Top‐Down Inhibition (TDi) and Baseline Activation (BLa): Controlling Signal Transduction When Endogenous Cytokines are Ruining Your Differentiation

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Abstract
In the 20 years since the first human pluripotent stem cell (hPSC) lines were established, there have been a plethora of protocols developed that allow us to generate a wide range of human cell types in vitro. Efforts to achieve a greater degree of specificity and efficiency in generating desired cell types have resulted in increasingly complex approaches. The magnitude and timing of signals has become key, and the concept of a “fully defined” system is a forever sought‐after goal with shifting goalposts. This overview discusses two related approaches that can be used to deliver a tightly regulated, intermediate‐strength signal, and which can also manage the impact of endogenous signaling variation and enable a switch away from bovine serum albumin–containing medium to a better‐defined system without suffering a subsequent loss of robustness or efficiency. The approaches, referred to as top‐down inhibition and baseline activation, were developed to deliver intermediate levels of BMP and WNT signaling during neural crest induction from hPSC, but could be applied to a variety of other signals and differentiation systems. © 2019 by John Wiley & Sons, Inc.

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