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| Poster, Friday, 19:00 |
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| Geometry, topology, and out-of-equilibrium
dynamics in epithelial morphogenesis
Benedetta Cerruti1,
Alberto Puliafito1, Annette M. Shewan2, Wei Yu3,
Keith E. Mostov3, Luca Primo1, Guido Serini1,
Antonio Celani4, Andrea Gamba1,5,6
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1
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Institute for Cancer Research and
Treatment, Str. Prov. 142 km 3.95, 10060 Candiolo, Torino, Italy |
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2
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School of Chemistry and Molecular
Biosciences, University of Queensland, St Lucia, Australia |
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3
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Department of Anatomy, University
of California, San Francisco, California, USA |
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4
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Institut Pasteur, Unit "Physics
of Biological Systems", CNRS URA 2171, F-75015 Paris, France |
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5
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Politecnico di Torino and CNISM,
Corso Duca degli Abruzzi 24, 10129 Torino, Italy |
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6
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INFN, via Pietro Giuria 1, 10125
Torino, Italy |
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| Contact:
| Website |
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Remodeling of epithelial sheets is fundamental for the formation of several
organs in metazoans. Epithelial morphogenesis is a complex process involving
cell divisions, cell-cell and cell-extracellular matrix (ECM) adhesion,
cell migration, cell shape changes and apoptosis. In vitro biological
models have been successfully used to reproduce some of the key events
involved in epithelial morphogenesis, and represent a fundamental tool
to dissect the molecular cascade of events leading to the formation of
tissues. Epithelial cysts serve as a paradigm for the formation of hollow
spherical structures in vivo, such as acini, follicles and alveoli.
The orderly development of cell aggregates into spheroidal monolayers delimiting
a single lumen is a process subject to mechanical constraints and depends
on the establishment and maintenance of cellular apico-basal polarity.
The correct architecture and particularly the formation and maintenance
of the lumen are crucial for a suitable cyst growth and are found to be
deficient in several common and often fatal human diseases such aspolycystic
kidney disease, hypertension, and many epithelial cancers. Despite the
specificity inherent to diverse types of tissues, recent findings support
the idea that cyst and tubule formation are led by common mechanisms, and
that shared features underlie the appearance of aberrant phenotypes: the
first key aspect is the mechanics of cell contacts; the second involves
apico-basal polarization and the de novo generation of a luminal space;
and the third is the spatial control of cell division. In order to study
the dynamical process of cyst growth we developed a mathematical model
based on these three aspects, that takes into account the properties of
cell-cell and cell-matrix interactions. On the basis of theoretical predictions
and of the full three-dimensional reconstruction of experimental MDCK cysts,
we demonstrate that cystogenesis occurs through a sequence of states that
are far away from mechanical equilibrium. Three-dimensional numerical simulations
of our theoretical model accurately mimic the dynamics of a growing cyst,
showing that a restricted set of simple rules is necessary and sufficient
to reproduce both wild-type and mutant experimental phenotypes. We provide
evidence that the appearance of the multilumen phenotype is determined
by misorientation of the spindle only in conjunction with strongly out-of-equilibrium
dynamics. Finally, we show that equilibrium regime along with the related
healthy phenotype can be achieved by biological manipulation resulting
in the speeding up of the dynamics. |
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