Title: Mechanosensing in the central nervous system.
Abstract: It is increasingly being recognized that cells measure
and respond to the mechanics of their environment. We are especially
interested in the influence of mechanics during CNS development
and pathologies. Using quantitative scanning force microscopy we have
shown that various neural tissues are very compliant (shear modulus < 1
kPa) and mechanically heterogeneous. We have recreated compliant
polyacrylamide (PAA) gel substrate with shear moduli between 0.1 and 30
kPa to match and exceed those of CNS tissue. Various primary neurons and
glial cells have been cultured on these gels and their reaction studied.
Both primary rat microglia and astrocytes responded to increasing
substrate stiffness by changes in morphology and upregulation of
inflammatory genes and proteins. Upon implantation of composite hydrogel
stripes into rat brains, foreign body reactions were significantly
enhanced around their stiff portions in vivo. It appears that the
mechanical mismatch between a neural implant and native tissue might be at
the root of foreign body reactions. Investigations into the molecular
mechanisms are underway. Also oligodendrocytes, another type of glial
cells, are mechanosensitive as their survival, proliferation, migration,
and differentiation capacity in vitro depend on the mechanical stiffness
of polymer hydrogel substrata. This finding might be linked to the failure
of remyelination in chronic demyelinating diseases such as
multiple sclerosis. And finally, we have also shown retinal ganglion axon
pathfinding in the early embryonic Xenopus brain development to be
instructed by stiffness gradients. We could even identify a
specific molecular mechanism involving piezo1, a stretch-activated ion
channel. These results form the basis for further investigations into the
mechanobiology of cell function in the CNS. Ultimately, this research
could help treating previously incurable neuropathologies such as spinal
cord injuries and neurodegenerative disorders.