Apical bulkheads accumulate as adaptive response to impaired bile flow in liver disease.

Hepatocytes form bile canaliculi that dynamically respond to the signalling activity of bile acids and bile flow. Little is known about their responses to intraluminal pressure. During embryonic development, hepatocytes assemble apical bulkheads that increase the canalicular resistance to intraluminal pressure. Here, we investigate whether they also protect bile canaliculi against elevated pressure upon impaired bile flow in adult liver. Apical bulkheads accumulate upon bile flow obstruction in mouse models and patients with primary sclerosing cholangitis (PSC). Their loss under these conditions leads to abnormally dilated canaliculi, resembling liver cell rosettes described in other hepatic diseases. 3D reconstruction reveals that these structures are sections of cysts and tubes formed by hepatocytes. Mathematical modelling establishes that they positively correlate with canalicular pressure and occur in early PSC stages. Using primary hepatocytes and 3D organoids, we demonstrate that excessive canalicular pressure causes the loss of apical bulkheads and formation of rosettes. Our results suggest that apical bulkheads are a protective mechanism of hepatocytes against impaired bile flow, highlighting the role of canalicular pressure in liver diseases.

Dynamics of CXCR4 positive circulating tumor cells in prostate cancer patients during radiotherapy.

Ablative radiotherapy is a highly efficient treatment modality for patients with metastatic prostate cancer (PCa). However, a subset of patients does not respond. Currently, this subgroup with bad prognosis cannot be identified before disease progression. We hypothesize that markers indicative of radioresistance, stemness and/or bone tropism may have a prognostic potential to identify patients profiting from metastases-directed radiotherapy. Therefore, circulating tumor cells (CTCs) were analyzed in patients with metastatic PCa (n = 24) during radiotherapy with CellSearch, multicolor flow cytometry and imaging cytometry. Analysis of copy-number alteration indicates a polyclonal CTC population that changes after radiotherapy. CTCs were found in 8 out of 24 patients (33.3%) and were associated with a shorter time to biochemical progression after radiotherapy. Whereas the total CTC count dropped after radiotherapy, a chemokine receptor CXCR4-expressing subpopulation representing 28.6% of the total CTC population remained stable up to 3 months. At once, we observed higher chemokine CCL2 plasma concentrations and proinflammatory monocytes. Additional functional analyses demonstrated key roles of CXCR4 and CCL2 for cellular radiosensitivity, tumorigenicity and stem-like potential in vitro and in vivo. Moreover, a high CXCR4 and CCL2 expression was found in bone metastasis biopsies of PCa patients. In summary, panCK+ CXCR4+ CTCs may have a prognostic potential in patients with metastatic PCa treated with metastasis-directed radiotherapy.

Mutual Zonated Interactions of Wnt and Hh Signaling Are Orchestrating the Metabolism of the Adult Liver in Mice and Human.

The Hedgehog (Hh) and Wnt/ß-Catenin (Wnt) cascades are morphogen pathways whose pronounced influence on adult liver metabolism has been identified in recent years. How both pathways communicate and control liver metabolic functions are largely unknown. Detecting core components of Wnt and Hh signaling and mathematical modeling showed that both pathways in healthy liver act largely complementary to each other in the pericentral (Wnt) and the periportal zone (Hh) and communicate mainly by mutual repression. The Wnt/Hh module inversely controls the spatiotemporal operation of various liver metabolic pathways, as revealed by transcriptome, proteome, and metabolome analyses. Shifting the balance to Wnt (activation) or Hh (inhibition) causes pericentralization and periportalization of liver functions, respectively. Thus, homeostasis of the Wnt/Hh module is essential for maintaining proper liver metabolism and to avoid the development of certain metabolic diseases. With caution due to minor species-specific differences, these conclusions may hold for human liver as well.

Three-dimensional spatially resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression.

Early disease diagnosis is key to the effective treatment of diseases. Histopathological analysis of human biopsies is the gold standard to diagnose tissue alterations. However, this approach has low resolution and overlooks 3D (three-dimensional) structural changes resulting from functional alterations. Here, we applied multiphoton imaging, 3D digital reconstructions and computational simulations to generate spatially resolved geometrical and functional models of human liver tissue at different stages of non-alcoholic fatty liver disease (NAFLD). We identified a set of morphometric cellular and tissue parameters correlated with disease progression, and discover profound topological defects in the 3D bile canalicular (BC) network. Personalized biliary fluid dynamic simulations predicted an increased pericentral biliary pressure and micro-cholestasis, consistent with elevated cholestatic biomarkers in patients' sera. Our spatially resolved models of human liver tissue can contribute to high-definition medicine by identifying quantitative multiparametric cellular and tissue signatures to define disease progression and provide new insights into NAFLD pathophysiology.

