Dataset Information

Modeling and analysis of collective cell migration in an in vivo three-dimensional environment.

ABSTRACT: A long-standing question in collective cell migration has been what might be the relative advantage of forming a cluster over migrating individually. Does an increase in the size of a collectively migrating group of cells enable them to sample the chemical gradient over a greater distance because the difference between front and rear of a cluster would be greater than for single cells? We combined theoretical modeling with experiments to study collective migration of the border cells in-between nurse cells in the Drosophila egg chamber. We discovered that cluster size is positively correlated with migration speed, up to a particular point above which speed plummets. This may be due to the effect of viscous drag from surrounding nurse cells together with confinement of all of the cells within a stiff extracellular matrix. The model predicts no relationship between cluster size and velocity for cells moving on a flat surface, in contrast to movement within a 3D environment. Our analyses also suggest that the overall chemoattractant profile in the egg chamber is likely to be exponential, with the highest concentration in the oocyte. These findings provide insights into collective chemotaxis by combining theoretical modeling with experimentation.

SUBMITTER: Cai D

PROVIDER: S-EPMC4839456 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Modeling and analysis of collective cell migration in an in vivo three-dimensional environment.

Cai Danfeng D Dai Wei W Prasad Mohit M Luo Junjie J Gov Nir S NS Montell Denise J DJ

Proceedings of the National Academy of Sciences of the United States of America 20160329 15

A long-standing question in collective cell migration has been what might be the relative advantage of forming a cluster over migrating individually. Does an increase in the size of a collectively migrating group of cells enable them to sample the chemical gradient over a greater distance because the difference between front and rear of a cluster would be greater than for single cells? We combined theoretical modeling with experiments to study collective migration of the border cells in-between ...[more]

PMID: 27035964

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Project description:Cell migration is essential in animal development, homeostasis, and disease progression, but many questions remain unanswered about how this process is controlled. While many kinds of individual cell movements have been characterized, less effort has been directed towards understanding how clusters of cells migrate collectively through heterogeneous, cellular environments. To explore this, we have focused on the migration of the border cells during Drosophila egg development. In this case, a cluster of different cell types coalesce and traverse as a group between large cells, called nurse cells, in the center of the egg chamber. We have developed a new model for this collective cell migration based on the forces of adhesion, repulsion, migration and stochastic fluctuation to generate the movement of discrete cells. We implement the model using Identical Math Cells, or IMCs. IMCs can each represent one biological cell of the system, or can be aggregated using increased adhesion forces to model the dynamics of larger biological cells. The domain of interest is filled with IMCs, each assigned specific biophysical properties to mimic a diversity of cell types. Using this system, we have successfully simulated the migration of the border cell cluster through an environment filled with larger cells, which represent nurse cells. Interestingly, our simulations suggest that the forces utilized in this model are sufficient to produce behaviors of the cluster that are observed in vivo, such as rotation. Our framework was developed to capture a heterogeneous cell population, and our implementation strategy allows for diverse, but precise, initial position specification over a three- dimensional domain. Therefore, we believe that this model will be useful for not only examining aspects of Drosophila oogenesis, but also for modeling other two or three-dimensional systems that have multiple cell types and where investigating the forces between cells is of interest.

Project description:Three-dimensional (3D) collective cell migration (CCM) is critical for improving liver cell therapies, eliciting mechanisms of liver disease, and modeling human liver development and organogenesis. Mechanisms of CCM differ in 2D vs. 3D systems, and existing models are limited to 2D or transwell-based systems, suggesting there is a need for improved 3D models of CCM. To recreate liver 3D CCM, we engineered in vitro 3D models based upon a morphogenetic transition that occurs during liver organogenesis, which occurs rapidly between E8.5 and E9.5 (mouse). During this morphogenetic transition, 3D CCM exhibits co-migration (multiple cell types), thick-strand interactions with surrounding septum transversum mesenchyme (STM), branching morphogenesis, and 3D interstitial migration. Here, we engineer several 3D in vitro culture systems, each of which mimics one of these processes in vitro. In mixed spheroids bearing both liver cells and uniquely MRC-5 (fetal lung) fibroblasts, we observed evidence of co-migration, and a significant increase in length and number of liver spheroid protrusions, which was highly sensitive to transforming growth factor beta 1 (TGFβ1) stimulation. In MRC-5-conditioned medium (M-CM) experiments, we observed dose-dependent branching morphogenesis associated with an upregulation of Twist1, which was inhibited by a broad TGFβ inhibitor. In models in which liver spheroids and MRC-5 spheroids were co-cultured, we observed complex strand morphogenesis, whereby thin, linear, 3D liver cell strands attach to the MRC-5 spheroid, anchor and thicken to form permanent and thick anchoring contacts between the two spheroids. In these spheroid co-culture models, we also observed spheroid fusion and strong evidence for interstitial migration. In conclusion, we present several novel cultivation systems that recreate distinct features of liver 3D CCM. These methodologies will greatly improve our molecular, cellular, and tissue-scale understanding of liver organogenesis, liver diseases like cancer, and liver cell therapy, and will also serve as a tool to bridge conventional 2D studies and preclinical in vivo studies.

Project description:During the past two decades, novel biomaterial scaffold for cell attachment and culture has been developed for applications in tissue engineering, biosensing and regeneration medicine. Tissue engineering of blood vessels remains a challenge owing to the complex three-layer histology involved. In order to engineer functional blood vessels, it is essential to recapitulate the characteristics of vascular smooth muscle cells (SMCs) inside the tunica media, which is known to be critical for vasoconstriction and vasodilation of the circulatory system. Until now, there has been a lack of understanding on the mechanotransduction of the SMC layer during the transformation from viable synthetic to quiescent contractile phenotypes. In this study, microfabricated arrays of discontinuous microwalls coated with fluorescence microbeads were developed to probe the mechanotransduction of the SMC layer. First, the system was exploited for stimulating the formation of a highly aligned orientation of SMCs in native tunica medium. Second, atomic force microscopy in combination with regression analysis was applied to measure the elastic modulus of a polyacrylamide gel layer coated on the discontinuous microwall arrays. Third, the conventional traction force assay for single cell measurement was extended for applications in three-dimensional cell aggregates. Then, the biophysical effects of discontinuous microwalls on the mechanotransduction of the SMC layer undergoing cell alignment were probed. Generally, the cooperative multiple cell-cell and cell-microwall interactions were accessed quantitatively by the newly developed assay with the aid of finite-element modelling. The results show that the traction forces of highly aligned cells lying in the middle region between two opposing microwalls were significantly lower than those lying adjacent to the microwalls. Moreover, the spatial distributions of Von Mises stress during the cell alignment process were dependent on the collective cell layer orientation. Immunostaining of the SMC sheet further demonstrated that the collective mechanotransduction induced by three-dimensional topographic cues was correlated with the reduction of actin and vinculin expression. In addition, the online two-dimensional LC-MS/MS analysis verified the modulation of focal adhesion formation under the influence of microwalls through the regulation in the expression of three key cytoskeletal proteins.

Dataset Information

Modeling and analysis of collective cell migration in an in vivo three-dimensional environment.

Publications

Modeling and analysis of collective cell migration in an in vivo three-dimensional environment.

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