A System-Level Model Reveals that Transcriptional Stochasticity is Required for Hematopoietic Stem Cell Differentiation

Abstract

Background The differentiation of hematopoietic stem cells towards their different cell fates, has been difficult to study experimentally due to the diverse number of physiological conditions involved in it. These experimental obstacles have generated antagonistic positions to explain this differentiation process.Methods Here, we build a gene regulation network that integrates several aspects documented in the literature on the regulation of the differentiation of hematopoietic stem cells towards their different cell fates. Based on this network, we used Boolean, stochastic and continuous models to simulate the conditions of the hematopoietic stem cell niche under physiological conditions.Results We found that the differentiation of hematopoietic stem cells is a process in which cell fates can transdifferentiate among themselves through plasticity phenomena, which are supported by the stochasticity of transcription. Finally, we found that oxygen activates the production of reactive oxygen species that inhibits the quiescence of hematopoietic stem cells and promote the growth and differentiation pathways of the hematopoietic stem cells.Conclusion Hematopoiesis is a plastic process strongly conditioned at a genetic level that can be altered by the microenvironment in which it takes place, as well as by metabolism.