Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Record number 540812
Title Paracrine mechanisms in early differentiation of human pluripotent stem cells : Insights from a mathematical model
Author(s) Gaspari, Erika; Franke, Annika; Robles-Diaz, Diana; Zweigerdt, Robert; Roeder, Ingo; Zerjatke, Thomas; Kempf, Henning
Source Stem Cell Research 32 (2018). - ISSN 1873-5061 - p. 1 - 7.
DOI https://doi.org/10.1016/j.scr.2018.07.025
Department(s) Systems and Synthetic Biology
Publication type Refereed Article in a scientific journal
Publication year 2018
Keyword(s) Differentiation - Human pluripotent stem cells - Mathematical modeling - Paracrine effects - Primitive streak
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 from double knock-down experiments and secreted protein enrichment allowed us to hypothesize on the identity of two of the three predicted factors. From a practical perspective, the mathematical model predicts optimal settings for directing lineage-specific differentiation. This opens new avenues for rational stem cell bioprocessing in more advanced culture systems, e.g. in perfusion-fed bioreactors enabling cell therapies.

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