Department of Pharmacy and Pharmacology
melanie_welham

Visiting Professor

Email: M.J.Welham@bath.ac.uk

Prof Melanie Welham 

Profile

Molecular Signalling and Regulation of Embryonic Stem Cell Fate

The Welham laboratory has focussed on understanding how molecular signals are coupled to the functional responses of target cells for many years. The primary interests of the group now focus on how signalling processes regulate the behaviour of embryonic stem cells (ESCs).

ESCs have two key properties: (i) Self-renewal – meaning they are able proliferate almost indefinitely while retaining an undifferentiated phenotype and (ii) Pluripotency – the ability to differentiate into all cells of an adult organism. We are addressing questions that are fundamental to our understanding of ESC behaviour, and key to their eventual exploitation, by investigating the molecular signals regulating ESC pluripotency and self-renewal as well as those controlling endoderm and mesoderm differentiation.

Regulation of ES cell self-renewal

We demonstrated that signalling via the phosphoinositide 3-kinase (PI3K) pathway plays an important role in maintenance of mouse ESC self-renewal (Paling et al., 2004), controlled at least in part by the ability of PI3K signalling to regulate expression of the transcription factor Nanog (Storm et al., 2007; 2009; Welham et al., 2011). Using transcriptional profiling, we defined the PI3K-dependent transcriptome and are currently focusing on the role of the Zscan4 family in ESC fate regulation (Storm et al., 2009). We have also demonstrated a key role for Glycogen synthase kinase-3 (Gsk-3) in promoting pluripotency of mouse ESCs (Bone et al., 2009; Welham et al., 2011) and are continuing to investigate its mode of action.

Regulation of ES cell Differentiation

We have previously used mouse ESCs as an in vitro model for developmental haemopoiesis (Paling et al., 2005; Bone and Welham, 2007). More recently, in collaboration with Prof David Tosh, we have focussed on exploiting small molecule-based approaches to chemically direct differentiation of human ESCs (Bone et al., 2011), with a view to generating functional hepatocyte-like cells for use by the pharmaceutical industry in toxicity screening.

Publications

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.

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).

Doughton, G., Wei, J., Tapon, N., Welham, M. J. and Chalmers, A. D., 2014. Formation of a polarised primitive endoderm layer in embryoid bodies requires Fgfr/Erk signalling. PLoS ONE, 9 (4), e95434.

Turinetto, V., Orlando, L., Sanchez Ripoll, Y., Kumpfmueller, B., Storm, M. P., Porcedda, P., Minieri, V., Saviozzi, S., Accomasso, L., Cibrario Rocchietti, E., Moorwood, K., Circosta, P., Cignetti, A., Welham, M. J. and Giachino, C., 2012. High basal γH2AX levels sustain self-renewal of mouse embryonic and induced pluripotent stem cells. Stem Cells, 30 (7), pp. 1414-1423.

Thompson, B. A. N., Storm, M. P., Hewinson, J., Hogg, S., Welham, M. J. and Mackenzie, A. B., 2012. A novel role for P2X7 receptor signalling in the survival of mouse embryonic stem cells. Cellular Signalling, 24 (3), pp. 770-778.

Orlando, L., Sanchez Ripoll, Y., Foster, J., Bone, H., Giachino, C. and Welham, M. J., 2012. Differential coupling of self-renewal signaling pathways in murine induced pluripotent stem cells. PLoS ONE, 7 (1), e30234.

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.

Welham, M. J., Kingham, E., Sanchez Ripoll, Y., Kumpfmueller, B., Storm, M. and Bone, H., 2011. Controlling embryonic stem cell proliferation and pluripotency: the role of PI3K-and GSK-3-dependent signalling. Biochemical Society Transactions, 39 (2), pp. 674-678.

Storm, M. P., Orchard, C. B., Bone, H. K., Chaudhuri, J. B. and Welham, M. J., 2010. Three-dimensional culture systems for the expansion of pluripotent embryonic stem cells. Biotechnology and Bioengineering, 107 (4), pp. 683-695.

Mackenzie, A., Welham, M. and Thompson, B., 2010. Expression of ATP-gated P2X7 receptors in mouse embryonic stem cells. Purinergic Signalling, 6 (Supplement 1), p. 129.

Storm, M. P., Kumpfmueller, B., Thompson, B., Kolde, R., Vilo, J., Hummel, O., Schulz, H. and Welham, M. J., 2009. Characterization of the phosphoinositide 3-kinase-dependent transcriptome in murine embryonic stem cells:identification of novel regulators of pluripotency. Stem Cells, 27 (4), pp. 764-775.

Bone, H. K., Damiano, T., Bartlett, S., Perry, A., Letchford, J., Ripoli, Y. S., Nelson, A. S. and Welham, M. J., 2009. Involvement of GSK-3 in regulation of murine embryonic stem cell self-renewal revealed by a series of bisindolylmaleimides. Chemistry & Biology, 16 (1), pp. 15-27.

Martin-Fernandez, C., Bales, J., Hodgkinson, C., Welman, A., Welham, M. J., Dive, C. and Morrow, C. J., 2009. Blocking phosphoinositide 3-kinase activity in colorectal cancer cells reduces proliferation but does not increase apoptosis alone or in combination with cytotoxic drugs. Molecular Cancer Research, 7 (6), pp. 955-965.

Wei, J., Sanchez Ripoll, Y., Welham, M. and Chalmers, A. D., 2009. Bmp4 promotes differentiation of the first vertebrate epithelium. Mechanisms of Development, 126 (Suppl S), S271.

Kingham, E. and Welham, M., 2009. Distinct roles for isoforms of the catalytic subunit of class-IA PI3K in the regulation of behaviour of murine embryonic stem cells. Journal of Cell Science, 122 (13), pp. 2311-2321.

Schulz, H., Kolde, R., Adler, P., Aksoy, I., Anastassiadis, K., Bader, M., Billon, N., Boeuf, H., Bourillot, P., Buchholz, F., Dani, C., Doss, M. X., Forrester, L., Gitton, M., Henrique, D., Hescheler, J., Himmelbauer, H., Hübner, N., Karantzali, E., Kretsovali, A., Lubitz, S., Pradier, L., Rai, M., Reimand, J., Rolletschek, A., Sachinidis, A., Savatier, P., Stewart, F., Storm, M. P., Trouillas, M., Vilo, J., Welham, M. J., Winkler, J., Wobus, A. M., Hatzopoulos, A. K., Sham, M. H. and , T. F. C., 2009. The FunGenES database: a genomics resource for mouse embryonic stem cell differentiation. PLoS ONE, 4 (9), e6804.

Dobbin, E., Corrigan, P. M., Walsh, C. P., Welham, M. J., Freeburn, R. W. and Wheadon, H., 2008. Tel/PDGFR beta inhibits self-renewal and directs myelomonocytic differentiation of ES cells. Leukemia Research, 32 (10), pp. 1554-1564.

This list was generated on Fri Oct 20 05:03:14 2017 IST.

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