Unravelling the role of beta-catenin in ground state pluripotency

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Stem cells are defined by two properties: they can proliferate indefinitely producing cells identical to themselves (self-renewal property), and can specialise (differentiate) into mature cells types (pluripotency property). In adults, stem cells, found for example in the bone marrow, have mainly a repair function in case of injury. Adult stem cells are currently used also in medical therapy; a typical example is bone marrow transplant for leukemia treatment. The major limit of using adult stem cells for medical purposes is the low availability, and the difficulty to expand them in culture maintaining their features intact. Moreover, adult stem cells have a poor regeneration range, as they are unable to differentiate into all desired cell types.Such issues were overcome thanks to the discovery of embryonic stem cells (ESCs): isolated from blastocysts, ESCs can be cultured in vitro indefinitely, and can give rise, under the appropriate conditions, to every cell type. Also, in 2006 the Nobel Prize winner Yamanaka made an astonishing discovery: somatic cells can be reprogrammed back to a stem-like state, obtaining the so-called induced pluripotent stem cells (iPSCs). ESCs and iPSCs were thought to be a great promise: many believed that their discovery would have fuelled an impressive expansion of regenerative medicine, gene therapy and personalised medicine fields in the short term, ultimately leading to the solution of many health-related problems. So far, only a part of this promise has been fulfilled, mainly because of the scarce knowledge we have about the basic biological processes that make these cells so special. In this research, we aim at improving our understanding of the molecular processes that orchestrate pluripotency focusing on beta-catenin (b-catenin), a pivotal protein in stemness maintenance. Indeed, we and others reported a central role of b-catenin in somatic cell reprogramming, differentiation, pluripotency and tissue regeneration in vivo. Still, the mechanisms through which b-catenin controls pluripotency of embryonic stem cells are highly debated.We will unfold this complexity using an interdisciplinary approach. Using cutting-edge technology, we will engineer mouse ESCs (mESCs) in which b-catenin can be modulated in a number of way (amount of protein, temporal dynamics, ability to regulate other genes). Subsequently, we will perform experiments to link specific b-catenin perturbed behaviours to mESCs self-renewal and differentiation ability. Finally, we will use potent computational approaches to understand how b-catenin interacts with other genes important for pluripotency.The project will provide a vital step of innovation and knowledge to the embryonic stem cells biology field: the results will reveal how b-catenin regulates the balance between pluripotency and differentiation, and indicate how to drive specific cell-fates in vitro.In the future, the output of the proposed project could be extended to control b-catenin dependent self-renewal and differentiation of human ESCs and iPSCs, shortening the distances between pluripotent stem cells and their applicative targets. Also, the developed techniques could be used in other biological processes in which b-catenin is involved, including development and cancer.