Dynamic Polarization of the Multiciliated Planarian Epidermis between Body Plan Landmarks.

Polarity is a universal design principle of biological systems that manifests at all organizational scales, yet its coordination across scales remains poorly understood. Here, we make use of the extreme anatomical plasticity of planarian flatworms to probe the interplay between global body plan polarity and local cell polarity. Our quantitative analysis of ciliary rootlet orientation in the epidermis reveals a dynamic polarity field with head and tail as independent determinants of anteroposterior (A/P) polarization and the body margin as determinant of mediolateral (M/L) polarization. Mathematical modeling rationalizes the global polarity field and its response to experimental manipulations as superposition of separate A/P and M/L fields, and we identify the core PCP and Ft/Ds pathways as their molecular mediators. Overall, our study establishes a framework for the alignment of cellular polarity vectors relative to planarian body plan landmarks and establishes the core PCP and Ft/Ds pathways as evolutionarily conserved 2D-polarization module.

Merkel cells and the individuality of friction ridge skin.

There is no definite theory yet for the mechanism by which the pattern of epidermal ridges on fingers, palms and soles forming friction ridge skin (FRS) patterns is created. For a long time growth forces in the embryonal epidermis have been believed to be involved in FRS formation. More recent evidence suggests that Merkel cells play an important part in this process as well. Here we suggest a model for the formation of FRS patterns that links Merkel cells to the epidermal stress distribution. The Merkel cells are modeled as agents in an agent based model that move anisotropically where the anisotropy is created by the epidermal stress tensor. As a result ridge patterns are created with pattern defects as they occur in real FRS patterns. As a consequence we suggest why the topology of FRS patterns is indeed unique as the arrangement of pattern defects is sensitive to the initial configuration of Merkel cells.

Nutritional resources as positional information for morphogenesis in the stony coral Stylophora pistillata.

We are interested in deciphering the mechanisms for morphogenesis in the Red Sea scleractinian coral Stylophora pistillata with the help of mathematical models. Previous mathematical models for coral morphogenesis assume that skeletal growth is proportional to the amount of locally available energetic resources like diffusible nutrients and photosynthetic products. We introduce a new model which includes factors like dissolved nutrients and photosynthates, but these resources do not serve as building blocks for growth but rather provide some kind of positional information for coral morphogenesis. Depending on this positional information side branches are generated, splittings of branches take place and branch growth direction is determined. The model results are supported by quantitative comparisons with experimental data obtained from young coral colonies.

An osmoregulatory basis for shape oscillations in regenerating hydra.

The freshwater polyp Hydra has considerable regeneration capabilities. A small fragment of tissue excised from an adult animal is sufficient to regenerate an entire Hydra in the course of a few days. During the initial stages of the regeneration process, the tissue forms a hollow sphere. Then the sphere exhibits shape oscillations in the form of repeated cycles of swelling and collapse. We propose a biophysical model for the swelling mechanism. Our model takes the osmotic pressure difference between Hydra's inner and outer media and the elastic forces of the Hydra shell into account. We validate the model by a comprehensive experimental study including variations in initial medium concentrations, Hydra sphere sizes and temperatures. Numerical simulations of the model provide values for the swelling rates that are in agreement with the ones measured experimentally. Based on our results we argue that the shape oscillations are a consequence of Hydra's osmoregulation.

Models for fingerprint pattern formation.

There is currently no general agreement on the process by which fingerprint (epidermal ridge) patterns form. Nevertheless, many possible mechanisms have been proposed. Based on an extensive literature review and mathematical modeling we argue that the pattern arises as the result of a buckling (folding) process in a cell layer of the epidermis. Using this model we were able to explain the long-known observation that the pattern type is related to the geometry of the embryonal fingertip.

Fingerprint formation.

Fingerprints (epidermal ridges) have been used as a means of identifications for more than 2000 years. They have also been extensively studied scientifically by anthropologists and biologists. However, despite all the empirical and experimental knowledge, no widely accepted explanation for the development of epidermal ridges on fingers, palms and soles has yet emerged. In this article we argue that fingerprint patterns are created as the result of a buckling instability in the basal cell layer of the fetal epidermis. Analysis of the well-known von Karman equations informs us that the buckling direction is perpendicular to the direction of greatest stress in the basal layer. We propose that this stress is induced by resistance of furrows and creases to the differential growth of the basal layer and regression of the volar pads during the time of ridge formation. These ideas have been tested by computer experiments. The results are in close harmony with observations. Specifically, they are consistent with the well-known observation that the pattern type is related to the geometry of the fingertip surface when fingerprint patterns are formed.