Dynamics of Cell Packing and Polar Order in Developing Epithelia

During development, organs with different shape and functionality form from a single fertilized egg cell. Mechanisms that control shape, size and morphology of tissues pose challenges for developmental biology. These mechanisms are tightly controlled by an underlying signaling system by which cells communicate to each other. However, these signaling networks can affect tissue size and morphology through limited processes such as cell proliferation, cell death and cell shape changes,which are controlled by cell mechanics and cell adhesion. One example of such a signaling system is the network of interacting proteins that control planar polarization of cells. These proteins distribute asymmetrically within cells and their distribution in each cell determines of the polarity of the neighboring cells. These proteins control the pattern of hairs in the adult Drosophila wing as well as hexagonal repacking of wing cells during development. Planar polarity proteins also control developmental processes such as convergent-extension. We present a theoretical study of cell packing geometry in developing epithelia. We use a vertex model to describe the packing geometry of tissues, for which forces are balanced throughout the tissue. We introduce a cell division algorithm and show that repeated cell division results in the formation of a distinct pattern of cells, which is controlled by cell mechanics and cell-cell interactions. We compare the vertex model with experimental measurements in the wing disc of Drosophila and quantify for the first time cell adhesion and perimeter contractility of cells. We also present a simple model for the dynamics of polarity order in tissues. We identify a basic mechanism by which long-range polarity order throughout the tissue can be established. In particular we study the role of shear deformations on polarity pattern and show that the polarity of the tissue reorients during shear flow. Our simple mechanisms for ordering can account for the processes observed during development of the Drosophila wing

Dynamics of Cell Packing and Polar Order in Developing Epithelia

During development, organs with different shape and functionality form from a single fertilized egg cell. Mechanisms that control shape, size and morphology of tissues pose challenges for developmental biology. These mechanisms are tightly controlled by an underlying signaling system by which cells communicate to each other. However, these signaling networks can affect tissue size and morphology through limited processes such as cell proliferation, cell death and cell shape changes,which are controlled by cell mechanics and cell adhesion. One example of such a signaling system is the network of interacting proteins that control planar polarization of cells. These proteins distribute asymmetrically within cells and their distribution in each cell determines of the polarity of the neighboring cells. These proteins control the pattern of hairs in the adult Drosophila wing as well as hexagonal repacking of wing cells during development. Planar polarity proteins also control developmental processes such as convergent-extension. We present a theoretical study of cell packing geometry in developing epithelia. We use a vertex model to describe the packing geometry of tissues, for which forces are balanced throughout the tissue. We introduce a cell division algorithm and show that repeated cell division results in the formation of a distinct pattern of cells, which is controlled by cell mechanics and cell-cell interactions. We compare the vertex model with experimental measurements in the wing disc of Drosophila and quantify for the first time cell adhesion and perimeter contractility of cells. We also present a simple model for the dynamics of polarity order in tissues. We identify a basic mechanism by which long-range polarity order throughout the tissue can be established. In particular we study the role of shear deformations on polarity pattern and show that the polarity of the tissue reorients during shear flow. Our simple mechanisms for ordering can account for the processes observed during development of the Drosophila wing

Cerebral Subdural Hematoma Following Spinal Anesthesia: Report of Two Cases

Postdural puncture headache and cerebral subdural hematoma are among complications of spinal anesthesia with some common characteristics; however misdiagnosis of these two could result in a catastrophic outcome or prevent unwanted results by urgent interventions. With the purpose of increasing awareness of such complications and a speedy diagnosis, we report two cases of postspinal anesthesia headache that was timely diagnosed as cerebral subdural hematoma and prevented the likelihood of a disastrous outcome

Characterising epithelial tissues using persistent entropy

In this paper, we apply persistent entropy, a novel topological statistic, for characterization of images of epithelial tissues. We have found out that persistent entropy is able to summarize topological and geometric information encoded by \alpha-complexes and persistent homology. After using some statistical tests, we can guarantee the existence of significant differences in the studied tissues.Comment: 12 pages, 7 figures, 4 table

