We aim to understand how human embryonic cells adopt different fates as they transit from pluripotency to lineage commitment, and exploit this knowledge for regenerative medicine and disease modelling applications. We are focusing particularly on defining the determinants of anteroposterior (A-P) axial identity (i.e. the position cells occupy along the head-tail axis) and how this influences cell fate decision-making in various multipotent progenitors of the central and peripheral nervous system. To address our questions we employ predominantly human pluripotent stem cell (hPSCs) differentiation as an in vitro model of early human embryonic development and utilise protocols we have recently established toward the production of spinal cord progenitors and neural crest cells (the precursors of various specialised cell types including peripheral neurons) that correspond to various levels of the A-P axis.
Current projects in our lab include:
1) Understanding how various cellular components of the trunk (e.g. motor neurons, paraxial mesoderm, trunk neural crest) are derived from multipotent axial progenitors
2) Defining the molecular/signalling basis of A-P axial identity acquisition/maintenance in distinct neural cell types
3) Deciphering the molecular/signalling logic of cell fate decisions in vagal neural crest derivatives focusing on the enteric nervous system
4) Determining how abnormal trunk neural crest development is linked to the initiation of neuroblastoma, the most common extra-cranial solid tumour of childhood
1) Wind, M., Gogolou, A., Manipur, I., Granata, I., Butler, L., Andrews, P. W. A., Barbaric, I., Ning, K., Guarracino, M. R.,
Placzek, M., Tsakiridis, A. (2021). Defining the signalling determinants of a posterior ventral spinal cord identity in human neuromesodermal progenitor derivatives. Development. Mar 23;148(6):dev194415. doi: 10.1242/dev.194415.
2) Frith, T.J.R., Gogolou, A., Hackland, J.O.S., Hewitt, Z.A, Moore, H.D., Barbacic, I., Thapar, N., Burns, A., Andrews, P.W.A., Tsakiridis, A., McCann, C. (2020). Retinoic acid accelerates the specification of enteric neural progenitors from in vitro-derived neural crest. Stem Cell Reports. DOI: https://doi.org/10.1016/j.stemcr.2020.07.024
3) Frith, T.J.R., Granata, I., Wind, Stout, E., M., Thompson, O., Neumman, K., Stavish, D., Heath, P.R., Hackland, J.O.S., Ortmann, D., Anastassiadis, K., Gouti, M., Briscoe, J., Wilson, V., Johnson, SL., Placzek, M., Guarracino, M.R., Andrews, P.W.A., Tsakiridis, A. (2018). Human axial progenitors generate trunk neural crest cells in vitro. Elife. 2018 Aug 10;7. pii: e35786. doi: 10.7554/eLife.35786. [Epub ahead of print].
We are grateful to the following funding bodies for their (past and present) support: BBSRC, The Royal Society, Children's Cancer and Leukaemia Group/Little Princess Trust, MRC Discovery Medicine North Doctoral Training Partnership, the White Rose Mechanistic Biology Doctoral Training program, Neuroblastoma UK, MRC and the EU Horizon 2020 (FET Proactive – Boosting emerging technologies) program.
"Newborn" neuron (marked by the expression of neurofilament heavy polypeptide, NF-H) emerging from a pool of hPSC-derived thoracic (HOXC9+) spinal cord progenitors
PRPH+ sympathetic neurons generated from hPSC-derived trunk neural crest. HOXC9 expression indicates a trunk identity.
Clusters of hPSC-derived spinal cord motor neurons marked by ISL1 and the pan-neuronal marker NF-H