Characterization of disrupted hematopoiesis by mathematical modelling

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Since their discovery at the University of Toronto in the 1960s, hematopoietic stem cells have been studied intensively. As a result, the blood system is perhaps the best understood stem cell differentiation system. Many of the multiple cytokine feedback mechanisms that regulate hematopoiesis have been successfully characterized, however gaps in our understanding remain. Hematopoietic control loops usually operate faultlessly throughout life, but pathological blood cell production can ensue when this machinery is disrupted. There is a need for new and innovative approaches to quantify and predict the mechanisms responsible for maintaining hematopoiesis, and to elucidate the response of the blood system to disruptions to its production. This research aims to understand and predict the dynamics of hematopoietic stem cell production and clarify the role these dynamics play in homeostatic and stress hematopoiesis. The focus here is to shed light on how disruptions to hematopoietic control systems emerge by leveraging research into two specific blood cell production disorders, namely clonal hematopoiesis (where the blood system is overtaken by descendants from a single blood cell) and chronic inflammation (the sustained overproduction of innate immune white blood cells).By constructing stochastic mathematical models and age-structured delay differential equation models in combination with pharmacokinetic/pharmacodynamic descriptions of the cytokines regulating hematopoiesis and their interactions with different types of blood cells, this interdisciplinary platform will elucidate key hematopoietic relationships and explore how they are modulated by stress. The work will also bring together stochastic and delay models, and develop mathematical methods for their analysis and simulation. In concert with experimental advances, this research program is foundational to understanding homeostatic blood cell production and untangling the biology of how perturbed hematopoiesis develops and is sustained.