Physical immune escape: Weakened mechanical communication leads to escape of metastatic colorectal carcinoma cells from macrophages.

The significance of biochemical cues in the tumor immune microenvironment in affecting cancer metastasis is well established, but the role of physical factors in the microenvironment remains largely unexplored. In this article, we investigated how the mechanical interaction between cancer cells and immune cells, mediated by extracellular matrix (ECM), influences immune escape of cancer cells. We focus on the mechanical regulation of macrophages' targeting ability on two distinct types of colorectal carcinoma (CRC) cells with different metastatic potentials. Our results show that macrophages can effectively target CRC cells with low metastatic potential, due to the strong contraction exhibited by the cancer cells on the ECM, and that cancer cells with high metastatic potential demonstrated weakened contractions on the ECM and can thus evade macrophage attack to achieve immune escape. Our findings regarding the intricate mechanical interactions between immune cells and cancer cells can serve as a crucial reference for further exploration of cancer immunotherapy strategies.

Morphological entropy encodes cellular migration strategies on multiple length scales.

Cell migration is crucial for numerous physiological and pathological processes. A cell adapts its morphology, including the overall and nuclear morphology, in response to various cues in complex microenvironments, such as topotaxis and chemotaxis during migration. Thus, the dynamics of cellular morphology can encode migration strategies, from which diverse migration mechanisms can be inferred. However, deciphering the mechanisms behind cell migration encoded in morphology dynamics remains a challenging problem. Here, we present a powerful universal metric, the Cell Morphological Entropy (CME), developed by combining parametric morphological analysis with Shannon entropy. The utility of CME, which accurately quantifies the complex cellular morphology at multiple length scales through the deviation from a perfectly circular shape, is illustrated using a variety of normal and tumor cell lines in different in vitro microenvironments. Our results show how geometric constraints affect the MDA-MB-231 cell nucleus, the emerging interactions of MCF-10A cells migrating on collagen gel, and the critical transition from proliferation to invasion in tumor spheroids. The analysis demonstrates that the CME-based approach provides an effective and physically interpretable tool to measure morphology in real-time across multiple length scales. It provides deeper insight into cell migration and contributes to the understanding of different behavioral modes and collective cell motility in more complex microenvironments.

Peptide Nucleic Acid Clamp-Assisted Photothermal Multiplexed Digital PCR for Identifying SARS-CoV-2 Variants of Concern.

The unprecedented demand for variants diagnosis in response to the COVID-19 epidemic has brought the spotlight onto rapid and accurate detection assays for single nucleotide polymorphisms (SNPs) at multiple locations. However, it is still challenging to ensure simplicity, affordability, and compatibility with multiplexing. Here, a novel technique is presented that combines peptide nucleic acid (PNA) clamps and near-infrared (NIR)-driven digital polymerase chain reaction (dPCR) to identify the Omicron and Delta variants. This is achieved by simultaneously identifying highly conserved mutated signatures at codons 19, 614, and 655 of the spike protein gene. By microfluidically introducing graphene-oxide-nanocomposite into the assembled gelatin microcarriers, they achieved a rapid temperature ramping-up rate and switchable gel-to-sol phase transformation synchronized with PCR activation under NIR irradiation. Two sets of duplex PCR reactions, each classifying respective PNA probes, are emulsified in parallel and illuminated together using a homemade vacuum-based droplet generation device and a programmable NIR control module. This allowed for selective amplification of mutant sequences due to single-base-pair mismatch with PNA blockers. Sequence-recognized bioreactions and fluorescent-color scoring enabled quick identification of variants. This technique achieved a detection limit of 5,100 copies and a 5-fold quantitative resolution, which is promising to unfold minor differences and dynamic changes.

Whole-genome detection using multivalent DNA-coated colloids.

