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

Autor:	Bargaje R; Institute for Systems Biology, Seattle, WA 98109., Trachana K; Institute for Systems Biology, Seattle, WA 98109., Shelton MN; Institute for Systems Biology, Seattle, WA 98109., McGinnis CS; Institute for Systems Biology, Seattle, WA 98109., Zhou JX; Institute for Systems Biology, Seattle, WA 98109., Chadick C; Institute for Systems Biology, Seattle, WA 98109., Cook S; Institute for Stem Cell & Regenerative Medicine, University of Washington Medicine Research, Seattle, WA 98109., Cavanaugh C; Institute for Stem Cell & Regenerative Medicine, University of Washington Medicine Research, Seattle, WA 98109., Huang S; Institute for Systems Biology, Seattle, WA 98109; sui.huang@systemsbiology.org Leroy.Hood@systemsbiology.org., Hood L; Institute for Systems Biology, Seattle, WA 98109; sui.huang@systemsbiology.org Leroy.Hood@systemsbiology.org.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Feb 28; Vol. 114 (9), pp. 2271-2276. Date of Electronic Publication: 2017 Feb 06.
DOI:	10.1073/pnas.1621412114
Abstrakt:	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.
Databáze:	MEDLINE
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