Mathematical model for of thrombopoiesis

Lead Research Organisation: University of Oxford
Department Name: Mathematical Institute

Abstract

In vivo, megakaryocytes (MKs) in the bone marrow (BM) produce thrombocytes (platelets), required for homeostasis and thrombosis. During this process, called thrombopoiesis, MKs extend large and flexible cytoplasmic structures, called proplatelets, across the fenestrated endothelium of bone marrow sinusoids. Once in the blood stream, the proplatelets are fragmented by the fluid shear to form platelets. In vivo, platelet production is highly efficient with 1011 platelets produced each day and an estimated 1-2 103 platelets released per MK cell.
Platelet transfusions are a key treatment for life-threatening conditions including cancer, chemotherapy and surgery. A potential alternative to donor platelet supply is the production of platelets from human pluripotent stem cells in vitro. Our collaborators, Dr Cedric Ghevaert (Department of Haematology, University of Cambridge) and Professor Ruth Cameron (Cambridge Centre for Medical Materials, University of Cambridge) have developed an in vitro system to engineer donor-independent platelets. The system involves a novel structurally-graded collagen scaffold within a flow bioreactor that is seeded with programmed stem cells. Large quantities of MKs can be produced from human pluripotent stem cells: fluid shear from the flow through the scaffold then provides the MKs with the mechanical cues needed to stimulate platelet production. To date, however, the number of platelets that can be harnessed per MK in this in vitro system is only 1-10 platelets per MK.
This project aims to develop a suite of mathematical models for platelet production (both in vivo and in vitro), providing mechanistic insights into platelet production in vivo that can be used to guide the in vitro bioreactor design and operating conditions. The modelling will take a continuum mechanics approach, with fluid and solid mechanics models coupled to models for topological changes to single cell geometry in response to mechanical cues. The mathematical models, which will consist of coupled systems of partial differential equations, will be solved using a combination of analytical and numerical methods. The mathematical models will be underpinned and validated against real data provided by our collaborators at the University of Cambridge. We aim to use our model in a predictive context to inform bioreactor design and operating conditions. The development of these models will reduce the required amount of laboratory testing and accelerate the clinical translation of this in vitro system.
This project falls into the EPSRC research areas of Mathematical Sciences and Healthcare Technologies, since we aim to optimise a regenerative medicine therapy through the use of mathematical modelling.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/R513295/1 01/10/2018 30/09/2023
2100109 Studentship EP/R513295/1 01/10/2018 31/03/2022 Helen Zha