Dynamical modeling predicts an inflammation-inducible CXCR7+ B cell precursor with potential implications in lymphoid blockage pathologies

Abstract

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

Patient-Derived Bone Marrow Spheroids Reveal Leukemia-Initiating Cells Supported by Mesenchymal Hypoxic Niches in Pediatric B-ALL

“…Therefore, due to their clinical and therapeutical implications, it is critical to characterize the relationship between LICs and their microenvironment. Computational modeling approaches have recently inferred a unique inflammation-inducible CXCR7 + B-precursor cell population, displaying abnormal phenotypes and presumably able to colonize distinct emergent inflammatory niches producing CXCL11 ( 19 ). Moreover, three-dimensional (3D) hematopoietic structures have been instrumental to advance our knowledge on cell-to-cell intercommunication, nutrient diffusion, oxygen gradients, hypoxic zone formation, and HSPC expansion ( 20 , 21 ).…”

SARS-CoV-2 Nsp5 Protein Causes Acute Lung Inflammation, A Dynamical Mathematical Model

“…Despite all the molecular knowledge rapidly accumulated on SARS-CoV-2 itself and the infection or inflammation processes in which it is involved in human cells, we still lack dynamical models to understand which are the key nodes underlying severe inflammation processes in some cases. Mathematical and computational dynamic network models are useful tools to integrate data, find experimental holes and also propose or understand the underlying dynamics mechanisms involved in the complex viral/human networks involved during SARS-CoV-2 infection (Breitling, 2010;Díaz, 2020a;Enciso et al, 2020;Weinstein et al, 2020). The number of nodes, the number of connections of each node to its neighbours, and the distribution of these connections in the network determine its complexity, structure and dynamical properties (Kumar et al, 2020).…”

SARS CoV 2 Nsp5 Protein Causes Acute Lung Inflammation, a Dynamical Mathematical Model

“…Despite all the molecular knowledge rapidly accumulated on SARS-CoV-2 itself and the infection or inflammation processes in which it is involved in human cells, we still lack dynamical models to understand which are the key nodes underlying severe inflammation processes in some cases. Mathematical and computational dynamic network models are useful tools to integrate data, find experimental holes and also propose or understand the underlying dynamics mechanisms involved in the complex viral/human networks involved during SARS-CoV-2 infection 1,14,15,16 . The number of nodes, the number of connections of each node to its neighbours, and the distribution of these connections in the network determine its complexity, structure and dynamical properties 17 .…”

“…function. A) When the external signal (t) is the step function of Eq (16). of main text and is applied to the ARS in absence of Nsp5 (black line) the level of cytokine IL-6 initially increases to a maximum value of 20 pg mL-1 , and becomes zero when the external signal is switched off.…”