Synthetic Morphogenesis


 

About

In the group we advance cross-disciplinary research at the interface between biology, physics and engineering by studying the mechanical biology and the biological mechanics of pathological development and disease progression. Specifically, we focus on soft tissue morphogenesis – the process by which a tissue takes or lose shape.

Controlling the biological and mechanical behaviour of cells at the molecular level is a central axiom of bioengineering in its pursuit of tissue and organ regeneration. However, steering living-cell aggregates towards predesigned tissue architectures requires the concertation of factors such as the signalling, shape, force, adhesion and motility of single cells at length- and time-scales still largely unknown. Moreover, increasing evidence points out that the emergence of collective behaviour in cellular assemblies such as tissues is governed by mesoscale physical principles that may also instruct cell biological function in an independent manner. Yet these principles at the tissue scale cannot be predicted from biochemical principles at the single-cell scale. Our research aims at understanding the role of cell mechanics in tissue (mal)formation by harnessing the mesoscale mechanical strategies that cellular collectives adopt to determine tissue form and function in physiological and pathological conditions in vivo and in vitro. By so doing, we wish to provide bioengineers with a modern swatch of fundamental principles that can be utilised to master synthetic morphogenesis and tissue design for regenerative and therapeutic purposes.

Two distinct colorectal cancer islands migrate to fuse together on an elastic substrate. Ezrin (red), Actin (green) and Nuclei (blue).

Human breast epithelium towards malignant transformation. Red – phalloidin, Green – E-cadherin and Blue – DAPI.


 

 

Staff

Vito Conte | Group Leader
Giulia Fornabaio | PhD Student
Adrià Villacrosa Ribas | PhD Student

 

 

Projects

Finished projects
CancerMechReg Regulacion biomecanica de la progresion del cancer (2016-2019) MINECO, Proyectos I+D Excelencia Vito Conte

 

Publications


Nyga, Agata, Muñoz, Jose J., Dercksen, Suze, Fornabaio, Giulia, Uroz, Marina, Trepat, Xavier, Baum, Buzz, Matthews, Helen K., Conte, Vito, (2021). Oncogenic RAS instructs morphological transformation of human epithelia via differential tissue mechanics Science Advances 7, eabg6467

Rubí-Sans G, Nyga A, Rebollo E, Pérez-Amodio S, Otero J, Navajas D, Mateos-Timoneda MA, Engel E, (2021). Development of Cell-Derived Matrices for Three-Dimensional in Vitro Cancer Cell Models Acs Applied Materials & Interfaces 13, 44108-44123

Most morphogenetic and pathological processes are driven by cells responding to the surrounding matrix, such as its composition, architecture, and mechanical properties. Despite increasing evidence for the role of extracellular matrix (ECM) in tissue and disease development, many in vitro substitutes still fail to effectively mimic the native microenvironment. We established a novel method to produce macroscale (>1 cm) mesenchymal cell-derived matrices (CDMs) aimed to mimic the fibrotic tumor microenvironment surrounding epithelial cancer cells. CDMs are produced by human adipose mesenchymal stem cells cultured in sacrificial 3D scaffold templates of fibronectin-coated poly-lactic acid microcarriers (MCs) in the presence of macromolecular crowders. We showed that decellularized CDMs closely mimic the fibrillar protein composition, architecture, and mechanical properties of human fibrotic ECM from cancer masses. CDMs had highly reproducible composition made of collagen types I and III and fibronectin ECM with tunable mechanical properties. Moreover, decellularized and MC-free CDMs were successfully repopulated with cancer cells throughout their 3D structure, and following chemotherapeutic treatment, cancer cells showed greater doxorubicin resistance compared to 3D culture in collagen hydrogels. Collectively, these results support the use of CDMs as a reproducible and tunable tool for developing 3D in vitro cancer models.

Keywords: 3d cell-derived matrices, adipose mesenchymal stem cells, collagen matrix, colorectal adenocarcinoma, cytotoxicity assay, deposition, expansion, extracellular microenvironment, extracellular-matrix, fibronectin, growth, macromolecular crowders, microcarriers, scaffolds, tissue, 3d cell-derived matrices, Adipose mesenchymal stem cells, Cytotoxicity assay, Extracellular microenvironment, Macromolecular crowders, Mesenchymal stem-cells, Microcarriers


Uroz, Marina, Garcia-Puig, Anna, Tekeli, Isil, Elosegui-Artola, Alberto, Abenza, Juan F., Marín-Llauradó, Ariadna, Pujals, Silvia, Conte, Vito, Albertazzi, Lorenzo, Roca-Cusachs, Pere, Raya, Ángel, Trepat, Xavier, (2019). Traction forces at the cytokinetic ring regulate cell division and polyploidy in the migrating zebrafish epicardium Nature Materials 18, 1015-1023

