M. and Tosh, D., 2010. Barrett's metaplasia: molecular mechanisms and nutritional influences. Biochemical Society Transactions, 38 (2), pp. 313-319.
Yuill, K. H., Tosh, D. and Hancox, J. C., 2010. Streptozotocin-induced diabetes modulates action potentials and ion channel currents from the rat atrioventricular node. Experimental Physiology, 95 (4), pp. 508-517.
Buchert, M., Athineos, D., Abud, H. E., Burke, Z. D., Faux, M. C., Samuel, M. S., Jarnicki, A. G., Winbanks, C. E., Newton, I. P., Meniel, V. S., Suzuki, H., Stacker, S. A., Nathke, I. S., Tosh, D., Huelsken, J., Clarke, A. R., Heath, J. K., Sansom, O. J. and Ernst, M., 2010. Genetic dissection of differential signaling threshold requirements for the Wnt/β-Catenin pathway in vivo. Plos Genetics, 6 (1), e1000816.
Eberhard, D., O’Neill, K., Burke, Z. D. and Tosh, D., 2010. In vitro reprogramming of pancreatic cells to hepatocytes. In: Ding, S., ed. Cellular Programming and Reprogramming: Methods and Protocols.636 ed. Humana Press, pp. 285-292.
Li, W.-C., Ralphs, K. L. and Tosh, D., 2010. Isolation and culture of adult mouse hepatocytes. In: Ward, A. and Tosh, D., eds. Mouse Cell Culture: Methods and Protocols.633 ed. Humana Press, pp. 185-196.
Burke, Z. D., Li, W.-C., Slack, J. and Tosh, D., 2010. Isolation and culture of embryonic pancreas and liver. In: Ward, A. and Tosh, D., eds. Mouse Cell Culture: Methods and Protocols.633 ed. Humana Press, pp. 91-99.
Quinian, J. M., Yu, W.-Y. and Tosh, D., 2010. Isolation, culture, and characterisation of mouse embryonic oesophagus and intestine. In: Ward, A. and Tosh, D., eds. Mouse Cell Culture: Methods and Protocols.633 ed. Humana Press, pp. 81-90.
Ward, A. and Tosh, D., eds., 2010. Mouse Cell Culture: Methods and Protocols.Vol. 633. Humana Press.
Colleypriest, B. J., Palmer, R. M., Ward, S. G. and Tosh, D., 2009. Cdx genes, inflammation and the pathogenesis of Barrett's metaplasia. Trends in Molecular Medicine, 15 (7), pp. 313-322.
Burke, Z. D., Reed, K. R., Phesse, T. J., Sansom, O. J., Clarke, A. R. and Tosh, D., 2009. Liver zonation occurs through a β-catenin–dependent, c-Myc–independent mechanism. Gastroenterology, 136 (7), 2316-2324e3.
Sahu, S., Joglekar, M. V., Dumbre, R., Phadnis, S. M., Tosh, D. and Hardikar, A. A., 2009. Islet-like cell clusters occur naturally in human gall bladder and are retained in diabetic conditions. Journal of Cellular and Molecular Medicine, 13 (5), pp. 999-1000.
Sumitran-Holgersson, S., Nowak, G., Thowfeequ, S., Begum, S., Joshi, M., Jaksch, M., Kjaeldgaard, A., Jorns, C., Ericzon, B. G. and Tosh, D., 2009. Generation of hepatocyte-like cells from in vitro transdifferentiated human fetal pancreas. Cell Transplantation, 18 (2), pp. 183-193.
Coad, R. A., Dutton, J. R., Tosh, D. and Slack, J., 2009. Inhibition of Hes1 activity in gall bladder epithelial cells promotes insulin expression and glucose responsiveness. Biochemistry and Cell Biology - Biochimie Et Biologie Cellulaire, 87 (6), pp. 975-987.
Thowfeequ, S., Li, W.-C., Slack, J. M. and Tosh, D., 2009. Reprogramming of liver to pancreas. In: Audet, J. and Stanford, W. L., eds. Stem Cells in Regenerative Medicine.482 ed. Humana Press, pp. 407-418.
Alliouachene, S., Tuttle, R. L., Boumard, S., Lapointe, T., Berissi, S., Germain, S., Jaubert, F., Tosh, D., Birnbaum, M. J. and Pende, M., 2008. Constitutively active Akt1 expression in mouse pancreas requires S6 kinase 1 for insulinoma formation. Journal of Clinical Investigation, 118 (11), pp. 3629-3638.
Pinto, J. P., Ribeiro, S., Pontes, H., Thowfeequ, S., Tosh, D., Carvalho, F. and Porto, G., 2008. Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBP alpha. Blood, 111 (12), pp. 5727-5733.
Eberhard, D. and Tosh, D., 2008. Transdifferentiation and metaplasia as a paradigm for understanding development and disease. Cellular and Molecular Life Sciences (CMLS), 65 (1), pp. 33-40.
Eberhard, D., Tosh, D. and Slack, J., 2008. Origin of pancreatic endocrine cells from biliary duct epithelium. Cellular and Molecular Life Sciences (CMLS), 65 (21), pp. 3467-3480.