To minimize the incorrect use of antibiotics, there is a great need for rapid and inexpensive tests to identify the pathogens that cause an infection. The gold standard of pathogen identification is based on the recognition of DNA sequences that are unique for a given pathogen. Here, we propose and test a strategy to develop simple, fast, and highly sensitive biosensors that make use of multivalency. Our approach uses DNA-functionalized polystyrene colloids that distinguish pathogens on the basis of the frequency of selected short DNA sequences in their genome. Importantly, our method uses entire genomes and does not require nucleic acid amplification. Polystyrene colloids grafted with specially designed surface DNA probes can bind cooperatively to frequently repeated sequences along the entire genome of the target bacteria, resulting in the formation of large and easily detectable colloidal aggregates. Our detection strategy allows "mix and read" detection of the target analyte; it is robust and highly sensitive over a wide concentration range covering, in the case of our test target genome Escherichia coli bl21-de3, 10 orders of magnitude from [Formula: see text] to [Formula: see text] copies/mL. The sensitivity compares well with state-of-the-art sensing techniques and has excellent specificity against nontarget bacteria. When applied to real samples, the proposed technique shows an excellent recovery rate. Our detection strategy opens the way to developing a robust platform for pathogen detection in the fields of food safety, disease control, and environmental monitoring.

Run-and-Tumble Dynamics and Mechanotaxis Discovered in Microglial Migration.

Microglia are resident macrophage cells in the central nervous system that search for pathogens or abnormal neural activities and migrate to resolve the issues. The effective search and targeted motion of macrophages mean dearly to maintaining a healthy brain, yet little is known about their migration dynamics. In this work, we study microglial motion with and without the presence of external mechanostimuli. We discover that the cells are promptly attracted by the applied forces (i.e., mechanotaxis), which is a tactic behavior as yet unconfirmed in microglia. Meanwhile, in both the explorative and the targeted migration, microglia display dynamics that is strikingly analogous to bacterial run-and-tumble motion. A closer examination reveals that microglial run-and-tumble is more sophisticated, e.g., they display a short-term memory when tumbling and rely on active steering during runs to achieve mechanotaxis, probably via the responses of mechanosensitive ion channels. These differences reflect the sharp contrast between microglia and bacteria cells (eukaryotes vs. prokaryotes) and their environments (compact tissue vs. fluid). Further analyses suggest that the reported migration dynamics has an optimal search efficiency and is shared among a subset of immune cells (human monocyte and macrophage). This work reveals a fruitful analogy between the locomotion of 2 remote systems and provides a framework for studying immune cells exploring complex environments.

High-throughput microfluidic droplets in biomolecular analytical system: A review.

Droplet microfluidic technology has revolutionized biomolecular analytical research, as it has the capability to reserve the genotype-to-phenotype linkage and assist for revealing the heterogeneity. Massive and uniform picolitre droplets feature dividing solution to the level that single cell and single molecule in each droplet can be visualized, barcoded, and analyzed. Then, the droplet assays can unfold intensive genomic data, offer high sensitivity, and screen and sort from a large number of combinations or phenotypes. Based on these unique advantages, this review focuses on up-to-date research concerning diverse screening applications utilizing droplet microfluidic technology. The emerging progress of droplet microfluidic technology is first introduced, including efficient and scaling-up in droplets encapsulation, and prevalent batch operations. Then the new implementations of droplet-based digital detection assays and single-cell muti-omics sequencing are briefly examined, along with related applications such as drug susceptibility testing, multiplexing for cancer subtype identification, interactions of virus-to-host, and multimodal and spatiotemporal analysis. Meanwhile, we specialize in droplet-based large-scale combinational screening regarding desired phenotypes, with an emphasis on sorting for immune cells, antibodies, enzymatic properties, and proteins produced by directed evolution methods. Finally, some challenges, deployment and future perspective of droplet microfluidics technology in practice are also discussed.

Microfluidic electrospray generation of porous magnetic Janus reduced graphene oxide/carbon composite microspheres for versatile adsorption.