Epithelial repair and regeneration are driven by collective cell migration and division. Both cellular functions involve tightly controlled mechanical events, but how physical forces regulate cell division in migrating epithelia is largely unknown. Here we show that cells dividing in the migrating zebrafish epicardium exert large cell–extracellular matrix (ECM) forces during cytokinesis. These forces point towards the division axis and are exerted through focal adhesions that connect the cytokinetic ring to the underlying ECM. When subjected to high loading rates, these cytokinetic focal adhesions prevent closure of the contractile ring, leading to multi-nucleation through cytokinetic failure. By combining a clutch model with experiments on substrates of different rigidity, ECM composition and ligand density, we show that failed cytokinesis is triggered by adhesion reinforcement downstream of increased myosin density. The mechanical interaction between the cytokinetic ring and the ECM thus provides a mechanism for the regulation of cell division and polyploidy that may have implications in regeneration and cancer.


Uroz, Marina, Wistorf, Sabrina, Serra-Picamal, Xavier, Conte, Vito, Sales-Pardo, Marta, Roca-Cusachs, Pere, Guimerà, Roger, Trepat, Xavier, (2018). Regulation of cell cycle progression by cell–cell and cell–matrix forces Nature Cell Biology 20, (6), 646-654

It has long been proposed that the cell cycle is regulated by physical forces at the cell–cell and cell–extracellular matrix (ECM) interfaces. However, the evolution of these forces during the cycle has never been measured in a tissue, and whether this evolution affects cell cycle progression is unknown. Here, we quantified cell–cell tension and cell–ECM traction throughout the complete cycle of a large cell population in a growing epithelium. These measurements unveil temporal mechanical patterns that span the entire cell cycle and regulate its duration, the G1–S transition and mitotic rounding. Cells subjected to higher intercellular tension exhibit a higher probability to transition from G1 to S, as well as shorter G1 and S–G2–M phases. Moreover, we show that tension and mechanical energy are better predictors of the duration of G1 than measured geometric properties. Tension increases during the cell cycle but decreases 3 hours before mitosis. Using optogenetic control of contractility, we show that this tension drop favours mitotic rounding. Our results establish that cell cycle progression is regulated cooperatively by forces between the dividing cell and its neighbours.


Munoz, J.J., Amat, D., Conte, V., (2018). Computation of forces from deformed visco-elastic biological tissues Inverse Problems 34, (4), 044001

Abstract We present a least-squares based inverse analysis of visco-elastic biological tissues. The proposed method computes the set of contractile forces (dipoles) at the cell boundaries that induce the observed and quantified deformations. We show that the computation of these forces requires the regularisation of the problem functional for some load configurations that we study here. The functional measures the error of the dynamic problem being discretised in time with a second-order implicit time-stepping and in space with standard finite elements. We analyse the uniqueness of the inverse problem and estimate the regularisation parameter by means of a L-curved criterion. We apply the methodology to a simple toy problem and to an in vivo set of morphogenetic deformations of the Drosophila embryo.


Rodriguez-Franco, P., Brugués, A., Marin-Llaurado, A., Conte, V., Solanas, G., Batlle, E., Fredberg, J. J., Roca-Cusachs, P., Sunyer, R., Trepat, X., (2017). Long-lived force patterns and deformation waves at repulsive epithelial boundaries Nature Materials 16, (10), 1029-1036

For an organism to develop and maintain homeostasis, cell types with distinct functions must often be separated by physical boundaries. The formation and maintenance of such boundaries are commonly attributed to mechanisms restricted to the cells lining the boundary. Here we show that, besides these local subcellular mechanisms, the formation and maintenance of tissue boundaries involves long-lived, long-ranged mechanical events. Following contact between two epithelial monolayers expressing, respectively, EphB2 and its ligand ephrinB1, both monolayers exhibit oscillatory patterns of traction forces and intercellular stresses that tend to pull cell-matrix adhesions away from the boundary. With time, monolayers jam, accompanied by the emergence of deformation waves that propagate away from the boundary. This phenomenon is not specific to EphB2/ephrinB1 repulsion but is also present during the formation of boundaries with an inert interface and during fusion of homotypic epithelial layers. Our findings thus unveil a global physical mechanism that sustains tissue separation independently of the biochemical and mechanical features of the local tissue boundary.