Comparison of the effects of gonadotropin-releasing hormone and raloxifeneon the size of uterine leiomyoma

BACKGROUND: Uterine leiomyoma is a prevalent benign tumor. Several studies have shown the positive effects of raloxifene in the treatment of leiomyomas. Since raloxifene has fewer side effects than the gonadotropin-releasing hormone (GnRH) agonist, if proven effective, it can be applied easily. This study aimed to compare the medical effects of raloxifene and GnRH on uterine leiomyoma size. METHODS: This clinical trial included 53 women with uterine leiomyoma. Participants were randomly divided into 2 groups of raloxifene and GnRH. The GnRH group received 1 dose per month (intramuscular injection) and the raloxifene group received 60 mg raloxifene orally/day for 3 months. The size of the leiomyoma, prior and during the intervention, was determined by a sonographist. During the study, repeated measurement was used for comparing the trend of alterations in the tumor size. RESULTS: Analysis of changes in leiomyoma tumor size (log of tumor size) by repeated measurement showed that decrease in tumor size in the raloxifene group was significantly higher than GnRH group (P = 0.042). The trends of changes in endometrial thickness were different in the 2 groups and the reduction of thickness was more significant in the GnRH group (P = 0.026). CONCLUSION: This study showed that raloxifene is an appropriate medicine to reduce the size of uterine leiomyoma and is more effective than GnRH.

Collective and single cell behavior in epithelial contact inhibition

Control of cell proliferation is a fundamental aspect of tissue physiology central to morphogenesis, wound healing and cancer. Although many of the molecular genetic factors are now known, the system level regulation of growth is still poorly understood. A simple form of inhibition of cell proliferation is encountered in vitro in normally differentiating epithelial cell cultures and is known as "contact inhibition". The study presented here provides a quantitative characterization of contact inhibition dynamics on tissue-wide and single cell levels. Using long-term tracking of cultured MDCK cells we demonstrate that inhibition of cell division in a confluent monolayer follows inhibition of cell motility and sets in when mechanical constraint on local expansion causes divisions to reduce cell area. We quantify cell motility and cell cycle statistics in the low density confluent regime and their change across the transition to epithelial morphology which occurs with increasing cell density. We then study the dynamics of cell area distribution arising through reductive division, determine the average mitotic rate as a function of cell size and demonstrate that complete arrest of mitosis occurs when cell area falls below a critical value. We also present a simple computational model of growth mechanics which captures all aspects of the observed behavior. Our measurements and analysis show that contact inhibition is a consequence of mechanical interaction and constraint rather than interfacial contact alone, and define quantitative phenotypes that can guide future studies of molecular mechanisms underlying contact inhibition

Incorporating chemical signalling factors into cell-based models of growing epithelial tissues

In this paper we present a comprehensive computational framework within which the effects of chemical signalling factors on growing epithelial tissues can be studied. The method incorporates a vertex-based cell model, in conjunction with a solver for the governing chemical equations. The vertex model provides a natural mesh for the finite element method (FEM), with node movements determined by force laws. The arbitrary Lagrangian–Eulerian formulation is adopted to account for domain movement between iterations. The effects of cell proliferation and junctional rearrangements on the mesh are also examined. By implementing refinements of the mesh we show that the finite element (FE) approximation converges towards an accurate numerical solution. The potential utility of the system is demonstrated in the context of Decapentaplegic (Dpp), a morphogen which plays a crucial role in development of the Drosophila imaginal wing disc. Despite the presence of a Dpp gradient, growth is uniform across the wing disc. We make the growth rate of cells dependent on Dpp concentration and show that the number of proliferation events increases in regions of high concentration. This allows hypotheses regarding mechanisms of growth control to be rigorously tested. The method we describe may be adapted to a range of potential application areas, and to other cell-based models with designated node movements, to accurately probe the role of morphogens in epithelial tissues

