Deciphering the dynamical origin of mixed population during neural stem cell developmental lineage commitment

Neural stem cells (NSC's) often give rise to mixed population of cells during differentiation. However, the dynamical origin of these mixed states is poorly understood. In this article, our mathematical modeling study demonstrates that the bone morphogenetic protein 2 (BMP2) driven differential differentiation dynamics of NSC's in central and peripheral nervous systems essentially function through two distinct bi-stable switches that are mutually interconnected. Stochastic simulations of the model reveal that the mixed population originates due to the existence of these bistable switching regulations while the maintenance of such mixed states depends on the level of stochastic fluctuations of the system. Importantly, the model predicts that by individually altering the expression level of key regulatory proteins, the NSC's can be converted entirely to a preferred phenotype for BMP2 doses that earlier resulted into mixed population. Our findings show that efficient neuronal regeneration can be achieved by systematically maneuvering the differentiation dynamics. One-sentence summary Unraveling the differential dynamical origin, maintenance and escape route of mixed population in the midst of developmental fate commitment in central and peripheral nervous systems