Integrating extrinsic and intrinsic cues into a minimal model of lineage commitment for hematopoietic progenitors

Santhosh Palani, Casim A. Sarkar

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Autoregulation of transcription factors and cross-antagonism between lineage-specific transcription factors are a recurrent theme in cell differentiation. An equally prevalent event that is frequently overlooked in lineage commitment models is the upregulation of lineage-specific receptors, often through lineage-specific transcription factors. Here, we use a minimal model that combines cell-extrinsic and cell-intrinsic elements of regulation in order to understand how both instructive and stochastic events can inform cell commitment decisions in hematopoiesis. Our results suggest that cytokine-mediated positive receptor feedback can induce a "switch- like" response to external stimuli during multilineage differentiation by providing robustness to both bipotent and committed states while protecting progenitors from noise-induced differentiation or decommitment. Our model provides support to both the instructive and stochastic theories of commitment: cell fates are ultimately driven by lineage-specific transcription factors, but cytokine signaling can strongly bias lineage commitment by regulating these inherently noisy cell-fate decisions with complex, pertinent behaviors such as ligand-mediated ultrasensitivity and robust multistability. The simulations further suggest that the kinetics of differentiation to a mature cell state can depend on the starting progenitor state as well as on the route of commitment that is chosen. Lastly, our model shows good agreement with lineage-specific receptor expression kinetics from microarray experiments and provides a computational framework that can integrate both classical and alternative commitment paths in hematopoiesis that have been observed experimentally.

Original languageEnglish (US)
Article numbere1000518
JournalPLoS computational biology
Volume5
Issue number9
DOIs
StatePublished - Sep 2009

Fingerprint Dive into the research topics of 'Integrating extrinsic and intrinsic cues into a minimal model of lineage commitment for hematopoietic progenitors'. Together they form a unique fingerprint.

Cite this