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The human amygdala is involved in processing of memory, decision-making, and emotional responses. Previous studies suggested that the amygdala may represent a neurogenic niche in mammals. By combining two distinct methodological approaches, lipofuscin quantification and C-14-based retrospective birth dating of neurons, along with mathematical modelling, we here explored whether postnatal neurogenesis exists in the human amygdala. We investigated post-mortem samples of twelve neurologically healthy subjects. The average rate of lipofuscin-negative neurons was 3.4%, representing a substantial proportion of cells substantially younger than the individual. Mass spectrometry analysis of genomic C-14-concentrations in amygdala neurons compared with atmospheric C-14-levels provided evidence for postnatal neuronal exchange. Mathematical modelling identified a best-fitting scenario comprising of a quiescent and a renewing neuronal population with an overall renewal rate of >2.7% per year. In conclusion, we provide evidence for postnatal neurogenesis in the human amygdala with cell turnover rates comparable to the hippocampus. Lipofuscin labeling and (14) C retrospective birth-dating of neurons, along with mathematical modelling, here suggest continued postnatal neurogenesis in the human amygdala, rather than protracted maturation of developmentally generated neurons.

International audience; Morphogenesis, wound healing and some cancer metastases depend upon migration of cell collectives that need to be guided to their destination as well as coordinated with other cell movements. During zebrafish gastrulation, extension of the embryonic axis is led by the mesendodermal polster that migrates towards the animal pole, followed by axial mesoderm that is undergoing convergence and extension. We here investigate how polster cells are guided towards the animal pole. Using a combination of precise laser ablations, advanced transplantations and functional as well as silico approaches, we establish that the directional information guiding polster cells is mechanical, and is provided by the anteriorward migration of the following cells. This information is detected by cell-cell contact through E-Cadherin/α-Catenin mechanotransduction and propagates from cell to cell over the whole tissue. Such guidance of migrating cells by followers ensures long-range coordination of movements and developmental robustness.

How epithelial cells coordinate their polarity to form functional tissues is an open question in cell biology. Here, we characterize a unique type of polarity found in liver tissue, nematic cell polarity, which is different from vectorial cell polarity in simple, sheet-like epithelia. We propose a conceptual and algorithmic framework to characterize complex patterns of polarity proteins on the surface of a cell in terms of a multipole expansion. To rigorously quantify previously observed tissue-level patterns of nematic cell polarity (Morales-Navarrete et al., eLife 2019), we introduce the concept of co-orientational order parameters, which generalize the known biaxial order parameters of the theory of liquid crystals. Applying these concepts to three-dimensional reconstructions of single cells from high-resolution imaging data of mouse liver tissue, we show that the axes of nematic cell polarity of hepatocytes exhibit local coordination and are aligned with the biaxially anisotropic sinusoidal network for blood transport. Our study characterizes liver tissue as a biological example of a biaxial liquid crystal. The general methodology developed here could be applied to other tissues and in-vitro organoids., Author summary Cell polarity enables cells to carry out specific functions. Cell polarity is characterized by the formation of different plasma membrane domains, each with specific composition of proteins, phospholipids and cytoskeletal components. In simple epithelial sheets, or tube-like tissues such as kidney, epithelial cells are known to display a single apical domain, facing a lumenal cavity, and a single basal domain on the opposite side of the cell, facing a basal layer of extracellular matrix. This apico-basal polarity defines a vector of cell polarity, which provides a direction of fluid transport, e.g., from the basal side of the sheet to the lumen-facing side. In more complex, three-dimensional epithelial tissues, such as liver tissue with its complex network of blood-transporting sinusoids, the membrane domains of hepatocyte cells display more intricate patterns, including rings and antipodal pairs of apical membrane. Here, we develop a mathematical framework to precisely characterize and quantify complex polarity patterns. Thereby, we reveal ordered patterns of cell polarity that span across a liver lobule. Our new method builds on physical concepts originally developed for ordered phases of liquid crystals. It provides a versatile tool to characterize the spatial organization of a complex three-dimensional tissue.

