Multiscale dynamics of branching morphogenesis.

Branching morphogenesis is a prototypical example of complex three-dimensional organ sculpting, required in multiple developmental settings to maximize the area of exchange surfaces. It requires, in particular, the coordinated growth of different cell types together with complex patterning to lead to robust macroscopic outputs. In recent years, novel multiscale quantitative biology approaches, together with biophysical modelling, have begun to shed new light of this topic. Here, we wish to review some of these recent developments, highlighting the generic design principles that can be abstracted across different branched organs, as well as the implications for the broader fields of stem cell, developmental and systems biology.wellcome trust royal societ

Statistical theory of branching morphogenesis

Branching morphogenesis remains a subject of abiding interest. Although much is known about the gene regulatory programs and signaling pathways that operate at the cellular scale, it has remained unclear how the macroscopic features of branched organs, including their size, network topology and spatial patterning, are encoded. Lately, it has been proposed that, these features can be explained quantitatively in several organs within a single unifying framework. Based on large- scale organ recon - structions and cell lineage tracing, it has been argued that morphogenesis follows from the collective dynamics of sublineage- restricted self- renewing progenitor cells, localized at ductal tips, that act cooperatively to drive a serial process of ductal elon - gation and stochastic tip bifurcation. By correlating differentiation or cell cycle exit with proximity to maturing ducts, this dynamic results in the specification of a com- plex network of defined density and statistical organization. These results suggest that, for several mammalian tissues, branched epithelial structures develop as a self- organized process, reliant upon a strikingly simple, but generic, set of local rules, without recourse to a rigid and deterministic sequence of genetically programmed events. Here, we review the basis of these findings and discuss their implications

Theory of mechanochemical patterning in biphasic biological tissues.

The formation of self-organized patterns is key to the morphogenesis of multicellular organisms, although a comprehensive theory of biological pattern formation is still lacking. Here, we propose a minimal model combining tissue mechanics with morphogen turnover and transport to explore routes to patterning. Our active description couples morphogen reaction and diffusion, which impact cell differentiation and tissue mechanics, to a two-phase poroelastic rheology, where one tissue phase consists of a poroelastic cell network and the other one of a permeating extracellular fluid, which provides a feedback by actively transporting morphogens. While this model encompasses previous theories approximating tissues to inert monophasic media, such as Turing's reaction-diffusion model, it overcomes some of their key limitations permitting pattern formation via any two-species biochemical kinetics due to mechanically induced cross-diffusion flows. Moreover, we describe a qualitatively different advection-driven Keller-Segel instability which allows for the formation of patterns with a single morphogen and whose fundamental mode pattern robustly scales with tissue size. We discuss the potential relevance of these findings for tissue morphogenesis

Mechanically-driven Stem Cell Separation in Tissues caused by Proliferating Daughter Cells

The homeostasis of epithelial tissue relies on a balance between the self-renewal of stem cell populations, cellular differentiation, and loss. Although this balance needs to be tightly regulated to avoid pathologies, such as tumor growth, the regulatory mechanisms, both cell-intrinsic and collective, which ensure tissue steady-state are still poorly understood. Here, we develop a computational model that incorporates basic assumptions of stem cell renewal into distinct populations and mechanical interactions between cells. We find that the model generates unexpected dynamic features: stem cells repel each other in the bulk tissue and are thus found rather isolated, as in a number of in vivo contexts. By mapping the system onto a gas of passive Brownian particles with effective repulsive interactions, that arise from the generated flows of differentiated cells, we show that we can quantitatively describe such stem cell distribution in tissues. The interaction potential between a pair of stem cells decays exponentially with a characteristic length that spans several cell sizes, corresponding to the volume of cells generated per stem cell division. Our findings may help understanding the dynamics of normal and cancerous epithelial tissues

