A Mecom—Cdk6 toggle switch governs hematopoietic stem-to-multipotent fate transitions via distinct multistable landscapes

Hematopoietic stem cells are required to regenerate the blood system throughout life. We previously discovered that transitions between quiescent stem and multipotent progenitor states are controlled by mutual inhibition between Mecom and Cdk6, with upstream regulation from the insulin-like growth factor (IGF) signaling pathway. To investigate the dynamics of exit from quiescence and the stem-to-multipotent cell state transition, we modeled the Mecom-Cdk6 regulatory network via coupled nonlinear differential equations. Bifurcation analysis revealed that the model permits tetrastability, with two stable intermediate states, suggesting that stem cell exit from quiescence proceeds via multiple fine-scale transitions. Perturbation of Mecom self-activation reorganized the multistable landscape, producing two IGF-dependent landscapes with distinct geometries. At high IGF, transitions proceeded only through an intermediate state, whereas at low IGF, a distinct landscape emerged permitting direct transitions between cell states. Stochastic simulations and minimum action path analysis showed that the multipotent attractor is deep at high IGF, whereas low IGF promotes a transition to quiescence by stabilizing the stem cell state. Simulated pharmacological intervention via CDK4/6 inhibitors destabilized the multipotent state and favored transitions towards a more stem-like quiescent state. Together, these results demonstrate how IGF signaling, Mecom self-activation, and Cdk6 inhibition jointly shape early stem cell fate decisions by dictating the accessible cell states on multistable landscapes and the transition paths that connect them.