The mechanisms of organ size control remain poorly understood. A key question is how cells collectively sense the overall status of a tissue. We addressed this problem focusing on mouse liver regeneration. Using digital tissue reconstruction and quantitative image analysis, we found that the apical surface of hepatocytes forming the bile canalicular network expands concomitant with an increase in F‐actin and phospho‐myosin, to compensate an overload of bile acids. These changes are sensed by the Hippo transcriptional co‐activator YAP, which localizes to apical F‐actin‐rich regions and translocates to the nucleus in dependence of the integrity of the actin cytoskeleton. This mechanism tolerates moderate bile acid fluctuations under tissue homeostasis, but activates YAP in response to sustained bile acid overload. Using an integrated biophysical–biochemical model of bile pressure and Hippo signaling, we explained this behavior by the existence of a mechano‐sensory mechanism that activates YAP in a switch‐like manner. We propose that the apical surface of hepatocytes acts as a self‐regulatory mechano‐sensory system that responds to critical levels of bile acids as readout of tissue status., This study shows that the apical surface of hepatocytes acts as a self‐regulatory mechano‐sensory system that responds to critical levels of bile acids as readout of tissue status and activates YAP, by a mechanism dependent on the actin cytoskeleton.

Functional tissue architecture originates by self-assembly of distinct cell types, following tissue-specific rules of cell-cell interactions. In the liver, a structural model of the lobule was pioneered by Elias in 1949. This model, however, is in contrast with the apparent random 3D arrangement of hepatocytes. Since then, no significant progress has been made to derive the organizing principles of liver tissue. To solve this outstanding problem, we computationally reconstructed 3D tissue geometry from microscopy images and analyzed it applying soft-condensed-matter-physics concepts. Surprisingly, analysis of the spatial organization of cell polarity revealed that hepatocytes are not randomly oriented but follow a long-range liquid-crystal order. This does not depend exclusively on hepatocytes receiving instructive signals by endothelial cells as generally assumed, since silencing Integrin-ß1 disrupted both liquid-crystal order and organization of the sinusoidal network. Our results suggest that bi-directional communication between hepatocytes and sinusoids underlies the self-organization of liver tissue.

Summary: The Hedgehog (Hh) and Wnt/β-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. : Wnt/β-catenin and Hh signaling contribute to embryogenesis as well as to the maintenance of organ homeostasis through intensive crosstalk. Here, Kolbe et al. describe that both pathways act largely complementary to each other in the healthy liver and that this crosstalk is responsible for the maintenance of metabolic zonation.

Axolotls are unique in their ability to regenerate the spinal cord. However, the mechanisms that underlie this phenomenon remain poorly understood. Previously, we showed that regenerating stem cells in the axolotl spinal cord revert to a molecular state resembling embryonic neuroepithelial cells and functionally acquire rapid proliferative divisions (Rodrigo Albors et al., 2015). Here, we refine the analysis of cell proliferation in space and time and identify a high- proliferation zone in the regenerating spinal cord that shifts posteriorly over time. By tracking sparsely-labeled cells, we also quantify cell influx into the regenerate. Taking a mathematical modeling approach, we integrate these quantitative datasets of cell proliferation, neural stem cell activation and cell influx, to predict regenerative tissue outgrowth. Our model shows that while cell influx and neural stem cell activation play a minor role, the acceleration of the cell cycle is the major driver of regenerative spinal cord outgrowth in axolotls., Facultad de Ciencias Exactas, Instituto de Física de Líquidos y Sistemas Biológicos

