Abstract
The induction of stem cells toward a desired differentiation direction is required for the advancement of stem cell-based therapies. Despite successful demonstrations of the control of differentiation direction, the effective use of stem cell-based therapies suffers from a lack of systematic knowledge regarding the mechanisms underlying directed differentiation. Using dynamic modeling and the temporal microarray data of three differentiation stages, three dynamic protein-protein interaction networks were constructed. The interaction difference networks derived from the constructed networks systematically delineated the evolution of interaction variations and the underlying mechanisms. A proposed relevance score identified the essential components in the directed differentiation. Inspection of well-known proteins and functional modules in the directed differentiation showed the plausibility of the proposed relevance score, with the higher scores of several proteins and function modules indicating their essential roles in the directed differentiation. During the differentiation process, the proteins and functional modules with higher relevance scores also became more specific to the neuronal identity. Ultimately, the essential components revealed by the relevance scores may play a role in controlling the direction of differentiation. In addition, these components may serve as a starting point for understanding the systematic mechanisms of directed differentiation and for increasing the efficiency of stem cell-based therapies.
Highlights
Stem cell-based therapies require precise control of the processes involved in the differentiation of pluripotent stem cells into specific cell types
We defined the three differentiation stages of pluripotent stem cells (PSCs) into dopamine (DA) neurons corresponding to the three induction conditions
From this a natural and basic question concerning the parts of the induced PSCs follows that are varied concurrent with the evolution of the three stages, as these varied parts may play crucial roles in influencing the differentiation direction
Summary
Stem cell-based therapies require precise control of the processes involved in the differentiation of pluripotent stem cells into specific cell types. Several experimental protocols to induce stem cells toward a desired differentiation direction have been developed based on knowledge of the molecular mechanisms of embryogenesis. Most of these protocols successfully produce the desired outcomes by manipulating the regulators or members of embryogenesis-related pathways. A robust and efficient process to direct differentiation using a series of temporal growth factor manipulations that mimicked embryonic intestinal development was established for the directed differentiation of human pluripotent cells into intestinal tissue [2]. The derivation of floor plate (FP) precursors was induced by a modified dual-SMAD inhibition protocol, progressing to dopamine (DA) neurons with fibroblast growth factors (FGF) and sonic hedgehog (SHH) signals that have the ability
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