Dynamically adjusted cell fate decisions and resilience to mutant invasion during steady state hematopoiesis revealed by an experimentally parameterized mathematical model

A major next step in hematopoietic stem cell (HSC) biology is to obtain a thorough quantitative understanding of cellular and evolutionary dynamics involved in undisturbed hematopoiesis. Mathematical models are key in this respect, and are most powerful when parameterized experimentally and containing sufficient biological complexity. Mathematical models of hematopoiesis have either been parameterized experimentally without non-linear dynamics, or they include these complexities but have not been parameterized to the same extent. We bridge this gap using mouse data to parameterize a mathematical model of hematopoiesis that includes homeostatic control mechanisms as well as clonal evolution. We find that non-linear feedback control drastically changes the interpretation of kinetic estimates at homeostasis. This suggests that short-term HSC and multipotent progenitors (MPPs) can dynamically adjust to sustain themselves in the absence of long-term HSCs, even if they differentiate more often than they self-renew in undisturbed homeostasis. Additionally, the presence of feedback control in the model renders the system resilient against mutant invasion. Invasion barriers, however, can be overcome by a combination of age-related changes in stem cell differentiation and a mutant-associated inflammatory environment. This helps us understand the evolution of e.g. TET2, DNMT3A , or JAK2 mutants, and how to potentially reduce mutant burden.