Paracrine mechanisms in early differentiation of human pluripotent stem cells: Insights from a mathematical model

Stem Cell Research
Erika GaspariHenning Kempf

Abstract

With their capability to self-renew and differentiate into derivatives of all three germ layers, human pluripotent stem cells (hPSCs) offer a unique model to study aspects of human development in vitro. Directed differentiation towards mesendodermal lineages is a complex process, involving transition through a primitive streak (PS)-like stage. We have recently shown PS-like patterning from hPSCs into definitive endoderm, cardiac as well as presomitic mesoderm by only modulating the bulk cell density and the concentration of the GSK3 inhibitor CHIR99021, a potent activator of the WNT pathway. The patterning process is modulated by a complex paracrine network, whose identity and mechanistic consequences are poorly understood. To study the underlying dynamics, we here applied mathematical modeling based on ordinary differential equations. We compared time-course data of early hPSC differentiation to increasingly complex model structures with incremental numbers of paracrine factors. Model simulations suggest at least three paracrine factors being required to recapitulate the experimentally observed differentiation kinetics. Feedback mechanisms from both undifferentiated and differentiated cells turned out to be crucial. Evidence f...Continue Reading

Citations

Aug 15, 2020·Frontiers in Bioengineering and Biotechnology·Bianca WilliamsSelen Cremaschi
Feb 10, 2021·Nature Biotechnology·Lika DrakhlisRobert Zweigerdt
Sep 8, 2021·Critical Reviews in Biotechnology·Miguel J S FerreiraSusan J Kimber

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