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1. Bistable Mathematical Model of Neutrophil Migratory Patterns After LPS-Induced Epigenetic Reprogramming

   https://doi.org/10.3389/fgene.2021.633963  

   Ciupe, Stanca M.; Boribong, Brittany P.; Kadelka, Sarah; Jones, Caroline N. (February 2021, Frontiers in Genetics)

   null (Ed.)

   The highly controlled migration of neutrophils toward the site of an infection can be altered when they are trained with lipopolysaccharides (LPS), with high dose LPS enhancing neutrophil migratory pattern toward the bacterial derived source signal and super-low dose LPS inducing either migration toward an intermediary signal or dysregulation and oscillatory movement. Empirical studies that use microfluidic chemotaxis-chip devices with two opposing chemoattractants showed differential neutrophil migration after challenge with different LPS doses. The epigenetic alterations responsible for changes in neutrophil migratory behavior are unknown. We developed two mathematical models that evaluate the mechanistic interactions responsible for neutrophil migratory decision-making when exposed to competing chemoattractants and challenged with LPS. The first model, which considers the interactions between the receptor densities of two competing chemoattractants, their kinases, and LPS, displayed bistability between high and low ratios of primary to intermediary chemoattractant receptor densities. In particular, at equilibrium, we observe equal receptor densities for low LPS (< 15ng/mL); and dominance of receptors for the primary chemoattractant for high LPS (> 15ng/mL). The second model, which included additional interactions with an extracellular signal-regulated kinase in both phosphorylated and non-phosphorylated forms, has an additional dynamic outcome, oscillatory dynamics for both receptors, as seen in the data. In particular, it found equal receptor densities in the absence of oscillation for super-low and high LPS challenge (< 0.4 and 1.1 <LPS< 375 ng/mL); equal receptor densities with oscillatory receptor dynamics for super-low LPS (0.5 < LPS< 1.1ng/mL); and dominance of receptors for the primary chemoattractant for super-high LPS (>376 ng/mL). Predicting the mechanisms and the type of external LPS challenge responsible for neutrophils migration toward pro-inflammatory chemoattractants, migration toward pro-tolerant chemoattractants, or oscillatory movement is necessary knowledge in designing interventions against immune diseases, such as sepsis. 

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2. Chemotaxis of Drosophila border cells is modulated by tissue geometry through dispersion of chemoattractants

   https://doi.org/10.1016/j.isci.2025.111959  

   George, Alexander; Akhavan, Naghmeh; Peercy, Bradford E; Starz-Gaiano, Michelle (March 2025, iScience)

   Cell migration is critical throughout a multicellular organism’s life from embryogenesis to immune response and tissue repair and can even go aberrantly wrong in diseases like metastatic cancer. In vitro, graded concentrations of diffusible chemoattractants can guide migrating cells, but less is known about chemoattractant distribution and chemotaxis within living organisms, which have complex tissue geometries. Using the border cells, which migrate collectively in the Drosophila egg chamber during oogenesis, we studied how tissue structure affects chemotaxis in vivo. Live-imaged border cells exhibited variations in their chemotactic migration, which correlated positionally within distinct tissue architectures, specifically acellular gaps at cell-cell intersections. To determine how different regions in the egg chamber’s geometry affect chemical cues, we developed a partial differential equation (PDE) model of chemoattractant distribution within a relevant in silico domain. Using a hybrid mathematical model that couples the chemoattractant PDE and an agent-based motion of the cluster, we found that larger extracellular volumes within intersections could locally dampen chemoattractant gradient magnitudes and slow cluster speed in simulations. In vivo, in response to genetically increasing the levels of a chemoattractant, PDGF- and VEGF-related factor 1, border cells exhibited delayed migration and behaved differently within specific architectural regions, consistent with results in silico. We next altered the architectural regions in the migration domain in half pint (hfp) mutant egg chambers and observed migration behaviors that still correlated with tissue features. Importantly, the abnormal tissue geometry was sufficient to rescue defects due to high levels of chemoattractant and resulted in punctual border cell migration indicating chemoattractant distribution can depend on tissue structure. Our modeling data indicate that chemoattractants are more concentrated in certain tissue architectures and dispersed in other regions, likely informing cell migration speeds and favoring clustered cell movements in tissue that contain varied architectures in vivo. Our results shed light on the intricate interplay between tissue geometry and the local distribution of important signaling molecules in orchestrating the essential process of cell migration. 

