Small leucine-rich proteoglycans inhibit CNS regeneration by modifying the structural and mechanical properties of the lesion environment

Abstract

Extracellular matrix (ECM) deposition after central nervous system (CNS) injury leads to inhibitory scarring in mammals, whereas it facilitates axon regeneration in the zebrafish. However, the molecular basis of these different fates is not understood. Here, we identify small leucine-rich proteoglycans (SLRPs) as a causal factor in regeneration failure. We demonstrate that the SLRPs Chondroadherin, Fibromodulin, Lumican, and Prolargin are enriched in human, but not zebrafish, CNS lesions. Targeting SLRPs to the zebrafish injury ECM inhibits axon regeneration and functional recovery. Mechanistically, we find that SLRPs confer structural and mechanical properties to the lesion environment that are adverse to axon growth. Our study reveals SLRPs as previously unknown inhibitory ECM factors in the human CNS that impair axon regeneration by modifying tissue mechanics and structure.

Estimation of the mass density of biological matter from refractive index measurements

“…As a consequence we have that for a vanishing relative deviation of the solute , the scaling behaviour of the effective RI increment and PSV determines the scaling behaviour of the deviations in the RI ∆ n . However for we obtain a constant deviation of the RI for large N 0 , consistent with the broad RI distributions obtained by ODT measurements of different cells and tissues [12, 15, 19, 39], and fluctuations in the water volume fraction measured by SRS [20]. Furthermore, while the dependence of ∆ n on the mean relative lipid volume fraction is determined by the deviations of the effective RI increment and PSV, we observe a vanishing impact of the deviation of the relative lipid volume fraction ∆ x lip .…”

“…Having delineated the good agreement between the assumptions used to derive an expression of the MD in dependence of the RI for two dilute, physiological samples, we now want to examine the capability of the proposed model in an in vivo scenario. To that aim we chose the larval zebrafish model system at 96 hours postfertilization (hpf), for which mass spectrometry (MS) and RI data, employing ODT, of the trunk tissue were recently obtained [19]. The RI data is given in Tab.…”

“…[18]. By employing e.g., mass spectrometry (MS) and/or (stimulated) Raman spectroscopy (SRS), individual components and their respective concentrations in the sample can be identified [19–21]. Additionally, correlative fluorescence information could be employed to segment RI maps acquired by ODT [12, 22].…”

“…After demonstrating the applicability of our method on bovine milk and intralipid emulsion, we explore the MD distribution of larval zebrafish trunk, compromising major tissue including muscle, spinal cord etc., employing the recent RI and MS measurements of [19]. This purely optical and computational approach shows how the MD can be estimated also in complex in vivo specimens, enabling a more profound interpretation of mechanical measurements.…”

Beyond comparison: Brillouin microscopy and AFM-based indentation reveal divergent insights into the mechanical profile of the murine retina

“…Due to this operation principle, indentation measurements necessitate almost always the preparation of ex vivo samples to enable the physical contact between the probe and the sample surface. The resistance to deformation is termed Young’s modulus, and has been shown to change in response to central nervous system (CNS) injury [4,5] , during CNS development [6] and aging [7] , and upon changes of extracellular matrix composition in the CNS [8,9] . As other tissues of the CNS [4,7,10] , the retina has been described as heterogeneous with respect to local tissue architecture and composition [11] , and concurrent mechancial properties [12,13] .…”