Control of blood cell emergence by YAP and environmental cues

The generation of all blood cells throughout adult life is maintained by blood stem cells. In the clinic, upon transplantation these blood stem cells can successfully restore a fully functional blood system which is compromised in diseases such leukaemia or multi-sclerosis. One major limitation to the use of blood stem cell transplantation in the clinic is the restricted availability of compatible donor for graft recipients. The possibility to generate these blood stem cells in vitro for clinical purposes would significantly advance the use of this curative treatment. Pluripotent stem cells can be efficiently differentiated in vitro to form all blood progenitors but researchers are still struggling to generate blood stem cells.

Using pluripotent stem cells as an in vitro model system to generate blood cells, we propose to investigate how the microenvironment created by the culture conditions may affect the generation of different types of blood cells. We will investigate the molecular mechanisms which control the generation of blood cells in response to signals from the microenvironment. Understanding this will allow us ultimately to precisely control and manipulate biophysical properties for the design of artificial niches to generate blood stem cells usable in the clinic.

The haematopoietic system is maintained throughout adult life by haematopoietic stem cells that produce a constant supply of all blood cells. In the clinic, these stem cells are the cells which upon transplantation successfully restore the blood system in a range of disease. One major limitation to the use of blood stem cell transplantation in the clinic is the restricted availability of compatible donor for graft recipients. The possibility to generate these blood stem cells in vitro for clinical purposes would significantly advance the use of this curative treatment. Pluripotent stem cells can be efficiently differentiated in vitro to form all blood progenitors but researchers are still struggling to generate blood stem cells.

Here we propose to investigate how the mechanotransducer YAP might regulate the emergence of blood cells from hemogenic endothelium during embryonic development. Through gain and loss of function, we will determine how changes in YAP activity impact the generation of blood progenitors upon the in vitro differentiation of embryonic stem cells. Additionally, we will determine whether cellular responses to change in environmental cues, such as adhesiveness, are controlled by YAP. Flow cytometry, time lapse imaging and clonogenic assays will be used to determine the outcome of the culture upon changes in the microenvironment and YAP activity level. This knowledge will allow us ultimately to more precisely control and manipulate biophysical properties for the design of artificial niches to generate blood stem cells usable in the clinic.

In the long term, the data obtained in this programme of research will help devise better protocols and culture conditions for the generation of blood progenitors usable in the clinic for regenerative purposes. This will result in improved "health and wealth" benefits. The data obtained as a result of support by MRC will be disseminated through publication in peer reviewed international academic journals, during conference presentations in the UK and abroad, and online making them available to the broader scientific community. Datasets will be made openly available by deposition in publicly accessible databases. We will communicate our research to a wider audience through public events organised by the University of Manchester. Every opportunity will be taken to engage the general public, politicians and journalists with our research.