Browsing by Author "Camacho-Aguilar, Elena"

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    Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR
    (Springer Nature, 2022) Sempou, Emily; Kostiuk, Valentyna; Zhu, Jie; Cecilia Guerra, M.; Tyan, Leonid; Hwang, Woong; Camacho-Aguilar, Elena; Caplan, Michael J.; Zenisek, David; Warmflash, Aryeh; Owens, Nick D. L.; Khokha, Mustafa K.
    Transitioning from pluripotency to differentiated cell fates is fundamental to both embryonic development and adult tissue homeostasis. Improving our understanding of this transition would facilitate our ability to manipulate pluripotent cells into tissues for therapeutic use. Here, we show that membrane voltage (Vm) regulates the exit from pluripotency and the onset of germ layer differentiation in the embryo, a process that affects both gastrulation and left-right patterning. By examining candidate genes of congenital heart disease and heterotaxy, we identify KCNH6, a member of the ether-a-go-go class of potassium channels that hyperpolarizes the Vm and thus limits the activation of voltage gated calcium channels, lowering intracellular calcium. In pluripotent embryonic cells, depletion of kcnh6 leads to membrane depolarization, elevation of intracellular calcium levels, and the maintenance of a pluripotent state at the expense of differentiation into ectodermal and myogenic lineages. Using high-resolution temporal transcriptome analysis, we identify the gene regulatory networks downstream of membrane depolarization and calcium signaling and discover that inhibition of the mTOR pathway transitions the pluripotent cell to a differentiated fate. By manipulating Vm using a suite of tools, we establish a bioelectric pathway that regulates pluripotency in vertebrates, including human embryonic stem cells.
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    Quantifying cell transitions in C. elegans with data-fitted landscape models
    (Public Library of Science, 2021) Camacho-Aguilar, Elena; Warmflash, Aryeh; Rand, David A.
    Increasing interest has emerged in new mathematical approaches that simplify the study of complex differentiation processes by formalizing Waddington’s landscape metaphor. However, a rational method to build these landscape models remains an open problem. Here we study vulval development in C. elegans by developing a framework based on Catastrophe Theory (CT) and approximate Bayesian computation (ABC) to build data-fitted landscape models. We first identify the candidate qualitative landscapes, and then use CT to build the simplest model consistent with the data, which we quantitatively fit using ABC. The resulting model suggests that the underlying mechanism is a quantifiable two-step decision controlled by EGF and Notch-Delta signals, where a non-vulval/vulval decision is followed by a bistable transition to the two vulval states. This new model fits a broad set of data and makes several novel predictions.