Transcript Document

Modelling Tissue Development
Rod Smallwood, Mike Holcombe, Sheila Mac Neil, Rod Hose, Richard
Clayton (University of Sheffield), Jenny Southgate (University of York)
University
of Sheffield
www.dcs.shef.ac.uk/~rod/
The social behaviour of cells
How do these individual cells …
… assemble into this complex tissue?
University
of Sheffield
www.dcs.shef.ac.uk/~rod/
Building an integrative systems
biology: the Human Physiome Project
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University
of Sheffield
www.dcs.shef.ac.uk/~rod/
The aim of the Human Physiome
Project is to provide a “quantitative
description of physiological dynamics
and functional behaviour of the intact
organism”
it is overseen by the Physiome and
Bioengineering Committee of the IUPS
(International Union of Physiological
Sciences)
projects include the Cardiome (heart),
the Endotheliome (lining of blood
vessels), Micro-circulation …
… and the Epitheliome – computational
modelling of the social behaviour of
(epithelial) cells
Where does cell modelling fit
into the Physiome Project?
The
Epitheliome
Cellular tissue
10-5m
Social model
of cell
University
of Sheffield
www.dcs.shef.ac.uk/~rod/
Hunter P, Robbins P, Noble D (2002) The IUPS human physiome project.
Eur J Physiol 445 1-9
The social life of the cell is
important!
• Essential step from single-cell to multi-cellular organisms
• Tissues and organs are self-assembling systems
• No organising principle above the level of a single cell
– so order is an emergent property of cellular interaction
• This is a salient feature of biological systems - order emerges as
the result of the interaction of large numbers of complex entities
University
of Sheffield
www.dcs.shef.ac.uk/~rod/
Courtesy of Sheila Mac Neil, Sheffield
What are the drivers?
Screening for epithelial cancers
Contraction of skin grafts
Wound healing
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of Sheffield
www.dcs.shef.ac.uk/~rod/
Courtesy of Dawn Walker & Sheila Mac Neil, Sheffield
What are the common
features?
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of Sheffield
Self assembly/disassembly
Forces between cells
Cell motility
Cell signalling as a result of
mechanical forces
Only an empirical understanding of
the processes
– e.g. differentiation at an airliquid interface
www.dcs.shef.ac.uk/~rod/
Courtesy of Sheila Mac Neil, Sheffield
From ants to epithelium
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University
of Sheffield
Existing models of tissue are either descriptive or derive function from
structure
– need a predictive model, not a descriptive model
– in advance of healing, there is no structure in a wound, so need to develop
structure from function
What paradigm can we use to model self-assembly of large numbers of very
complex entities?
The basic idea came from work
on the social behaviour of ants
– we are interested in the social
behaviour of cells
Two key insights were essential
– a mechanism for integrating
cellular biology into the
‘social model’
– linking the ‘social model’ to a
physical model of the tissue
behaviour
www.dcs.shef.ac.uk/~rod/
Courtesy of Francis Ratnieks, Sheffield
Simulation of monolayer
growth
STEM CELL
TRANSIT
AMPLIFYING
CELL
MITOTIC CELL
QUIESCENT
CELL
University
of Sheffield
Low Ca2+
(0.09 mM)
NO. CELLS
Physiological
Ca2+ (2 mM)
Ca2+ = 2mM
Ca2+ = 0.09mM
www.dcs.shef.ac.uk/~rod/
ITERATION NUMBER
in silico wound healing
Physiological Ca2+ (2mM)
University
of Sheffield
www.dcs.shef.ac.uk/~rod/
Low Ca2+ (0.09mM)
in vitro wound healing
Physiological Ca2+
University
of Sheffield
www.dcs.shef.ac.uk/~rod/
Low Ca2+
(Cell movie from Gemma Hill, Jack Birch Unit for Molecular
Carcinogenesis, University of York)
Major challenges
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University
of Sheffield
Developing a ‘realistic’ physical model that is computationally
tractable for ~106 cells
Deciding what is important - sparseness (parsimony)
Linking individual cell dynamics to a continuum model of tissue
– how does stress at the tissue level affect
mechano-transduction at the cytoskeletal
level
– how is the signalling resulting from a wound
related to cellular-level response
Comparing tissue growth in vitro and in silico
– how do we validate the computational model
www.dcs.shef.ac.uk/~rod/
Balaban et al 2001 Nature Cell Biology 3 466
Summary
• We have developed a proof-of-concept model of the social
behaviour of cells
• The model shows similar behaviour to urothelial cells grown in
vitro
• In principle, the model:
– can incorporate the biological mechanisms which control
cell behaviour
– can be scaled up to realistic numbers of cells
• In practice, sparseness will be essential!
• The model is changing biologists’ thinking and driving
biological experiments
• Strong validation is essential
University
of Sheffield
www.dcs.shef.ac.uk/~rod/
Acknowledgements
Cell biology:
Jenny Southgate (York)
Sheila Mac Neil
Eva Qwarnstrom
Modelling:
Mike Holcombe
Dawn Walker
Steven Wood
Engineering:
Rod Hose
Peter Hunter (Auckland)
Funding:
Engineering & Physical Sciences Research Council (EPSRC)
Higher Education Funding Council for England (HEFCE)
University
of Sheffield
www.dcs.shef.ac.uk/~rod/
University
of Sheffield
www.dcs.shef.ac.uk/~rod/