Speaker
Description
Hematopoietic stem cells maintain the blood system. In previous work, we discovered that transitions between hematopoietic stem and multipotent progenitor cells can be controlled by mutual inhibition of MECOM and CDK6. High MECOM corresponds to a quiescent stem cell state and high CDK6 to a multipotent progenitor state. The IGF pathway, under the influence of metabolism and diet, promotes CDK6 and inhibits MECOM. To investigate stem cell-to-multipotent transitions, we modeled the MECOM-CDK6 dynamics using coupled differential equations. Bifurcation analysis revealed that the model permits tetrastability, with two stable intermediates, suggesting that early stem cell differentiation proceeds by fine-scaled transitions. Bifurcation analyses to examine the impact of MECOM self-activation on the transition landscape revealed two IGF-dependent tristable regimes with distinct geometries. At high IGF, transitions occurred through a stable intermediate via a cusp geometry. At low IGF, a very different landscape emerged, reminiscent of an elliptic umbilic-like catastrophe. On this landscape, transitions bypassed the intermediate state. Stochastic simulations and minimum action path analysis revealed that while the multipotent state was most stable at high IGF, the stem cell state was highly stable at low IGF, locking cells into a quiescent state. Overall, we show how MECOM self-activation reshapes stem cell fate decisions under the influence of diet and metabolism.