HYPOTHESIS: Graphene-based microparticles materials are broadly utilized in all sorts of fields owing to their outstanding properties. Despite great progress, the present graphene microparticles still face challenges in the aspects of size uniformity, motion flexibility, and tailorable surface chemistry, which limit their application in some specific fields, such as versatile adsorption. Hence, the development of novel graphene microparticles with the aforementioned characteristics is urgently required. EXPERIMENTS: We presented a simple microfluidic electrospray strategy to generate magnetic Janus reduced graphene oxide/carbon (rGO/C) composite microspheres with a variety of unique features. Specifically, the microfluidic electrospray method endowed the obtaiend microspheres with sufficient size uniformity as well as magnetic responsive motion ability. Additionally, magnetic-mediated surface assembly of phase transition lysozyme (PTL) nanofilm on the microspheres rendered the deposited area hydrophilic while non-deposited area hydrophobic. FINDINGS: Such magnetic Janus rGO/C composite microspheres with regionalized wettability characteristics not only showed prominent performance in adsorbing organic liquids with high adsorption capacity and remarkable reusability but also displayed satisfying biocompatibility for the efficient uptake of bilirubin. More encouragingly, the microspheres could serve as adsorbents in a simulative hemoperfusion setup, which further demonstrated the clinical application potential of the magnetic Janus rGO/C microspheres. Thus, we anticipate that the obtained magnetic Janus rGO/C composite microspheres could show multifunctional properties toward water treatment and blood molecule cleaning.

Emerging digital PCR technology in precision medicine.

Digital PCR (dPCR) is built on partitioning reagent to the extent that single template molecules are amplified and visualized individually, whereby offers higher precision and other better indicators than the former PCR techniques. Accordingly, dPCR is particular suited for precision medicine applications that require accurate molecular characterization with high sensitivity. This review aims to summarize different applications of dPCR in precision medicine. The state-of-the-art progress of dPCR technique is first introduced, including novel prototype machines and dPCR-integrated biochips. Then the clinical applications based on dPCR technique are briefly described, for instance, detecting biomarkers from tissues and various biopsies components including cell free DNA, circulating tumor cells, extracellular vesicles, and proteins. These emerging dPCR applications have been accepted as auxiliary diagnostic methods in various areas like oncology, infectious disease, and the like. Meanwhile, a usage overview is provided, focusing on successful clinical pilot studies that dPCR is utilized to improve the performances of rare event detection, fine resolution of gene expression analysis, and multiplexing. Finally, some implications and challenges in future research concerning dPCR technique are also discussed.

Construction of in vitro 3-D model for lung cancer-cell metastasis study.

BACKGROUND: Cancer metastasis is the main cause of mortality in cancer patients. However, the drugs targeting metastasis processes are still lacking, which is partially due to the short of effective in vitro model for cell invasion studies. The traditional 2-D culture method cannot reveal the interaction between cells and the surrounding extracellular matrix during invasion process, while the animal models usually are too complex to explain mechanisms in detail. Therefore, a precise and efficient 3-D in vitro model is highly desirable for cell invasion studies and drug screening tests. METHODS: Precise micro-fabrication techniques are developed and integrated with soft hydrogels for constructing of 3-D lung-cancer micro-environment, mimicking the pulmonary gland or alveoli as in vivo. RESULTS: A 3-D in vitro model for cancer cell culture and metastasis studies is developed with advanced micro-fabrication technique, combining microfluidic system with soft hydrogel. The constructed microfluidic platform can provide nutrition and bio-chemical factors in a continuous transportation mode and has the potential to form stable chemical gradient for cancer invasion research. Hundreds of micro-chamber arrays are constructed within the collagen gel, ensuring that all surrounding substrates for tumor cells are composed of natural collagen hydrogel, like the in vivo micro-environment. The 3-D in vitro model can also provide a fully transparent platform for the visual observation of the cell morphology, proliferation, invasion, cell-assembly, and even the protein expression by immune-fluorescent tests if needed. The lung-cancer cells A549 and normal lung epithelial cells (HPAEpiCs) have been seeded into the 3-D system. It is found out that cells can normally proliferate in the microwells for a long period. Moreover, although the cancer cells A549 and alveolar epithelial cells HPAEpiCs have the similar morphology on 2-D solid substrate, in the 3-D system the cancer cells A549 distributed sparsely as single round cells on the extracellular matrix (ECM) when they attached to the substrate, while the normal lung epithelial cells can form cell aggregates, like the structure of normal tissue. Importantly, cancer cells cultured in the 3-D in vitro model can exhibit the interaction between cells and extracellular matrix. As shown in the confocal microscope images, the A549 cells present round and isolated morphology without much invasion into ECM, while starting from around Day 5, cells changed their shape to be spindle-like, as in mesenchymal morphology, and then started to destroy the surrounding ECM and invade out of the micro-chambers. CONCLUSIONS: A 3-D in vitro model is constructed for cancer cell invasion studies, combining the microfluidic system and micro-chamber structures within hydrogel. To show the invasion process of lung cancer cells, the cell morphology, proliferation, and invasion process are all analyzed. The results confirmed that the micro-environment in the 3-D model is vital for revealing the lung cancer cell invasion as in vivo.

