RESUMEN
Collectively migrating Xenopus mesendoderm cells are arranged into leader and follower rows with distinct adhesive properties and protrusive behaviors. In vivo, leading row mesendoderm cells extend polarized protrusions and migrate along a fibronectin matrix assembled by blastocoel roof cells. Traction stresses generated at the leading row result in the pulling forward of attached follower row cells. Mesendoderm explants removed from embryos provide an experimentally tractable system for characterizing collective cell movements and behaviors, yet the cellular mechanisms responsible for this mode of migration remain elusive. We introduce a novel agent-based computational model of migrating mesendoderm in the Cellular-Potts computational framework to investigate the respective contributions of multiple parameters specific to the behaviors of leader and follower row cells. Sensitivity analyses identify cohesotaxis, tissue geometry, and cell intercalation as key parameters affecting the migration velocity of collectively migrating cells. The model predicts that cohesotaxis and tissue geometry in combination promote cooperative migration of leader cells resulting in increased migration velocity of the collective. Radial intercalation of cells towards the substrate is an additional mechanism contributing to an increase in migratory speed of the tissue. Model outcomes are validated experimentally using mesendoderm tissue explants.
Asunto(s)
Movimiento Celular , Modelos Biológicos , Xenopus , Animales , Xenopus/embriología , Mesodermo/citología , Mesodermo/embriología , Adhesión Celular , Xenopus laevis/embriología , Simulación por ComputadorRESUMEN
During early kidney organogenesis, nephron progenitor (NP) cells move from the tip to the corner region of the ureteric bud (UB) branches in order to form the pretubular aggregate, the early structure giving rise to nephron formation. NP cells derive from metanephric mesenchymal cells and physically interact with them during the movement. Chemotaxis and cell-cell adhesion differences are believed to drive the cell patterning during this critical period of organogenesis. However, the effect of these forces to the cell patterns and their respective movements are known in limited details. We applied a Cellular Potts Model to explore how these forces and organizations contribute to directed cell movement and aggregation. Model parameters were estimated based on fitting to experimental data obtained in ex vivo kidney explant and dissociation-reaggregation organoid culture studies. Our simulations indicated that optimal enrichment and aggregation of NP cells in the UB corner niche requires chemoattractant secretion from both the UB epithelial cells and the NP cells themselves, as well as differences in cell-cell adhesion energies. Furthermore, NP cells were observed, both experimentally and by modelling, to move at higher speed in the UB corner as compared to the tip region where they originated. The existence of different cell speed domains along the UB was confirmed using self-organizing map analysis. In summary, we saw faster NP cell movements near aggregation. The applicability of Cellular Potts Model approach to simulate cell movement and patterning was found to be good during for this early nephrogenesis process. Further refinement of the model should allow us to recapitulate the effects of developmental changes of cell phenotypes and molecular crosstalk during further organ development.
Asunto(s)
Nefronas , Organogénesis , Movimiento Celular , Simulación por Computador , Riñón , Organogénesis/genética , Células MadreRESUMEN
Endothelial to mesenchymal transformation (EndMT) is a process in which endothelial cells gain a mesenchymal-like phenotype in response to mechanobiological signals that results in the remodeling or repair of underlying tissue. While initially associated with embryonic development, this process has since been shown to occur in adult tissue remodeling including wound healing, fibrosis, and cancer. In an attempt to understand the role of EndMT in cancer progression and metastasis, we present a multiscale, three-dimensional, in silico model. The model couples tissue level phenomena such as extracellular matrix remodeling, cellular level phenomena such as migration and proliferation, and chemical transport in the tumor microenvironment to mimic in vitro tissue models of the cancer microenvironment. The model is used to study the presence of EndMT-derived activated fibroblasts (EDAFs) and varying substrate stiffness on tumor cell migration and proliferation. The simulations accurately model the behavior of tumor cells under given conditions. The presence of EDAFs and/or an increase in substrate stiffness resulted in an increase in tumor cell activity. This model lays the foundation of further studies of EDAFs in a tumor microenvironment on a cellular and subcellular physiological level.
Asunto(s)
Transformación Celular Neoplásica/patología , Simulación por Computador , Endotelio/patología , Mesodermo/patología , Modelos Biológicos , Microambiente Tumoral , Animales , Movimiento Celular , Matriz Extracelular/metabolismo , Fibroblastos/patología , HumanosRESUMEN
This chapter reviews some currently available methodologies for constructing mathematical models in kidney development. Mammalian nephrogenesis is a complex biological process, which in its earliest stages involves migration, condensation, proliferation, and differentiation of metanephric mesenchymal (MM) cells interacting with the uroepithelial cells of the ureteric bud (UB). First, the mathematical modelling in biology is generally described. Secondly, some accounts to biological pattern formation in modelling are given in general, including models that transcend the Turing model. This is followed by a short assessment on the main branch of models in the kidney development, the evaluation of the branching morphogenesis of the kidney. Finally, two alternative models in the early kidney development processes are given as an example. They also elucidate the difficulties in the model building process. Firstly, a computational model building with the CompuCell3D program for the early nephron progenitor cell movements with the key extracellular signaling effectors is depicted. This collective migration leads to the first pretubular aggregate (PTA). The simulation parameters of the program imitate the program's cell sorting example with different adhesions and chemoattractants. The program utilizes Cellular Potts Model (CPM) to describe the development. Secondly, an example of PTA to renal vesicle (RV) transition modelling is described. In that case, the model is unique, where the model process is based on the chemoattractants from UB.