The polarisation of cells and tissues is fundamental for tissue morphogenesis during biological development and regeneration. A deeper understanding of biological polarity pattern formation can be gained from the consideration of pattern reorganisation in response to an opposing instructive cue, which we here consider by example of experimentally inducible body axis inversions in planarian flatworms. Our dynamically diluted alignment model represents three processes: entrainment of cell polarity by a global signal, local cell-cell coupling aligning polarity among neighbours and cell turnover inserting initially unpolarised cells. We show that a persistent global orienting signal determines the final mean polarity orientation in this stochastic model. Combining numerical and analytical approaches, we find that neighbour coupling retards polarity pattern reorganisation, whereas cell turnover accelerates it. We derive a formula for an effective neighbour coupling strength integrating both effects and find that the time of polarity reorganisation depends linearly on this effective parameter and no abrupt transitions are observed. This allows to determine neighbour coupling strengths from experimental observations. Our model is related to a dynamic $8$-Potts model with annealed site-dilution and makes testable predictions regarding the polarisation of dynamic systems, such as the planarian epithelium., Preprint as prior to first submission to Journal of the Royal Society Interface. 25 pages, 6 figures, plus supplement (18 pages, contains 1 table and 7 figures). A supplementary movie is available from https://dx.doi.org/10.6084/m9.figshare.c3887818

Bile, the central metabolic product of the liver, is transported by the bile canaliculi network. The impairment of bile flow in cholestatic liver diseases has urged a demand for insights into its regulation. Here, we developed a predictive 3D multi-scale model that simulates fluid dynamic properties successively from the subcellular to the tissue level. The model integrates the structure of the bile canalicular network in the mouse liver lobule, as determined by high-resolution confocal and serial block-face scanning electron microscopy, with measurements of bile transport by intravital microscopy. The combined experiment-theory approach revealed spatial heterogeneities of biliary geometry and hepatocyte transport activity. Based on this, our model predicts gradients of bile velocity and pressure in the liver lobule. Validation of the model predictions by pharmacological inhibition of Rho kinase demonstrated a requirement of canaliculi contractility for bile flow in vivo. Our model can be applied to functionally characterize liver diseases and quantitatively estimate biliary transport upon drug-induced liver injury. Graphical Abstract

The muscle segments of fish have a folded shape, termed a chevron, which is thought to be optimal for the undulating body movements of swimming. However, the mechanism shaping the chevron during embryogenesis is not understood. Here, we use time-lapse microscopy of developing zebrafish embryos spanning the entire somitogenesis period to quantitate the dynamics of chevron shape development. Comparing such time courses with the start of movements in wildtype zebrafish and analyzing immobile mutants, we show that the previously implicated body movements do not play a role in chevron formation. Further, the monotonic increase of chevron angle along the anteroposterior axis revealed by our data constrains or rules out possible contributions by previously proposed mechanisms. In particular, we find that muscle pioneers are not required for chevron formation. We put forward a tension-and-resistance mechanism involving interactions between intra-segmental tension and segment boundaries. To evaluate this mechanism, we derive and analyze a mechanical model of a chain of contractile and resisting elements. The predictions of this model are verified by comparison to experimental data. Altogether, our results support the notion that a simple physical mechanism suffices to self-organize the observed spatiotemporal pattern in chevron formation.

In many animals, regenerative processes can replace lost body parts. Organ and tissue regeneration consequently also hold great medical promise. The regulation of regenerative processes is achieved through concerted actions of multiple organizational levels of the organism, from diffusing molecules and cellular gene expression patterns up to tissue mechanics. Our intuition is usually not adapted well to this degree of complexity and the quantitative aspects of the regulation of regenerative processes remain poorly understood. One way out of this dilemma lies in the combination of experimentation and mathematical modeling within an iterative process of model development/refinement, model predictions for novel experimental conditions, quantitative experiments testing these predictions, and subsequent model refinement. This interdisciplinary approach has already provided key insights into smaller scale processes during embryonic development and a so-far limited number of more complex regeneration processes. This review discusses selected theoretical and interdisciplinary studies and is structured along the three phases of regeneration: (1) initiation of a regeneration response, (2) tissue patterning during regenerate growth, (3) arresting the regeneration response. Moreover, we highlight the opportunities provided by extensions of mathematical models from developmental processes toward the study of related regenerative processes.