Production of hepatocyte-like cells from human umbilical vein mesenchymal stem cells

The human umbilical vein, as a readily available stem cell source, is a good alternative to harvest mesenchymal stem cells. Human umbilical cord vein mesenchymal stem cells have recently been isolated and have demonstrated the ability to differentiate into various cell types such as fat, bone, cartilage and neuronal cells. In this study, we have investigated whether human umbilical cord vein mesenchymal stem cells are also able to differentiate into hepatocyte-like cells. Hepatic differentiation was performed with a 2-step protocol and the use of hepatocyte growth factor and oncostatin M for cell culture. During four weeks of induction, most cells displayed a cuboidal morphology. Immunological analysis indicated that umbilical cord vein mesenchymal stem cells-derived hepatocyte-like cells expressed liver-specific protein markers such as albumin and cytokeratin-18. The hepatocyte-like cells also displayed several characteristics of hepatocytes, including expression of transthyretin, glucose 6-phosphatase, cytokeratin-8,18, alpha-fetoprotein, hepatocyte nuclear factor-3β and albumin. The result of indocyanine green cell uptake, as a test substance to evaluate hepatocyte-like cell function, was positive for differentiated cells. Glycogen storage was examined by periodic acid-Schiff staining. Accumulation of intracellular glycogen was detected in the hepatocyte-like cells. Based on these observations, we have concluded that umbilical cord vein mesenchymal stem cells are endowed with hepatogenic potential and may provide a stem cell source to be used as cell therapy for liver diseases

Comparison of the effects of gonadotropin-releasing hormone and raloxifeneon the size of uterine leiomyoma

BACKGROUND: Uterine leiomyoma is a prevalent benign tumor. Several studies have shown the positive effects of raloxifene in the treatment of leiomyomas. Since raloxifene has fewer side effects than the gonadotropin-releasing hormone (GnRH) agonist, if proven effective, it can be applied easily. This study aimed to compare the medical effects of raloxifene and GnRH on uterine leiomyoma size. METHODS: This clinical trial included 53 women with uterine leiomyoma. Participants were randomly divided into 2 groups of raloxifene and GnRH. The GnRH group received 1 dose per month (intramuscular injection) and the raloxifene group received 60 mg raloxifene orally/day for 3 months. The size of the leiomyoma, prior and during the intervention, was determined by a sonographist. During the study, repeated measurement was used for comparing the trend of alterations in the tumor size. RESULTS: Analysis of changes in leiomyoma tumor size (log of tumor size) by repeated measurement showed that decrease in tumor size in the raloxifene group was significantly higher than GnRH group (P = 0.042). The trends of changes in endometrial thickness were different in the 2 groups and the reduction of thickness was more significant in the GnRH group (P = 0.026). CONCLUSION: This study showed that raloxifene is an appropriate medicine to reduce the size of uterine leiomyoma and is more effective than GnRH

Active Tension Network model suggests an exotic mechanical state realized in epithelial tissues.

Mechanical interactions play a crucial role in epithelial morphogenesis, yet understanding the complex mechanisms through which stress and deformation affect cell behavior remains an open problem. Here we formulate and analyze the Active Tension Network (ATN) model, which assumes that the mechanical balance of cells within a tissue is dominated by cortical tension and introduces tension-dependent active remodeling of the cortex. We find that ATNs exhibit unusual mechanical properties. Specifically, an ATN behaves as a fluid at short times, but at long times supports external tension like a solid. Furthermore, an ATN has an extensively degenerate equilibrium mechanical state associated with a discrete conformal - "isogonal" - deformation of cells. The ATN model predicts a constraint on equilibrium cell geometries, which we demonstrate to approximately hold in certain epithelial tissues. We further show that isogonal modes are observed in the fruit y embryo, accounting for the striking variability of apical areas of ventral cells and helping understand the early phase of gastrulation. Living matter realizes new and exotic mechanical states, the study of which helps to understand biological phenomena