Regulation of neural stem cell fate decisions by mitochondrial dynamics

Stem cells possess the ability to divide symmetrically or asymmet- rically to allow for maintenance of the stem cell pool or become committed progenitors and differentiate into various cell lineages. The unique self-renewal capabilities and pluripotency of stem cells are integral to tissue regeneration and repair （Oh et al., 2014）. Mul- tiple mechanisms including intracellular programs and extrinsic cues are reported to regulate neural stem cell （NSC） fate （Bond et al., 2015）. A recent study, published in Cell Stern Cell, identified a novel mechanism whereby mitochondrial dynamics drive NSC fate （Khacho et al., 2016）.

Mathematical modeling reveals the mechanisms of feedforward regulation in cell fate decisions in budding yeast

The determination of cell fate is one of the key questions of developmental biology. Recent experiments showed that feedforward regulation is a novel feature of regulatory networks that controls reversible cellular transitions. However, the underlying mechanism of feedforward regulation-mediated cell fate decision is still unclear. Therefore, using experimental data, we develop a full mathematical model of the molecular network responsible for cell fate selection in budding yeast. To validate our theoretical model, we first investigate the dynamical behaviors of key proteins at the Start transition point and the G1/S transition point; a crucial three-node motif consisting of cyclin （Clnl/2）, Substrate/Subunit Inhibitor of cyclin-dependent protein kinase （Sic1） and cyclin B （C165/6） is considered at these points. The rapid switches of these important components between high and low levels at two transition check points are demonstrated reasonably by our model. Many experimental observations about cell fate decision and cell size control are also theoretically reproduced. Interestingly, the feedforward regulation provides a reliable separation between different cell fates. Next, our model reveals that the threshold for the amount of WHiskey OVhi5） removed from the nucleus is higher at the Reentry point in pheromone-arrested cells compared with that at the Start point in cycling cells. Furthermore, we analyze the hysteresis in the cell cycle kinetics in response to changes in pheromone concentration, showing that Cln3 is the primary driver of reentry and Clnl/2 is the secondary driver of reentry. In particular, we demonstrate that the inhibition of C1nl/2 due to the accumulation of Factor ARrest （Far1） directly reinforces arrest. Finally, theoretical work verifies that the three-node coherent feedforward motif created by cell FUSion （Fus3）, Farl and STErile （Stel2） ensures the rapid arrest and reversibility of a cellular state. The combination of our theoretical model and the previous experimental data contributes to the understanding of the molecular mechanisms of the cell fate decision at the G1 phase in budding yeast and will stimulate further biological experiments in future.

Induced Pluripotency for Translational Research

The advent of induced pluripotent stem cells （iPSCs） has revolutionized the concept of cellular reprogramming and potentially will solve the immunological compatibility issues that have so far hindered the application of human pluripotent stem cells in regenerative medicine. Recent findings showed that pluripotency is defined by a state of balanced lineage potency, which can be artificially instated through various procedures, including the conventional Yamanaka strategy. As a type of pluripotent stem cell, iPSCs are subject to the usual concerns over purity of differen- tiated derivatives and risks of tumor formation when used for cell-based therapy, though they pro- vide certain advantages in translational research, especially in the areas of personalized medicine, disease modeling and drug screening, iPSC-based technology, human embryonic stem cells （hESCs） and direct lineage conversion each will play distinct roles in specific aspects of translational medi- cine, and continue yielding surprises for scientists and the public.