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3. Ranking migration cue contributions to guiding individual fibroblasts faced with a directional decision in simple microfluidic bifurcations

   https://doi.org/10.1093/intbio/zyz018  

   Pham, Quang Long; Tong, Anh; Rodrigues, Lydia N; Zhao, Yang; Surblyte, Migle; Ramos, Diomar; Brito, John; Rahematpura, Adwik; Voronov, Roman S (May 2019, Integrative Biology)

   Abstract Directed cell migration in complex micro-environments, such as in vivo pores, is important for predicting locations of artificial tissue growth and optimizing scaffold architectures. Yet, the directional decisions of cells facing multiple physiochemical cues have not been characterized. Hence, we aim to provide a ranking of the relative importance of the following cues to the decision-making of individual fibroblast cells: chemoattractant concentration gradient, channel width, mitosis, and contact-guidance. In this study, bifurcated micro-channels with branches of different widths were created. Fibroblasts were then allowed to travel across these geometries by following a gradient of platelet-derived growth factor-BB (PDGF-BB) established inside the channels. Subsequently, a combination of statistical analysis and image-based diffusion modeling was used to report how the presence of multiple complex migration cues, including cell-cell influences, affect the fibroblast decision-making. It was found that the cells prefer wider channels over a higher chemoattractant gradient when choosing between asymmetric bifurcated branches. Only when the branches were symmetric in width did the gradient become predominant in directing which path the cell will take. Furthermore, when both the gradient and the channels were symmetric, contact guidance became important for guiding the cells in making directional choices. Based on these results we were able to rank these directional cues from most influential to the least as follows: mitosis > channel width asymmetry > chemoattractant gradient difference > and contact-guidance. It is expected that these results will benefit the fields of regenerative medicine, wound healing and developmental biology. 

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4. Mechanosensitive mTORC2 independently coordinates leading and trailing edge polarity programs during neutrophil migration

   https://doi.org/10.1091/mbc.E22-05-0191  

   Saha, Suvrajit; Town, Jason P.; Weiner, Orion D. (May 2023, Molecular Biology of the Cell)

   Huttenlocher, Anna (Ed.)

   By acting both upstream and downstream of biochemical organizers of the cytoskeleton, physical forces function as central integrators of cell shape and movement. Here we use a combination of genetic, pharmacological, and optogenetic perturbations to probe the role of the conserved mechanosensitive mTORC2 programs in neutrophil polarity and motility. We find that the tension-based inhibition of leading edge signals (Rac, F-actin) that underlies protrusion competition is gated by the kinase-independent role of the complex, whereas the regulation of RhoA and Myosin II-based contractility at the trailing edge depend on mTORC2 kinase activity. mTORC2 is essential for spatial and temporal coordination of the front and back polarity programs for persistent migration under confinement. This mechanosensory pathway integrates multiple upstream signals, and we find that membrane stretch synergizes with biochemical co-input PIP3 to robustly amplify mTORC2 activation. Our results suggest that different signalling arms of mTORC2 regulate spatially and molecularly divergent cytoskeletal programs for efficient coordination of neutrophil shape and movement. [Media: see text] [Media: see text] 

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5. A microphysiological system reveals neutrophil contact-dependent attenuation of pancreatic tumor progression by CXCR2 inhibition-based immunotherapy

   https://doi.org/10.1038/s41598-024-64780-4  

   Shao, Shuai; Delk, Nikki_A; Jones, Caroline_N (June 2024, Scientific Reports)

   Abstract Cancer cells recruit neutrophils from the bloodstream into the tumor tissue, where these immune cells promote the progression of numerous solid tumors. Studies in mice suggest that blocking neutrophil recruitment to tumors by inhibition of neutrophil chemokine receptor CXCR2 could be a potential immunotherapy for pancreatic cancer. Yet, the mechanisms by which neutrophils promote tumor progression in humans, as well as how CXCR2 inhibition could potentially serve as a cancer therapy, remain elusive. In this study, we developed a human cell-based microphysiological system to quantify neutrophil-tumor spheroid interactions in both “separated” and “contact” scenarios. We found that neutrophils promote the invasion of tumor spheroids through the secretion of soluble factors and direct contact with cancer cells. However, they promote the proliferation of tumor spheroids solely through direct contact. Interestingly, treatment with AZD-5069, a CXCR2 inhibitor, attenuates invasion and proliferation of tumor spheroids by blocking direct contact with neutrophils. Our findings also show that CXCR2 inhibition reduces neutrophil migration toward tumor spheroids. These results shed new light on the tumor-promoting mechanisms of human neutrophils and the tumor-suppressive mechanisms of CXCR2 inhibition in pancreatic cancer and may aid in the design and optimization of novel immunotherapeutic strategies based on neutrophils. 

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