H. G. E. Hentschel

Dynamical mechanisms for skeletal pattern formation in the vertebrate limb

We describe a ‘reactor–diffusion’ mechanism for precartilage condensation based on recent experiments on chondrogenesis in the early vertebrate limb and additional hypotheses. Cellular differentiation of mesenchymal cells into subtypes with different fibroblast growth factor (FGF) receptors occurs in the presence of spatio–temporal variations of FGFs and transforming growth factor–betas (TGF–βs). One class of differentiated cells produces elevated quantities of the extracellular matrix protein fibronectin, which initiates adhesion–mediated preskeletal mesenchymal condensation. The same class of cells also produces an FGF–dependent laterally acting inhibitor that keeps condensations from expanding beyond a critical size. We show that this ‘reactor–diffusion’ mechanism leads naturally to patterning consistent with skeletal form, and describe simulations of spatio–temporal distribution of these differentiated cell types and the TGF–β and inhibitor concentrations in the developing limb bud.

On multiscale approaches to three-dimensional modelling of morphogenesis

In this paper we present the foundation of a unified, object-oriented, three-dimensional biomodelling environment, which allows us to integrate multiple submodels at scales from subcellular to those of tissues and organs. Our current implementation combines a modified discrete model from statistical mechanics, the Cellular Potts Model, with a continuum reaction–diffusion model and a state automaton with well-defined conditions for cell differentiation transitions to model genetic regulation. This environment allows us to rapidly and compactly create computational models of a class of complex-developmental phenomena. To illustrate model development, we simulate a simplified version of the formation of the skeletal pattern in a growing embryonic vertebrate limb.

Multiscale Models for Vertebrate Limb Development

Dynamical systems in which geometrically extended model cells produce and interact with diffusible (morphogen) and nondiffusible (extracellular matrix) chemical fields have proved very useful as models for developmental processes. The embryonic vertebrate limb is an apt system for such mathematical and computational modeling since it has been the subject of hundreds of experimental studies, and its normal and variant morphologies and spatiotemporal organization of expressed genes are well known. Because of its stereotypical proximodistally generated increase in the number of parallel skeletal elements, the limb lends itself to being modeled by Turing-type systems which are capable of producing periodic, or quasiperiodic, arrangements of spot- and stripe-like elements. This chapter describes several such models, including, (i) a system of partial differential equations in which changing cell density enters into the dynamics explicitly, (ii) a model for morphogen dynamics alone, derived from the latter system in the morphostatic limit where cell movement relaxes on a much slower time-scale than cell differentiation, (iii) a discrete stochastic model for the simplified pattern formation that occurs when limb cells are placed in planar culture, and (iv) several hybrid models in which continuum morphogen systems interact with cells represented as energy-minimizing mesoscopic entities. Progress in devising computational methods for handling 3D, multiscale, multimodel simulations of organogenesis is discussed, as well as for simulating reaction-diffusion dynamics in domains of irregular shape.

Stability of n-dimensional patterns in a generalized Turing system: implications for biological pattern formation

The stability of Turing patterns in an n-dimensional cube (0 ,π ) n is studied, where n 2. It is shown by using a generalization of a classical result of Ermentrout concerning spots and stripes in two dimensions that under appropriate assumptions only sheet-like or nodule-like structures can be stable in an n-dimensional cube. Other patterns can also be stable in regions comprising products of lower-dimensional cubes and intervals of appropriate length. Stability results are applied to a new model of skeletal pattern formation in the vertebrate limb.