Biomimetic Alveolus-on-a-Chip for SARS-CoV-2 Infection Recapitulation.

SARS-CoV-2 has caused a severe pneumonia pandemic worldwide with high morbidity and mortality. How to develop a preclinical model for recapitulating SARS-CoV-2 pathogenesis is still urgent and essential for the control of the pandemic. Here, we have established a 3D biomimetic alveolus-on-a-chip with mechanical strain and extracellular matrix taken into consideration. We have validated that the alveolus-on-a-chip is capable of recapitulating key physiological characteristics of human alveolar units, which lays a fundamental basis for viral infection studies at the organ level. Using virus-analogous chemicals and pseudovirus, we have explored virus pathogenesis and blocking ability of antibodies during viral infection. This work provides a favorable platform for SARS-CoV-2-related researches and has a great potential for physiology and pathophysiology studies of the human lung at the organ level in vitro.

Droplet microfluidics-based biomedical microcarriers.

Droplet microfluidic technology provides a new platform for controllable generation of microdroplets and droplet-derived materials. In particular, because of the ability in high-throughput production and accurate control of the size, structure, and function of these materials, droplet microfluidics presents unique advantages in the preparation of functional microcarriers, i.e., microsized liquid containers or solid particles that serve as substrates of biomolecules or cells. These microcarriers could be extensively applied in the areas of cell culture, tissue engineering, and drug delivery. In this review, we focus on the fabrication of microcarriers from droplet microfluidics, and discuss their applications in the biomedical field. We start with the basic principle of droplet microfluidics, including droplet generation regimes and its control methods. We then introduce the fabrication of biomedical microcarriers based on single, double, and multiple emulsion droplets, and emphasize the various applications of microcarriers in biomedical field, especially in 3D cell culture, drug development and biomedical detection. Finally, we conclude this review by discussing the limitations and challenges of droplet microfluidics in preparing microcarriers. STATEMENT OF SIGNIFICANCE: Because of its precise control and high throughput, droplet microfluidics has been employed to generate functional microcarriers, which have been widely used in the areas of drug development, tissue engineering, and regenerative medicine. This review is significant because it emphasizes recent progress in research on droplet microfluidics in the preparation and application of biomedical microcarriers. In addition, this review suggests research directions for the future development of biomedical microcarriers based on droplet microfluidics by presenting existing shortcomings and challenges.

Abnormal Aggregation of Invasive Cancer Cells Induced by Collective Polarization and ECM-Mediated Mechanical Coupling in Coculture Systems.

Studies on pattern formation in coculture cell systems can provide insights into many physiological and pathological processes. Here, we investigate how the extracellular matrix (ECM) may influence the patterning in coculture systems. The model coculture system we use is composed of highly motile invasive breast cancer cells, initially mixed with inert nonmetastatic cells on a 2D substrate and covered with a Matrigel layer introduced to mimic ECM. We observe that the invasive cells exhibit persistent centripetal motion and yield abnormal aggregation, rather than random spreading, due to a "collective pulling" effect resulting from ECM-mediated transmission of active contractile forces generated by the polarized migration of the invasive cells along the vertical direction. The mechanism we report may open a new window for the understanding of biological processes that involve multiple types of cells.

Porous carbon nanotube microspheres with tailorable surface wettability areas for oil adsorption.

HYPOTHESIS: Oil adsorption is significant for water purification and environmental protection. However, the conventional bulk sorbents face the predicament of uncontrollable motion as well as hydrophobic nature the whole body, which largely restricts their uptake capacity underwater. Hence, novel adsorbent material for high-efficient oil uptake both at the surface and under the water is urgently required. EXPERIMENTS: We presented a phase-transition lysozyme coating approach to fabricate porous carbon nanotube microspheres with tailorable surface wettability areas for versatile oil adsorption. Because of the existence of magnetic nanoparticle in one hemisphere, the multi-sites coating was easily achieved by constantly changing orientations of the magnetic field. Owing to the integration of various hydrophilic functional groups in lysozyme as well as remarkable adhesion to virtually arbitrary materials, the intrinsically hydrophobic surface of the microspheres was partially modified hydrophilic on multiple sites. FINDINGS: It was demonstrated that the unique surface wettability feature and the porous structure enabled the microspheres to adsorb multiple contaminants both floating on the water and underwater. Besides, the magnetic-responsive ability allowed for controllable collection of oil contaminants. These features, along with the reusability, make the porous carbon nanotube microspheres excellent adsorbents for water purification.

Biological gel-based microchamber array for tumor cell proliferation and migration studies in well-controlled biochemical gradients.

Breast cancer metastasis is a complex process controlled by multiple factors, including various cell-cell interactions, cell-environment coupling, and oxygen, nutrient and drug gradients that are intimately related to the heterogeneous breast tissue structure. In this study, we constructed a high-throughput in vitro biochip system containing an array of 642 microchambers arranged in a checkerboard configuration, with each chamber embedded in a composite extracellular matrix (ECM) composed of engineered collagen and Matrigel to mimic local heterogeneous environment in vivo. In addition, a controllable complex tetragonal chemical concentration profile can be achieved by imposing chemical compounds at the four boundaries of the chip, leading to distinct local nutrient and/or drug gradients in the individual microchambers. Here, the microchamber array with composite ECM (MACECM) device aims to simulate multiple tumor cell niches composed of both breast epithelial cells (MCF-10A-GFP) and metastatic breast cancer cells (MDA-MB-231-RFP), which enables systematic studies of cell responses to a variety of biochemical conditions. The results obtained from the MACECM studies indicate that discoidin domain receptor 1 (DDR1) inhibitor 7rh and matrix metalloproteinase inhibitor batimastat, in association with epidermal growth factor (EGF) had no significant effects on the growth of MCF-10A-GFP cells, but had significant effects on DDR1 expression and the related migratory behavior of MDA-MB-231-RFP cells. The MACECM design not only enables the construction of a more realistic in vitro model for investigating cancer cell migration mechanisms but also has considerable potential for further development as a platform for next-generation high-throughput and therapeutic screening (e.g., anti-cancer drug evaluation) and personalized medicine.

Shannon entropy for time-varying persistence of cell migration.

