Endogenous Network Theory And Its Application In The Study Of Early Myeloid Development

Revealing the cell-fate determination and coordination during hematopoietic development is fundamental to our understanding of tissue-homeostasis,malignancy and regenerative medicine.A standard roadmap for the cell-fate diversification during hematopoiesis has been established experimentally,which highlights the stepwise and hierarchical features,yet little is known for its underpinning dynamical mechanism.In addition,many aspects of the hematopoietic development are still controversial: further experimental evidences have led to a series of suggested revisions of the standard roadmap,but a clear consensus on hematopoiesis is still missing;the “reprogramming” or “trans-programming” events have been extensively observed in experiments,which raised questions for the hierarchical model of development.We proposed a unifying and mechanistic dynamical framework to understand hematopoietic development coherently.We constructed a core molecular endogenous network from gene regulation and signal transduction experiments and turned the network into a set of dynamical equations.The landscape computed via the network dynamics served as a quantitative scheme to reveal various developmental possibilities: robust states correspond to cell phenotypes and their interconnections suggested various developmental routes.We obtained a natural explanation of the experimental observations from mechanistic point of view,including the standard roadmap,the revised models and the cell-fate inter-conversion events.In addition,a pool of new cell intermediates and routes in myeloid development were predicted,which are testable by future experiments.The quantitative model provides a unified framework to understand cell-fate determination process and suggested a more complex picture of development.