The mechanobiology of nervous system development and pathology
Key aspects in the development of the central nervous system (CNS) include the formation of neuronal axons, their subsequent growth and guidance through thick layers of nervous tissue, and the folding of the brain. All these processes involve motion and must thus be driven by forces. However, while our understanding of the biochemical and molecular control of these processes is increasing rapidly, the contribution of mechanics remains poorly understood.
Cell motion is also crucially involved in CNS pathologies such as foreign body reactions, in which activated glial cells migrate towards and encapsulate implants (e.g., electrodes), and the failing regeneration of neurons after CNS (e.g., spinal cord) injuries. Repair can currently not be promoted. So far, research has - without any major breakthrough - mainly focused on chemical signals impeding and promoting neuronal (re)growth.
We are taking a different, interdisciplinary approach and investigate how cellular forces, local cell and tissue compliance and cellular mechanosensitivity contribute to CNS development and disease. Methods we are exploiting include atomic force microscopy, traction force microscopy, custom-built simple and complex compliant cell culture substrates, optical microscopy including confocal laser scanning microscopy and cell biological techniques. We have shown, for example, that nervous tissue is mechanically inhomogeneous. Furthermore, we found that neurons constantly exert forces on their environment and that both neurons and glial cells respond to mechanical cues. Understanding how and when CNS cells actively exert forces and respond to their mechanical environment will shed new light on CNS development, and it could eventually lead to novel biomedical approaches to treat or circumvent pathologies that involve mechanical signalling.
Main sources of funding: MRC, BBSRC, HFSP, NIH, Royal Society, Wellcome Trust, Newton Trust
Christoph Ballestrem (Centre for Cell Matrix Research, University of Manchester)
Kevin Chalut (Physics and SCRI, Cambridge)
James Fawcett (Brain Repair Centre, Cambridge)
Malte Gather (Physics & Astronomy, University of St. Andrews)
Jochen Guck (Technical University Dresden, Germany)
Bill Harris (PDN, Cambridge)
Christine Holt (PDN, Cambridge)
Thora Karadottir (SCRI, Cambridge)
Andreas Reichenbach (University of Leipzig, Germany)
Giuliano Scarcelli (Wellman Center for Photomedicine, Harward Medical School, USA)
Mechanobiology Lectures in the Part II PDN/Zoology P9/M6 Cell Assembly and Interactions
Veterinary Anatomy: Practicals (Part IA and IB)
Moeendarbary E, Weber IP, Sheridan GK, Koser DE, Solemane S, Haenzie B, Bradbury EJ, Fawcett J, Franze K: The soft mechanical signature of glial scars in the central nervous system. Nature Communications 8:14787 (2017)
MacDonald RB, Randlett O, Oswald J, Yoshimatsu T, Franze K*, Harris WA*: Muller Glia Provide Essential Tensile Strength to the Developing Retina. Journal of Cell Biology 210(7):1075-1083 (2015)
Pagliara S*, Franze K*, McClain CR, Wylde G, Fisher CL, Franklin RJM, Kabla AJ, Keyser UF, Chalut KJ: Auxetic nuclei in embryonic stem cells exiting pluripotency. Nature Materials 13:638-644 (2014)
Hardie RC and Franze K: Photomechanical responses in Drosophila photoreceptors. Science 338(6104):260-263 (2012)
Franze K, Grosche J, Skatchkov SN, Schinkinger S, Foja C, Schild D, Uckermann O, Travis K, Reichenbach A, Guck J: Müller cells are living optical fibers in the vertebrate retina. PNAS 104(20):8287-8292 (2007)