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Cell population structure prior to bifurcation predicts efficiency of directed differentiation in human induced pluripotent cells

Significance Induced pluripotent stem cells (iPSCs) open new possibilities for generating personalized disease models and drug testing. However, iPSC differentiation to a specific cell type can take weeks to complete, delaying the optimization process (maximize yield of desired cell types) for each patient’s iPSC. This task can be accelerated if the destination cell type can be determined early during cell lineage trajectory before cells manifest the desired phenotype. Our results indicate such a possibility: by quantifying the cell population structure during a critical state transition, we identified key regulators of lineages commitment and predicted the percentage of desired cell types for several protocol variations 2 wk in advance. Steering the differentiation of induced pluripotent stem cells (iPSCs) toward specific cell types is crucial for patient-specific disease modeling and drug testing. This effort requires the capacity to predict and control when and how multipotent progenitor cells commit to the desired cell fate. Cell fate commitment represents a critical state transition or “tipping point” at which complex systems undergo a sudden qualitative shift. To characterize such transitions during iPSC to cardiomyocyte differentiation, we analyzed the gene expression patterns of 96 developmental genes at single-cell resolution. We identified a bifurcation event early in the trajectory when a primitive streak-like cell population segregated into the mesodermal and endodermal lineages. Before this branching point, we could detect the signature of an imminent critical transition: increase in cell heterogeneity and coordination of gene expression. Correlation analysis of gene expression profiles at the tipping point indicates transcription factors that drive the state transition toward each alternative cell fate and their relationships with specific phenotypic readouts. The latter helps us to facilitate small molecule screening for differentiation efficiency. To this end, we set up an analysis of cell population structure at the tipping point after systematic variation of the protocol to bias the differentiation toward mesodermal or endodermal cell lineage. We were able to predict the proportion of cardiomyocytes many days before cells manifest the differentiated phenotype. The analysis of cell populations undergoing a critical state transition thus affords a tool to forecast cell fate outcomes and can be used to optimize differentiation protocols to obtain desired cell populations.