Characterising the organisation and dynamics of the IMS and cytoskeleton in human iPSC-derived megakaryocytes and platelet production (Ms Natasha Pavey)

Platelet production is a tightly regulated process where an average adult produces approximately 1.5 x 10^11 platelets per day.

Disruption of platelet production leads to platelet disorders, including thrombocytopenia, thrombocytosis and platelet dysfunction, all of which have serious implications for cardiovascular health.

Furthermore, the clinical requirement for platelet transfusions continues to rise (by ~25% between 2007-14 in the UK) due to an aging population, increased number of patients with haematological malignancies and advances in treatment, such as chemotherapy.

To meet the current and projected demand for blood platelets for transfusion, we need to move to in vitro platelet production, from human induced pluripotent stem cell-derived megakaryocytes (hiPSC-MKs).

The Invaginated Membrane System (IMS) is a critical reservoir of lipid plasma membrane that forms in maturing megakaryocytes and is critical for platelet production. However, the details of its formation are not fully understood and has never been studied in iPSC-MKs.

In this proposal we will investigate mechanisms that drive proper IMS formation and how the microenvironment influences this process.

This knowledge will help in improving the platelet producing potential of iPSC-MKs in vitro, and also in our understanding of diseases relating to platelet count and dysfunction.