Keywords: Biological physics, Cellular motility


Roca-Cusachs, Pere, Conte, Vito, Trepat, Xavier, (2017). Quantifying forces in cell biology Nature Cell Biology 19, (7), 742-751

Cells exert, sense, and respond to physical forces through an astounding diversity of mechanisms. Here we review recently developed tools to quantify the forces generated by cells. We first review technologies based on sensors of known or assumed mechanical properties, and discuss their applicability and limitations. We then proceed to draw an analogy between these human-made sensors and force sensing in the cell. As mechanics is increasingly revealed to play a fundamental role in cell function we envisage that tools to quantify physical forces may soon become widely applied in life-sciences laboratories.


Perez-Mockus, Gantas, Mazouni, Khalil, Roca, Vanessa, Corradi, Giulia, Conte, Vito, Schweisguth, François, (2017). Spatial regulation of contractility by Neuralized and Bearded during furrow invagination in Drosophila Nature Communications 8, (1), 1594

Embryo-scale morphogenesis arises from patterned mechanical forces. During Drosophila gastrulation, actomyosin contractility drives apical constriction in ventral cells, leading to furrow formation and mesoderm invagination. It remains unclear whether and how mechanical properties of the ectoderm influence this process. Here, we show that Neuralized (Neur), an E3 ubiquitin ligase active in the mesoderm, regulates collective apical constriction and furrow formation. Conversely, the Bearded (Brd) proteins antagonize maternal Neur and lower medial–apical contractility in the ectoderm: in Brd-mutant embryos, the ventral furrow invaginates properly but rapidly unfolds as medial MyoII levels increase in the ectoderm. Increasing contractility in the ectoderm via activated Rho similarly triggers furrow unfolding whereas decreasing contractility restores furrow invagination in Brd-mutant embryos. Thus, the inhibition of Neur by Brd in the ectoderm differentiates the mechanics of the ectoderm from that of the mesoderm and patterns the activity of MyoII along the dorsal–ventral axis.

Keywords: Drosophila, Gastrulation, Morphogenesis


Sunyer, R., Conte, V., Escribano, J., Elosegui-Artola, A., Labernadie, A., Valon, L., Navajas, D., García-Aznar, J. M., Muñoz, J. J., Roca-Cusachs, P., Trepat, X., (2016). Collective cell durotaxis emerges from long-range intercellular force transmission Science 353, (6304), 1157-1161

The ability of cells to follow gradients of extracellular matrix stiffness-durotaxis-has been implicated in development, fibrosis, and cancer. Here, we found multicellular clusters that exhibited durotaxis even if isolated constituent cells did not. This emergent mode of directed collective cell migration applied to a variety of epithelial cell types, required the action of myosin motors, and originated from supracellular transmission of contractile physical forces. To explain the observed phenomenology, we developed a generalized clutch model in which local stick-slip dynamics of cell-matrix adhesions was integrated to the tissue level through cell-cell junctions. Collective durotaxis is far more efficient than single-cell durotaxis; it thus emerges as a robust mechanism to direct cell migration during development, wound healing, and collective cancer cell invasion.


 

 

Equipment

  • Mechanical quantification in vitro and in vivo
  • Experimental physical modelling in silico
  • Nikon Ti2 Epifluorescent microscope optimized for long-live imaging in Traction Force Microscopy and Microfluidics modes

 

 

Collaborations

  • José Muñoz
    Polytechnic University of Catalonia (UPC)
  • François Schweisguth
    Pasteur Institute, France
  • Wayne Brodland
    UW, Canada
  • Buzz Baum, UK
    UCL, London and MRC LMB Cambridge
  • Carlijn Bouten, the Netherlands
    TU/e, Eindhoven
  • Jaap den Toonder, the Netherlands 
    TU/e, Eindhoven
  • Kees Storm, the Netherlands
    TU/e, Eindhoven
  • Cecilia Sahlgren, Finland
    TurkuBioscience, Turku 
  • Dr Funny Jaulin 
    Institut/Hospital Gustave Roussy  Paris, France 

 

 

News

IBEC’s newest junior group leader: Vito Conte

vitoconteVito Conte may be familiar to many, having spent more than four years in Xavier Trepat’s Integrative Cell and Tissue Dynamics group, first as a postdoc and later as a Juan de la Cierva fellow. Vito now is a Ramon y Cajal fellow and leads the Mechanics of Development and Disease group, which will take a new direction as he develops new biophysical tools to quantify the mechanics of cell and tissues in 3D environments.

“With a strong background in studying how cell and tissue mechanics determine structure and function from my time as a postdoc, I want to carry on exploring the physical mechanisms of development and disease in biological organisms” says Vito, who completed his PhD in biomechanical engineering at King’s College London in the group of Prof. Mark Miodownik, now director of the Institute of Making at UCL. “To do this, my group will develop novel tools to carry out in vivo and in vitro mechanical measurements, which we will integrate into 2D and 3D models of the biological organisms being studied.”

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