Cell migration, which can be significantly affected by intracellular signaling pathways and extracellular matrix, plays a crucial role in many physiological and pathological processes. Cell migration is typically modeled as a persistent random walk, which depends on two critical motility parameters, i.e., migration speed and persistence time. It is generally very challenging to efficiently and accurately quantify the migration dynamics from noisy experimental data. Here, we introduce the normalized Shannon entropy (SE) based on the FPS of cellular velocity autocovariance function to quantify migration dynamics. The SE introduced here possesses a similar physical interpretation as the Gibbs entropy for thermal systems in that SE naturally reflects the degree of order or randomness of cellular migration, attaining the maximal value of unity for purely diffusive migration (i.e., SE = 1 for the most "random" dynamics) and the minimal value of 0 for purely ballistic dynamics (i.e., SE = 0 for the most "ordered" dynamics). We also find that SE is strongly correlated with the migration persistence but is less sensitive to the migration speed. Moreover, we introduce the time-varying SE based on the WPS of cellular dynamics and demonstrate its superior utility to characterize the time-dependent persistence of cell migration, which typically results from complex and time-varying intra- or extracellular mechanisms. We employ our approach to analyze experimental data of in vitro cell migration regulated by distinct intracellular and extracellular mechanisms, exhibiting a rich spectrum of dynamic characteristics. Our analysis indicates that the SE and wavelet transform (i.e., SE-based approach) offers a simple and efficient tool to quantify cell migration dynamics in complex microenvironment.

Deriving time-varying cellular motility parameters via wavelet analysis.

Cell migration, which is regulated by intracellular signaling pathways (ICSP) and extracellular matrix (ECM), plays an indispensable role in many physiological and pathological process such as normal tissue development and cancer metastasis. However, there is a lack of rigorous and quantitative tools for analyzing the time-varying characteristics of cell migration in heterogeneous microenvironment, resulted from, e.g. the time-dependent local stiffness due to microstructural remodeling by migrating cells. Here, we develop a wavelet-analysis approach to derive the time-dependent motility parameters from cell migration trajectories, based on the time-varying persistent random walk model. In particular, the wavelet denoising and wavelet transform are employed to analyze migration velocities and obtain the wavelet power spectrum. Subsequently, the time-dependent motility parameters are derived via Lorentzian power spectrum. Our results based on synthetic data indicate the superiority of the method for estimating the intrinsic transient motility parameters, robust against a variety of stochastic noises. We also carry out a systematic parameter study and elaborate the effects of parameter selection on the performance of the method. Moreover, we demonstrate the utility of our approach via analyzing experimental data ofin vitrocell migration in distinct microenvironments, including the migration of MDA-MB-231 cells in confined micro-channel arrays and correlated migration of MCF-10A cells due to ECM-mediated mechanical coupling. Our analysis shows that our approach can be as a powerful tool to accurately derive the time-dependent motility parameters, and further analyze the time-dependent characteristics of cell migration regulated by complex microenvironment.

Dynamically Re-Organized Collagen Fiber Bundles Transmit Mechanical Signals and Induce Strongly Correlated Cell Migration and Self-Organization.

Correlated cell migration in fibrous extracellular matrix (ECM) is important in many biological processes. During migration, cells can remodel the ECM, leading to the formation of mesoscale structures such as fiber bundles. However, how such mesoscale structures regulate correlated single-cells migration remains to be elucidated. Here, using a quasi-3D in vitro model, we investigate how collagen fiber bundles are dynamically re-organized and guide cell migration. By combining laser ablation technique with 3D tracking and active-particle simulations, we definitively show that only the re-organized fiber bundles that carry significant tensile forces can guide strongly correlated cell migration, providing for the first time a direct experimental evidence supporting that matrix-transmitted long-range forces can regulate cell migration and self-organization. This force regulation mechanism can provide new insights for studies on cellular dynamics, fabrication or selection of biomedical materials in tissue repairing, and many other biomedical applications.

Subnanometer-Precision Measurements of Transmembrane Motions of Biomolecules in Plasma Membranes Using Quenchers in Extracellular Environment.

