Publikationen Abteilung Neuronale Mechanik

Fibrosis and persistent inflammation are interconnected processes that inhibit axon regeneration in the mammalian central nervous system (CNS). In zebrafish, by contrast, fibroblast-derived extracellular matrix deposition and inflammation are tightly regulated to facilitate regeneration. However, the regulatory cross-talk between fibroblasts and the innate immune system in the regenerating CNS remains poorly understood. Here, we show that zebrafish fibroblasts possess a dual role in inducing and resolving inflammation, which are both essential for regeneration. We identify a transient, injury-specific cthrc1a+ fibroblast state with an inflammation-associated, less differentiated, and non-fibrotic profile. Induction of this fibroblast state precedes and contributes to the initiation of the inflammatory response. At the peak of neutrophil influx, cthrc1a+ fibroblasts coordinate the resolution of inflammation. Disruption of these inflammation dynamics alters the mechano-structural properties of the lesion environment and inhibits axon regeneration. This establishes the biphasic inflammation control by dedifferentiated fibroblasts as a pivotal mechanism for CNS regeneration.

An enlarged brain underlies the complex central nervous system of vertebrates. The dramatic expansion of the brain that diverges its shape from the spinal cord follows neural tube closure during embryonic development. Here, we show that this differential deformation is encoded by a pre-pattern of tissue material properties in chicken embryos. Using magnetic droplets and atomic force microscopy, we demonstrate that the dorsal hindbrain is more fluid than the dorsal spinal cord, resulting in a thinning versus a resisting response to increasing lumen pressure, respectively. The dorsal hindbrain exhibits reduced apical actin and a disorganized laminin matrix consistent with tissue fluidization. Blocking the activity of neural-crest-associated matrix metalloproteinases inhibits hindbrain expansion. Transplanting dorsal hindbrain cells to the spinal cord can locally create an expanded brain-like morphology in some cases. Our findings raise questions in vertebrate head evolution and suggest a general role of mechanical pre-patterning in sculpting epithelial tubes.

For several decades, many attempts have been made to characterize the mechanical properties of gray and white matter, which constitute the two main compartments of the central nervous system, with various methods and contradictory results. In particular, the ratio of gray-to-white-matter elasticity is sometimes larger than 1 and sometimes smaller; the reason for this apparent discrepancy is currently unknown. Here, we exploited atomic force microscopy-based indentation measurements to systematically investigate how the measurement force, measurement speed, postmortem interval, and temperature affect the measured elasticity of spinal cord tissue and, in particular, the ratio of gray-to-white-matter elasticity (Kg/Kw). Within the explored parameter space, increasing measurement force and speed increased the measured elasticity of both gray and white matter. However, Kg/Kw declined from values as high as ∼5 at low forces and speeds to ∼1 for high forces and speeds. Kg/Kw also strongly depended on the anatomical plane in which the measurements were conducted and was considerably higher in transverse sections compared with longitudinal sections. Furthermore, the postmortem interval impacted both the absolute measured tissue elasticity and Kg/Kw. Gray matter elasticity started decreasing ∼3 h postmortem until reaching a plateau after ∼6 h. In contrast, white matter elasticity started declining from the beginning of the measurements until ∼6 h postmortem, when it also leveled off. As a result, Kg/Kw increased until ∼6 h postmortem before stabilizing. Between 20 and 38°C, both gray and white matter elasticity decreased at a similar rate without affecting Kg/Kw. We have thus identified differences in the response of gray and white matter to varying strains and strain rates, and the postmortem interval, and excluded temperature as a factor affecting Kg/Kw. These differential responses likely contribute to the contradictory results obtained with different methods working in different strain regimes.