Systematic dynamical analysis reveals the hierarchical hematopoietic differentiation.

Abstract

The differentiation of hematopoietic stem cells has been investigated through extensive experimental studies, establishing a paradigm for stem cell differentiation studies. However, a systematic dynamical analysis of the intricate lineage progression in hematopoiesis has yet to be fully elucidated. In this paper, we construct a dynamical model which allows us to identify seven essential cell states throughout the hierarchical process of hematopoietic differentiation. Starting from common myeloid progenitors, the model tracks the progression through granulocyte-monocyte progenitors and megakaryocyte-erythrocyte progenitors, ultimately giving rise to the generation of monocytes, granulocytes, erythrocytes, and megakaryocytes. By performing systematic perturbations and statistical analyses, we uncover the core networks associated with these cell states and the mechanisms underlying cell fate transitions. For a system of ordinary differential equations describing a known gene regulatory network, by performing random searches within a high-dimensional parameter space, we can create a mapping between specific parameter configurations and diverse cell fates, thus providing profound insights into the intricate processes underlying cellular differentiation. The model presented here provides a comprehensive description of the underlying dynamics and gives deeper insights into the intricate mechanisms of cellular fate determination during the hierarchical cascade of hematopoietic differentiation.