Characterization of biomolecular dynamics at cellular membranes lags far behind that in solutions because of challenges to measure transmembrane trafficking with subnanometer precision. Herein, by introducing nonfluorescent quenchers into extracellular environment of live cells, we adopted Förster resonance energy transfer from one donor to multiple quenchers to measure positional changes of biomolecules in plasma membranes. We demonstrated the method by monitoring flip-flops of individual lipids and by capturing transient states of the host defense peptide LL-37 in plasma membranes. The method was also applied to investigate the interaction of the necroptosis-associated protein MLKL with plasma membranes, showing a few distinct depths of MLKL insertion. Our method is especially powerful to quantitate the dynamics of proteins at the cytosolic leaflets of plasma membranes which are usually not accessible by conventional techniques. The method will find wide applications in the systematic analysis of fundamental cellular processes at plasma membranes.

Modeling multicellular dynamics regulated by extracellular-matrix-mediated mechanical communication via active particles with polarized effective attraction.

Collective cell migration is crucial to many physiological and pathological processes such as embryo development, wound healing, and cancer invasion. Recent experimental studies have indicated that the active traction forces generated by migrating cells in a fibrous extracellular matrix (ECM) can mechanically remodel the ECM, giving rise to bundlelike mesostructures bridging individual cells. Such fiber bundles also enable long-range propagation of cellular forces, leading to correlated migration dynamics regulated by the mechanical communication among the cells. Motivated by these experimental discoveries, we develop an active-particle model with polarized effective attractions (APPA) to investigate emergent multicellular migration dynamics resulting from ECM-mediated mechanical communications. In particular, the APPA model generalizes the classic active-Brownian-particle (ABP) model by imposing a pairwise polarized attractive force between the particles, which depends on the instantaneous dynamic states of the particles and mimics the effective mutual pulling between the cells via the fiber bundle bridge. The APPA system exhibits enhanced aggregation behaviors compared to the classic ABP system, and the contrast is more apparent at lower particle densities and higher rotational diffusivities. Importantly, in contrast to the classic ABP system where the particle velocities are not correlated for all particle densities, the high-density phase of the APPA system exhibits strong dynamic correlations, which are characterized by the slowly decaying velocity correlation functions with a correlation length comparable to the linear size of the high-density phase domain (i.e., the cluster of particles). The strongly correlated multicellular dynamics predicted by the APPA model is subsequently verified in in vitro experiments using MCF-10A cells. Our studies indicate the importance of incorporating ECM-mediated mechanical coupling among the migrating cells for appropriately modeling emergent multicellular dynamics in complex microenvironments.

Modeling cell migration regulated by cell extracellular-matrix micromechanical coupling.

Cell migration in fibrous extracellular matrix (ECM) is crucial to many physiological and pathological processes such as tissue regeneration, immune response, and cancer progression. During migration, individual cells can generate active pulling forces via actomyosin contraction, which are transmitted to the ECM fibers through focal adhesion complexes, remodel the ECM, and eventually propagate to and can be sensed by other cells in the system. The microstructure and physical properties of the ECM can also significantly influence cell migration, e.g., via durotaxis and contact guidance. Here, we develop a computational model for two-dimensional cell migration regulated by cell-ECM micromechanical coupling. Our model explicitly takes into account a variety of cellular-level processes, including focal adhesion formation and disassembly, active traction force generation and cell locomotion due to actin filament contraction, transmission and propagation of tensile forces in the ECM, as well as the resulting ECM remodeling. We validate our model by accurately reproducing single-cell dynamics of MCF-10A breast cancer cells migrating on collagen gels and show that the durotaxis and contact guidance effects naturally arise as a consequence of the cell-ECM micromechanical interactions considered in the model. Moreover, our model predicts strongly correlated multicellular migration dynamics, which are resulted from the ECM-mediated mechanical coupling among the migrating cell and are subsequently verified in in vitro experiments using MCF-10A cells. Our computational model provides a robust tool to investigate emergent collective dynamics of multicellular systems in complex in vivo microenvironment and can be utilized to design in vitro microenvironments to guide collective behaviors and self-organization of cells.