Home » Growth, Form & Function: the Mathematics of 3D Tissue Morphogenesis and Regenerative Medicine (MRM)

This project puts in place an internationally-leading multidisciplinary research team, with a unique blend of skills, at the interface between the Wolfson Centre for Stem Cells, Tissue Engineering & Modelling (STEM) and the Centre for Mathematical Medicine and Biology (CMMB). The project is built around three research strands (A-C below) that lie in major and highly topical fields of tissue morphogenesis and regenerative medicine. Two broad mathematical themes run through the project: (i) the development of novel models, firmly rooted in applications, that will lead to advances of genuine biological relevance and (ii) the development and application of multiscale techniques that permit integration of models across disparate length and time scales (Strand D). These activities will be supported by a programme of interdisciplinary training and dissemination activities (also within Strand D), providing all participants in the programme with broad exposure to systems-biology approaches and enabling them to respond to the rapid pace of biological developments.

A: Cell signalling. Cell-signalling pathways that lead to altered gene transcription and cell differentiation are of primary importance in many aspects of regenerative medicine. However, the traditional view that single stimuli lead to single responses has been replaced by a paradigm wherein a host of different stimuli converge and are integrated to give a response that may be determined not just by the type (agonist, antagonist or inverse agonist) and magnitude of those stimuli, but also by the details of their time-course. Strand A will develop mathematical models for relevant signalling pathways, supported by experimental data from the the Institute for Cell Signalling, led by Professor Stephen Hill.
B: Stem cells. The organisation of tissue constituents (including different cell types, extracellular material and blood vessels) into complex three-dimensional functional structures relies on numerous spatial, biomechanical and biochemical cues. In developmental biology, the tissue constituents self-assemble within their unique environment. A challenge facing tissue engineers is to recreate this environment in vitro to obtain functional three-dimensional tissues from populations of stem cells. Strand B will address the question of how growth factors and mechanical effects may be manipulated to better control the differentiation of stem cells in order to generate more efficiently and predictably the number and variety of cells needed to produce new tissues.
C: Tissue organisation. In vitro tissue engineering typically involves seeding cells onto application-specific scaffolds that seek to mimic the in vivo spatial structure of the desired tissue. These scaffolds are then placed in bioreactors that aim to recreate the in vivo biomechanochemical environment, i.e. soluble growth factors are added to the cell-culture media and mechanical stimuli applied. Strand C will investigate the hypothesis that the development and organisation of differentiated tissue following commitment of stem cells to a defined cell lineage is influenced by the spatial confinement of cells within a defined structure and exposure to cell signalling and mechanical stimuli specific to that environment.
D: Training, dissemination and integration. Strand D will co-ordinate and facilitate interactions between the strands, including the multiscale-modelling aspects of the programme, exploiting a variety of approaches to embed the microscale (subcellular and cell-scale) developments in a mathematically-reliable and precise way into the interaction terms in the (multiphase) tissue-level models. In addition, the research environment of the project will be underpinned by a range of activities, aimed at promoting integration of different disciplines and approaches and at fostering dissemination of research results. This will include a visiting-fellow programme, seminars, short courses and workshops.