International audience; The Hedgehog (Hh) signalling cascade is highly conserved and involved in development and disease throughout evolution. Nevertheless, in comparison with other pathways, our mechanistic understanding of Hh signal transduction is remarkably incomplete. In the absence of ligand, the Hh receptor Patched (Ptc) represses the key signal transducer Smoothened (Smo) through an unknown mechanism. Hh binding to Ptc alleviates this repression, causing Smo redistribution to the plasma membrane, phosphorylation and opening of the Smo cytoplasmic tail, and Smo oligomerisation. However, the order and interdependence of these events is as yet poorly understood. We have mathematically modelled and simulated Smo activation for two alternative modes of pathway activation, with Ptc primarily affecting either Smo localisation or phosphorylation. Visualising Smo activation through a novel, fluorescence-based reporter allowed us to test these competing models. Here, we show that Smo localisation to the plasma membrane is sufficient for phosphorylation of the cytoplasmic tail in the presence of Ptc. Using fluorescence cross-correlation spectroscopy (FCCS), we also demonstrate that inactivation of Ptc by Hh induces Smo clustering irrespective of Smo phosphorylation. Our observations therefore support a model of Hh signal transduction whereby Smo subcellular localisation and not phosphorylation is the primary target of Ptc function.

The cell fate decision of multi-potent pancreatic progenitor cells between the exocrine and endocrine lineages is regulated by Notch signalling, mediated by cell–cell interactions. However, canonical models of Notch-mediated lateral inhibition cannot explain the scattered spatial distribution of endocrine cells and the cell-type ratio in the developing pancreas. Based on evidence from acinar-to-islet cell transdifferentiationin vitro, we propose that lateral stabilization, i.e. positive feedback between adjacent progenitor cells, acts in parallel with lateral inhibition to regulate pattern formation in the pancreas. A simple mathematical model of transcriptional regulation and cell–cell interaction reveals the existence of multi-stability of spatial patterns whose simultaneous occurrence causes scattering of endocrine cells in the presence of noise. The scattering pattern allows for control of the endocrine-to-exocrine cell-type ratio by modulation of lateral stabilization strength. These theoretical results suggest a previously unrecognized role for lateral stabilization in lineage specification, spatial patterning and cell-type ratio control in organ development.

International audience; Many internal epithelial organs derive from cysts, which are tissues comprised of bent epithelial cell layers enclosing a lumen. Ion accumulation in the lumen drives water influx and consequently water accumulation and cyst expansion. Lumen-size recognition is important for the regulation of organ size. When lumen size and cyst size are not controlled, diseases can result; for instance, renal failure of the kidney. We develop a mechanistic mathematical model of lumen expansion in order to investigate the mechanisms for saturation of cyst growth. We include fluid accumulation in the lumen, osmotic and elastic pressure, ion transport and stretch-induced cell division. We find that the lumen volume increases in two phases: first, due to fluid accumulation stretching the cells, then in the second phase, the volume increase follows the increase in cell number until proliferation ceases as stretch forces relax. The model is quantitatively fitted to published data of in vitro cyst growth and predicts steady state lumen size as a function of the model parameters.

Cell fate reprogramming, such as the generation of insulin-producing β cells from other pancreas cells, can be achieved by external modulation of key transcription factors. However, the known gene regulatory interactions that form a complex network with multiple feedback loops make it increasingly difficult to design the cell reprogramming scheme because the linear regulatory pathways as schemes of causal influences upon cell lineages are inadequate for predicting the effect of transcriptional perturbation. However, sufficient information on regulatory networks is usually not available for detailed formal models. Here we demonstrate that by using the qualitatively described regulatory interactions as the basis for a coarse-grained dynamical ODE (ordinary differential equation) based model, it is possible to recapitulate the observed attractors of the exocrine and β, δ, α endocrine cells and to predict which gene perturbation can result in desired lineage reprogramming. Our model indicates that the constraints imposed by the incompletely elucidated regulatory network architecture suffice to build a predictive model for making informed decisions in choosing the set of transcription factors that need to be modulated for fate reprogramming.