Exploring the importance of mechanosensitivity for the peripheral nervous system
Developmental Biology
Final Report Abstract
The principal glial cells of the peripheral nervous system (PNS) are Schwann cells (SCs). SC generation is a multi-step process starting with neural crest cell migration from the dorsal root ganglion (DRG), developing first into SC precursors, then into immature SCs. These immature SCs transition into either myelinating or non-myelinating cells, determined by the associated axon size and influenced by the neuronal expression of Neuregulin-1 (NRG1) type III growth factor through ErbB2 receptors in SCs. SCs are crucial for myelin production and various functions essential for PNS development, maintenance, and regeneration, which involve interaction with the basal lamina and extracellular matrix (ECM). Mounting evidence suggests that ECM stiffness directs cell behavior, viability, and differentiation, impacting development and disease progression, and that mechanical forces play an important role in nervous system development. Mechanotransduction, the process where cells sense and respond to mechanical signals from the ECM environment, involves cytoskeletal proteins, integrins, and nesprins among others. Furthermore, cellular ECM mechanosensing processes can be investigated in vitro by generating artificial ECM-protein cross-linked polyacrylamide (PAAm) substrates of tunable stiffness that mimic the biochemical and mechanical properties of the ECM environment. The goal of the present project was to investigate the importance of mechanosensitivity for the PNS. Therefore, generated artificial matrices within the PNS physiological stiffness range were used to culture neuronal and SCs cells to investigate their mechanosensitivity. Understanding mechanosensitivity in the PNS can improve insights into PNS development, physiology, and neuropathies, and enhance treatment strategies for PNS injuries, such as the design of bioengineered nerve grafts. During the course of this DFG project, we have published two works at high impact factor journals, which highlight the importance of studying cell mechanics and mechanosensitivity in the PNS. Briefly, in the first publication, we investigate the mechanical properties of SCs and their nuclei. We showed that SCs are mechanically more robust when compared to vascular endothelial cells and hypothesized these differences could be explained by the native mechanical environments that both cells are exposed to in the living tissue. In the second publication, we showed that ECM stiffness can control SC plasticity by directing the expression of key transcription factors important for cell differentiation and myelination in the PNS. Furthermore, we show that neuronal morphology and outgrowth are affected by matrix stiffness, and this could be exploited in the design of bioengineered nerve grafts for PNS repair.
Publications
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In Situ Investigation of Interrelationships Between Morphology and Biomechanics of Endothelial and Glial Cells and their Nuclei. Advanced Science, 6(1).
Rosso, Gonzalo; Liashkovich, Ivan & Shahin, Victor
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Matrix stiffness mechanosensing modulates the expression and distribution of transcription factors in Schwann cells. Bioengineering & Translational Medicine, 7(1).
Rosso, Gonzalo; Wehner, Daniel; Schweitzer, Christine; Möllmert, Stephanie; Sock, Elisabeth; Guck, Jochen & Shahin, Victor
