Mechanical cell-matrix feedback explains pairwise and collective endothelial cell behavior in vitro

In vitro cultures of endothelial cells are a widely used model system of the collective behavior of endothelial cells during vasculogenesis and angiogenesis. When seeded in an extracellular matrix, endothelial cells can form blood vessel-like structures, including vascular networks and sprouts. Endothelial morphogenesis depends on a large number of chemical and mechanical factors, including the compliancy of the extracellular matrix, the available growth factors, the adhesion of cells to the extracellular matrix, cell-cell signaling, etc. Although various computational models have been proposed to explain the role of each of these biochemical and biomechanical effects, the understanding of the mechanisms underlying in vitro angiogenesis is still incomplete. Most explanations focus on predicting the whole vascular network or sprout from the underlying cell behavior, and do not check if the same model also correctly captures the intermediate scale: the pairwise cell-cell interactions or single cell responses to ECM mechanics. Here we show, using a hybrid cellular Potts and finite element computational model, that a single set of biologically plausible rules describing (a) the contractile forces that endothelial cells exert on the ECM, (b) the resulting strains in the extracellular matrix, and (c) the cellular response to the strains, suffices for reproducing the behavior of individual endothelial cells and the interactions of endothelial cell pairs in compliant matrices. With the same set of rules, the model also reproduces network formation from scattered cells, and sprouting from endothelial spheroids. Combining the present mechanical model with aspects of previously proposed mechanical and chemical models may lead to a more complete understanding of in vitro angiogenesis.Comment: 25 pages, 6 figures, accepted for publication in PLoS Computational Biolog

Mechanical Cell-Matrix Feedback Explains Pairwise and Collective Endothelial Cell Behavior In Vitro

During the embryonic development of multicellular organisms, millions of cells cooperatively build structured tissues, organs and whole organisms, a process called morphogenesis. How the behavior of so many cells is coordinated to produce complex structures is still incompletely understood. Most biomedical research focuses on the molecular signals that cells exchange with one another. It has now become clear that cells also communicate biomechanically during morphogenesis. In cell cultures, endothelial cells—the building blocks of blood vessels—can organize into structures resembling networks of capillaries. Experimental work has shown that the endothelial cells pull onto the protein gel that they live in, called the extracellular matrix. On sufficiently compliant matrices, the strains resulting from these cellular pulling forces slow down and reorient adjacent cells. Here we propose a new computational model to show that this simple form of mechanical cell-cell communication suffices for reproducing the formation of blood vessel-like structures in cell cultures. These findings advance our understanding of biomechanical signaling during morphogenesis, and introduce a new set of computational tools for modeling mechanical interactions between cells and the extracellular matrix

Cellular-based Computational Model of hMSC Differentiation into Neuronal Lineage on Nanofibrous PCL- Graphene Scaffolds

In the last decade, stem cell research and nanotechnology have played a crucial role in the rapid advancement of tissue engineering. In this project, we utilize biological observations and develop a computational model, using Cellular Potts Model (a.k.a the Glazier-Graner-Hogeweg model), a lattice-based, cellular level computational framework that accurately describes biological phenomena including stem cell differentiation. Particularly we focus on cellular level interactions of hMSC derived neuronal cells on a Poly(ε-caprolactone) (PCL)-graphene scaffolds which are proven to provide better protein and cell adhesion. In this study, the Cellular Potts Model is used to design a dynamic microenvironment for cellular organization and its functioning at a Nano-scale level and also study the cells-biomaterial interactions

Cellular Potts modeling of complex multicellular behaviors in tissue morphogenesis

Mathematical modeling is an essential approach for the understanding of complex multicellular behaviors in tissue morphogenesis. Here, we review the cellular Potts model (CPM; also known as the Glazier-Graner-Hogeweg model), an effective computational modeling framework. We discuss its usability for modeling complex developmental phenomena by examining four fundamental examples of tissue morphogenesis: (i) cell sorting, (ii) cyst formation, (iii) tube morphogenesis in kidney development, and (iv) blood vessel formation. The review provides an introduction for biologists for starting simulation analysis using the CPM framework

Facile fabrication of microperforated membranes with re-useable SU-8 molds for organs-on-chips

Microperforated membranes are essential components of various organ-on-a-chip (OOC) barrier models devel- oped to study transport of molecular compounds and cells across cell layers in e.g. the intestine and blood-brain barrier. These OOC membranes have two functions: 1) to support growth of cells on one or both sides, and 2) to act as a filter-like barrier to separate adjacent compartments. Thin, microperforated poly(dimethylsiloxane) (PDMS) membranes can be fabricated by micromolding from silicon molds comprising arrays of micropillars for the formation of micropores. However, these molds are made by deep reactive ion etching (DRIE) and are expensive to fabricate. We describe the micromolding of thin PDMS membranes with easier-to-make, SU-8 epoxy photoresist molds. With a multilayer, SU-8, pillar microarray mold, massively parallel arrays of micropores can be formed in a thin layer of PDMS, resulting in a flexible barrier membrane that can be easily incorporated and sealed between other layers making up the OOC device. The membranes we describe here have a 30-μm thickness, with 12-μm-diameter circular pores arranged at a 100-μm pitch in a square array. We show application of these membranes in gut-on-a-chip devices, and expect that the reported fabrication strategy will also be suitable for other membrane dimension