Modeling heterogeneity in the pluripotent state: A promising strategy for improving the efficiency and fidelity of stem cell differentiation

Abstract

Pluripotency can be considered a functional characteristic of pluripotent stem cells (PSCs) populations and their niches, rather than a property of individual cells. In this view, individual cells within the population independently adopt a variety of different expression states, maintained by different signaling, transcriptional, and epigenetics regulatory networks. In this review, we propose that generation of integrative network models from single cell data will be essential for getting a better understanding of the regulation of self‐renewal and differentiation. In particular, we suggest that the identification of network stability determinants in these integrative models will provide important insights into the mechanisms mediating the transduction of signals from the niche, and how these signals can trigger differentiation. In this regard, the differential use of these stability determinants in subpopulation‐specific regulatory networks would mediate differentiation into different cell fates. We suggest that this approach could offer a promising avenue for the development of novel strategies for increasing the efficiency and fidelity of differentiation, which could have a strong impact on regenerative medicine.

Nuclear Respiratory Factor 1 Acting as an Oncoprotein Drives Estrogen-Induced Breast Carcinogenesis

“…Our findings appear to support stochastic acquisition of different CSC fates presumably through NRF1 mediated stochastic transcriptional programming. The same seems to be true in generating heterogeneous ER-BCSCs during the evolution of human breast tumors [32,33]. These findings suggest that estrogenic chemical (17β-estradiol)-dependent stochastic NRF1 transcriptional programming of genetically homogeneous CSC populations results in heterogeneous BCSC-like subsets, with each lineage containing unique surface markers and specific NRF1 molecular signatures.…”

Pluripotency gene network dynamics: System views from parametric analysis

“…Along with whole-genome technologies, high-resolution imaging and other experimental approaches, mathematical modeling becomes one of the tools for understanding of molecular mechanisms behind cell pluripotency and differentiation (reviewed in [ 7 , 8 ]). For simulations, a molecular genetic process represents as a regulatory gene network handling of input signals.…”

Stabilization of mouse haploid embryonic stem cells with combined kinase and signal modulation

“…Environmental cues can trigger different responses in ESC cultures, leading to distinct gene expression networks under different culture conditions 48 , 49 . In this study, we found that RDF/PD166285 could facilitate long-term maintenance of haESCs in the 2i culture medium, but not in the ES medium, indicating that the culture condition is also critical in stabilizing the haploid state.…”