A Unifying Theory of Branching Morphogenesis

The morphogenesis of branched organs remains a subject of abiding interest. Although much is known about the underlying signaling pathways, it remains unclear how macroscopic features of branched organs, including their size, network topology and spatial patterning, are encoded. Here we show that, in mouse mammary gland, kidney and human prostate, these features can be explained quantitatively within a single unifying framework of branching and annihilating random walks. Based on quantitative analyses of large-scale organ reconstructions and proliferation kinetics measurements, we propose that morphogenesis follows from the proliferative activity of equipotent tips that stochastically branch and randomly explore their environment, but compete neutrally for space, becoming proliferatively inactive when in proximity with neighboring ducts. These results show that complex branched epithelial structures in mammalian tissues develop as a self-organized process, reliant upon a strikingly simple, but generic, rule, without recourse to a rigid and deterministic sequence of genetically programmed events.This work was supported by an ERC consolidator grant (648804), research grants from the Dutch Organization of Scientific Research (NWO; 823.02.017), the Dutch Cancer Society (KWF; HUBR 2009-4621), the Association for International Cancer Research (AICR; 13-0297) (all J.v.R), the Wellcome Trust (110326/Z/15/Z to E.H. and 098357/Z/12/Z to B.D.S.), and equipment grants from the Dutch Organization of Scientific Research (NWO; 175.010.2007.00 and 834.11.002). E.H. is funded by a JRF from Trinity College and acknowledges the Bettencourt-Schueller Young Researcher Prize for support. C.L.G.J.S. is funded by a Boehringer Ingelheim Fonds PhD Fellowship. R.S. was supported by the Norman S. Coplon Extramural Grant. R.H. and M.M. were funded by a Cancer Research UK Clinician Scientist Fellowship (Ref C10169/A12173)

Rigidity percolation uncovers a structural basis for embryonic tissue phase transitions

Embryo morphogenesis is impacted by dynamic changes in tissue material properties, which have been proposed to occur via processes akin to phase transitions (PTs). Here, we show that rigidity percolation provides a simple and robust theoretical framework to predict material/structural PTs of embryonic tissues from local cell connectivity. By using percolation theory, combined with directly monitoring dynamic changes in tissue rheology and cell contact mechanics, we demonstrate that the zebrafish blastoderm undergoes a genuine rigidity PT, brought about by a small reduction in adhesion-dependent cell connectivity below a critical value. We quantitatively predict and experimentally verify hallmarks of PTs, including power-law exponents and associated discontinuities of macroscopic observables. Finally, we show that this uniform PT depends on blastoderm cells undergoing meta-synchronous divisions causing random and, consequently, uniform changes in cell connectivity. Collectively, our theoretical and experimental findings reveal the structural basis of material PTs in an organismal context

Mechanical Instabilities of Biological Tubes

We study theoretically the shapes of biological tubes affected by various pathologies. When epithelial cells grow at an uncontrolled rate, the negative tension produced by their division provokes a buckling instability. Several shapes are investigated : varicose, enlarged, sinusoidal or sausage-like, all of which are found in pathologies of tracheal, renal tubes or arteries. The final shape depends crucially on the mechanical parameters of the tissues : Young modulus, wall-to-lumen ratio, homeostatic pressure. We argue that since tissues must be in quasistatic mechanical equilibrium, abnormal shapes convey information as to what causes the pathology. We calculate a phase diagram of tubular instabilities which could be a helpful guide for investigating the underlying genetic regulation

Cell Migration Driven by Cooperative Substrate Deformation Patterns

Most eukaryotic cells sense and respond to the mechanical properties of their surroundings. This can strongly influence their collective behavior in embryonic development, tissue function, and wound healing. We use a deformable substrate to measure collective behavior in cell motion due to substrate mediated cell-cell interactions. We quantify spatial and temporal correlations in migration velocity and substrate deformation, and show that cooperative cell-driven patterns of substrate deformation mediate long-distance mechanical coupling between cells and control collective cell migration

Three-dimensional geometry controls division symmetry in stem cell colonies.

Proper control of division orientation and symmetry, largely determined by spindle positioning, is essential to development and homeostasis. Spindle positioning has been extensively studied in cells dividing in two-dimensional (2D) environments and in epithelial tissues, where proteins such as NuMA (also known as NUMA1) orient division along the interphase long axis of the cell. However, little is known about how cells control spindle positioning in three-dimensional (3D) environments, such as early mammalian embryos and a variety of adult tissues. Here, we use mouse embryonic stem cells (ESCs), which grow in 3D colonies, as a model to investigate division in 3D. We observe that, at the periphery of 3D colonies, ESCs display high spindle mobility and divide asymmetrically. Our data suggest that enhanced spindle movements are due to unequal distribution of the cell-cell junction protein E-cadherin between future daughter cells. Interestingly, when cells progress towards differentiation, division becomes more symmetric, with more elongated shapes in metaphase and enhanced cortical NuMA recruitment in anaphase. Altogether, this study suggests that in 3D contexts, the geometry of the cell and its contacts with neighbors control division orientation and symmetry. This article has an associated First Person interview with the first author of the paper