Spatial sensing and mechanotransdution at cell adhesions during mesenchymal condensation

Nanobioengineering  · Josep Samitier  / Cellular and molecular mechanobiology · Pere Roca-Cusachs

 

Research project


The Nanobioengineering group at IBEC is a multidisciplinary team applying nanotechnology for the development of new biomedical systems and devices, mainly for diagnostic purposes, and integrated microfluidic Organ-on-Chip devices for the study of organ physiology, disease etiology, or drug screening. The group uses nanotechnology applied to biomolecule interaction studies and micro/nano-environments for regenerative medicine applications. Particularly, we work on the development of bioengineered 2D and 3D micro/nanoenvironments with a topography and chemical composition controlled at the nanoscale for cell behavior studies (adhesion, proliferation, differentiation) and the biophysical description of cellular phenomena (cell migration, differentiation) using micro/nanotechnologies, cell biology tools and soft matter physics.

The Cellular and Molecular Mechanobiology lab at IBEC studies cell mechanical interactions with their environment. These physical interactions determine how cells proliferate, differentiate, and move, and regulate development, tumorigenesis, or wound healing. Just like biochemical stimuli initiate signaling cascades, mechanical forces affect the links and conformation of a network of molecules connecting cells to the extracellular matrix. Research in the group aims precisely at unraveling the mechanisms that these molecules use to detect and respond to mechanical stimuli like forces or tissue rigidity, triggering downstream cell responses. To this end, we combine biophysical techniques like magnetic tweezers, Atomic Force Microscopy, traction microscopy, and microfabricated force sensors with molecular biology, advanced optical microscopy, and theoretical modelling.

In this project we are interested in developing nanotechnological tools for the in vitro study of the mechanochemical control of mesenchymal condensation, and its effects on final tissue architecture.

Job position


Mesenchymal condensation is a prevalent morphogenetic transition mediated by cell adhesion, where mesenchymal cells cluster tightly together, acquire a rounded morphology, and differentiate towards a tissue. It represents the earliest stage in the organogenesis of many organs, including cartilage, bone, muscle and tendon, among others, and it engages a series of dynamic morphological and molecular events1. Among the different signaling pathways involved, TGF-β family morphogens upregulate the expression of the extracellular matrix (ECM) protein fibronectin (FN), and induce mesenchymal cells to accumulate (condense) in regions of increased cell-fibronectin adhesion2,3. Active cell movement (haptotaxis) towards the condensate center4 occurs during this condensation. Cells then acquire epithelioid properties by the upregulation of cell-cell adhesion molecules. The size and shape of the condensed cell mass regulate the final three-dimensional architecture of the organ, and abnormal condensation can result in developmental defects5.

The lack of proper model systems in vitro limits the study of the mechanisms of mesenchymal condensation and compaction, and of its link to cell fate determination6. Given the crucial role of the ECM in the process, we propose the use of a previously developed platform7  that permits to locally control surface adhesiveness at the nanoscale as a reliable model system for the study of mesenchymal condensation in vitro. The formation of mesenchymal condensates on the nanopatterns will be studied at the molecular level, deciphering the mechanical and chemical events driving the processes. Effects of the condensation phase on tissue differentiation will be evaluated with especial emphasis on chondrogenic and tenogenic commitments.

During the thesis project, the student will learn how to work in a multidisciplinary and dynamic environment. He/she will develop tasks involving advanced technologies in bioengineering, nanotechnology, cell biology, microscopy, image processing and mechanobiology.

 

References

[1] Hall, B. K. & Miyake, T. All for one and one for all: condensations and the initiation of skeletal development. BioEssays 22, 138–147 (2000).

[2] Singh, P. & Schwarzbauer, J. E. Fibronectin and stem cell differentiation-lessons from chondrogenesis. J. Cell Sci. 125, 3703-3712 (2012).

[3] Frenz, D. A., Jaikaria, N. S. & Newman, S. A. The mechanism of precartilage mesenchymal condensation: a major role for interaction of the cell surface with the amino-terminal heparin-binding domain of fibronectin. Dev. Biol. 136, 97-103 (1989).

[4] Christley, S., Alber, M. S. & Newman, S. A. Patterns of mesenchymal condensation in a multiscale, discrete stochastic model. PLOS Comput. Biol. 3, 743-753 (2007).

[5] Mammoto, T. et al. Mechanochemical Control of Mesenchymal Condensation and Embryonic Tooth Organ Formation. Dev. Cell 21, 758-769 (2011).

[6] Klumpers, D. D., Mao, A. S., Smit, T. H. & Mooney, D. J. Linear patterning of mesenchymal condensations is modulated by geometric constraints. J. R. Soc. Interface 11, 20140215 (2014).

[7] Casanellas, I. et al. Dendrimer-based uneven nanopatterns to locally control surface adhesiveness: A method to direct chondrogenic differentiation. J. Vis. Exp. 131, e56347 (2018).