Growth Form and Function: the Mathematics of 3D Tissue Morphogenesis and Regenerative Medicine

Lead Research Organisation: University of Nottingham
Department Name: Sch of Mathematical Sciences


Recent advances in regenerative medicine promise major breakthroughs for healthcare and in the understanding of cell and tissue function. Moreover, the field provokes a host of important systems-biology questions that raise formidable challenges at the forefront of current developments in mathematics. This proposal seeks to capitalise on areas of world-class expertise within the University of Nottingham (in mathematical medicine, cell signalling, tissue engineering and stem-cell biology) to establish an internationally-leading group equipped to address these challenges. The investigations that the research programme will pursue will seek to further the understanding of the mechanisms by which cells communicate with one another, and of how this communication influences both the behaviour of individual cells and the manner in which aggregates of cells assemble and function. The results will have implications for a wide range of topics of great current importance, including for stem-cell behaviour and for the generation of gut tissue and of bone. The integration of this work within the Centre for Regenerative Medicine at Nottingham should generate enormous added value, producing powerful computational tools whose range of application, for example in providing insight into experimentally or ethically inaccessible in vivo systems, will be immense.

Technical Summary

The biology underlying regenerative medicine is inherently complex, with multiple interacting mechanisms controlling the behaviour of individual cells and the tissues they constitute. The level of complexity of this nascent field offers massive opportunities for mathematically-focussed systems-biology studies: such approaches have a key role to play in systematically uncovering the behaviour of systems whose understanding would typically defy intuition alone. The resulting mathematics will also be of significant interest in its own right, requiring the development of, inter alia, multiscale models involving genetic networks and their implications for cell fate, cross-talk between distinct intracellular signalling pathways, intercellular signalling (including mechanotransduction) within mixed populations of cells, and tissue growth and biomechanics. The proposed research will involve four multidisciplinary strands, three of which will focus primarily on single-scale phenomena, specifically (subcellular) cell-signalling networks, (cell-scale) behaviour of stems cells and (tissue-scale) organisation of aggregates of cells. There is significant and crucial interplay between the different scales and the final strand will involve the integration of these results into a widely-applicable modelling framework, as well as the training of project participants in appropriate cross-disciplinary skills. Testing of the theoretical predictions against experimental data will form a central part of every component of the research programme.


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Description The research programme involved the field of regenerative medicine. This is a topic that promises major breakthroughs both for healthcare and in the understanding of cell and tissue function. As such, it raises a host of important integrative systems-biology questions i.e. ones that can be addressed effectively only through cross-disciplinary studies applying
mathematical modelling approaches able to describe phenomena operating over a wide range of spatial and temporal scales in tandem with experimental investigations designed to inform the models and thereby give them genuine predictive capability.

The research programme comprised four strands.

Strand A focussed on signalling networks operating within an individual cell, whereby a ligand binding to a receptor on the cell membrane can trigger a cascade of responses within the cell, ultimately influencing gene expression and hence potentially the differentiation pathway undertaken by a stem cell, for example. Models have been developed for complete pathways from receptor to gene expression. The upstream components of these models have been subject to detailed parameterisation against experimental data (much of it new); work to characterise the downstream parts is ongoing.

Strand B focussed on stem-cell differentiation and, in particular, how this is influenced by the cell's environment (such as its location within an embryoid body or the amounts of signalling molecules produced by other cells). The models have been formulated at the level both of individual cells and of aggregates of cells; multiscale mathematical methods based on homogenisation theory have been refined in order to transfer information between the distinct scales and the results of the modelling have been applied in providing insight into the complementary experimental programmes, clarifying in particular how exogeneous factors influence the pathways the cells follow and hence the cell type into which they differentiate. The research programme has sought to capture stochastic (random) effects as well as average behaviour described by deterministic models.

Strand C concerned behaviour at the tissue level. The mathematical models necessary for the description of the
experimental systems in question were particularly varied, involving cell-based approaches representing the behaviour of large numbers of cells within a pore in a tissue-engineering scaffold, partial differential equations that describe both the spatial and the temporal structure within tissue at the macroscale and ordinary differential equations that average over spatial variations to allow highly complex interactions (such as those involved in the formation of new blood vessels) to be captured within tractable formulations. Moreover, the models were required to describe numerous distinct effects,
associated both with mechanical properties (for example in the buckling of a growing sheet of cells) and with the transport of various molecular species (including nutrients and growth factors). The corresponding experimental work involved a wide range of demanding techniques, a noteworthy feature being the application of rapid prototyping approaches in producing arrays of pores, the growth of tissue within which provided a considerable amount of valuable data.

Finally, Strand D involved the development of multiscale mathematical techniques able to combine the processes operating on the widely different scales, with the potential for application in diverse contexts in integrative systems biology. This work featured both generic studies able to characterise gene-regulation mechanisms (Delta-Notch signalling representing a widely studied paradigm) and more specific investigations, as alluded to above.

The above programme of research was complemented by a broad ranging outreach and training programme, promoting engagement with numerous internationally leading figures within systems biology and facilitating wide dissemination of the results.
Exploitation Route The methodologies developed are widely applicable in multiscale-systems-biology applications and are naturally of particular relevance to the implementation of such approaches in furthering the understanding of regenerative-medicine approaches.
Sectors Education,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

Description The results have informed a number of developments in systems biology and regenerative medicine, within the University of Nottingham (including through the BBSRC/EPSRC-funded Centre for Plant Integrative Biology), at other academic institutions and, in part through many of the research staff employed on the grant taking up subsequent research positions, more broadly in guiding technological developments.
First Year Of Impact 2009
Sector Education,Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic