Unravelling the molecular mechanisms that drive mitotic defects in human Pluripotent Stem Cells and their potential impact in tumourigenic potential

The Regenerative Medicine of the future will rely on being able to produce a wide variety of "designer" tissues of choice (neurons, heart cells, liver cells, etc) that can be used for tissue replacement in the clinic. This dream has become achievable thanks to the Nobel Prize winning discovery a decade ago of human induced Pluripotent Stem Cells (hiPSCs), a revolutionary technology allowing any cells in our body to be converted into pluripotent stem cells from which almost any desired target tissue of choice could be derived by differentiation in vitro. However, key challenges have to be overcome before the promise of stem cell therapeutics becomes a reality, particularly the fact hiPSC-derived differentiated tissues often retain proliferative and tumourigenic potential for reasons that are not well understood. Recently, the lab of Rafael Carazo Salas (University of Bristol, UK) discovered that human Pluripotent Stem Cells (hPSCs, that is human Embryonic Stem Cells (hESCs) and hiPSCs) display multiple mitotic defects indicative of genome instability, suggesting that some of those defects might be involved in underpinning future tumourigenic potential of hPSC derived cells and tissues.
Therefore, the aim of this project is to identify the molecular mechanisms that drive mitotic defects in hPSCs and the role of these mitotic defects in the tumourigenic potential of stem cells.
Specifically, we aim to:
1. Identify genes that are responsible/involved in the mitotic defects observed in hPSCs, particularly hiPSCs.
2. Investigate whether their deregulation persists beyond differentiation and could be responsible for tumourigenic potential in hPSC derived differentiated cells/tissues.
3. Ask whether their deregulation could be pharmacologically reverted, and whether it is possible to identify potential small molecule compounds that may alleviate those defects.
4. Seek to define predictive properties and features ("Precision Diagnostics" predictors) that might tell for cells, populations or cell lines how mitotically compromised they are, what molecular machineries are dysfunctional, and allow to predict possible tumourigenic potential. In particular, investigate if those Precision Diagnostics can be obtained without exogenous genetically encoded reporters in a label free manner.
5. Time permitting, establish/test whether the predictive power of those "Precision Diagnostics" can be translated to simpler histological assays and readouts, closer to what could be used in more medical settings.