Abstract
The fate choice of human embryonic stem cells (hESCs) is controlled by complex signaling milieu synthesized by diverse chemical factors in the growth media. Prevalence of crosstalks and interactions between parallel pathways renders any analysis probing the process of fate transition of hESCs elusive. This work presents an important step in the evaluation of network level interactions between signaling molecules controlling endoderm lineage specification from hESCs using a statistical network identification algorithm. Network analysis was performed on detailed signaling dynamics of key molecules from TGF-β/SMAD, PI3K/AKT and MAPK/ERK pathways under two common endoderm induction conditions. The results show the existence of significant crosstalk interactions during endoderm signaling and they identify differences in network connectivity between the induction conditions in the early and late phases of signaling dynamics. Predicted networks elucidate the significant effect of modulation of AKT mediated crosstalk leading to the success of PI3K inhibition in inducing efficient endoderm from hESCs in combination with TGF-β/SMAD signaling.
Highlights
Human embryonic stem cells are a promising raw material for regenerative medicine applications because of their potential for directed differentiation into clinically relevant cell types
In differentiating Human embryonic stem cells (hESCs) to lineages of pancreas, liver, etc., an important first step is the induction of Definitive Endoderm [1]
The quality of later stage maturation is dictated by the initial pathway of endoderm differentiation [2]
Summary
Human embryonic stem cells (hESCs) are a promising raw material for regenerative medicine applications because of their potential for directed differentiation into clinically relevant cell types. Extensive research over a decade have given rise to alternate protocols for endoderm induction of hESCs that employ unique combinations of growth factors and small molecules [3,4,5,6,7]. These protocols aim to recapitulate signaling dynamics mimicking in vivo development of endoderm. Among these signaling mediators, activation of TGF-β/SMAD2,3 pathway by ligand molecules like Activin A (called Activin ) has been identified as necessary to induce endoderm differentiation of hESCs [8]. The resulting endoderm cells show good potential to transform into pancreatic β-like cells with continued differentiation [2,10]
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