作者: Jennifer Enciso , Luis Mendoza , Elena R. Álvarez-Buylla , Rosana Pelayo
DOI: 10.7717/PEERJ.9902
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摘要: Background The blockage at the early B lymphoid cell development pathway within bone marrow is tightly associated with hematopoietic and immune diseases, where disruption of basal regulatory networks prevents continuous replenishment functional cells. Dynamic computational models may be instrumental for comprehensive understanding mechanisms underlying complex differentiation processes provide novel prediction/intervention platforms to reinvigorate system. Methods By reconstructing a three-module network including genetic transcription, intracellular transduction, microenvironment communication, we have investigated lineage fate decisions in normal pathological settings. was simulated as Boolean model then transformed, using fuzzy logic, model. We tested null overexpression mutants analyze emergent behavior network. Due its importance inflammation, effect NFkB induction different stages. Results While exhaustive synchronous asynchronous simulation (eBCRN) reproduced configurations progenitors precursors pathway, logics suggested transient IL-7R+ ProB-to-Pre-B subset expressing pre-BCR series dominant B-cell transcriptional factors. This conspicuous differentiating population up-regulated CXCR7 reduced CXCR4 FoxO1 expression levels. Strikingly, constant but intermediate signaling specific stages allowed stabilization an aberrant CXCR7+ pre-B like phenotype apparent affinity proliferative signals, while under constitutive overactivation NFkB, such aberrantly exacerbated from earliest stage common progenitors. Our mutant revealed abnormal delay BCR assembly upon activation, concomitant sustained Flt3 signaling, down-regulation Ebf1, Irf4 Pax5 genes Ig recombination, pointing potential commitment blockage. Discussion For first time, inducible CXCR7hi precursor endowed capability shifting central niches, inferred by modeling. Its compatible that leukemia-initiating cells might foundation bridges inflammation blockage-related malignancies wide range immunological diseases. Besides predicted impairment, inflammation-inducible phenotypes open possibility newly formed niches colonized reported precursor. Thus, ecosystems are following pro-inflammatory induction, lead instability pathologies.