Abstract
Peripheral nerves are constantly exposed to mechanical stresses associated with body growth and limb movements. Although some aspects of these nerves' biomechanical properties are known, the link between nerve biomechanics and tissue microstructures during development is poorly understood. Here, we used atomic force microscopy to comprehensively investigate the elastic modulus of living peripheral nerve tissue cross sections ex vivo at distinct stages of development and correlated these elastic moduli with various cellular and extracellular aspects of the underlying histological microstructure. We found that local nerve tissue stiffness is spatially heterogeneous and evolves biphasically during maturation. Furthermore, we found the intracellular microtubule network and the extracellular matrix collagens type I and type IV as major contributors to the nerves' biomechanical properties, but surprisingly not cellular density and myelin content as previously shown for the central nervous system. Overall, these findings characterize the mechanical microenvironment that surrounds Schwann cells and neurons and will further our understanding of their mechanosensing mechanisms during nerve development. These data also provide the design of artificial nerve scaffolds to promote biomedical nerve regeneration therapies by considering mechanical properties that better reflect the nerve microenvironment.
Highlights
During the development and maturation of the peripheral nervous system (PNS), nerve fibers are exposed to mechanical forces imposed by the surrounding tissue microenvironment and the musculoskeletal system
The nerve fibers are bundled together by the perineurium, which is composed of multiple concentric layers of flattened epithelial-like perineurial cells embedded in yet another layer of connective tissue made of collagens and elastin fibers arranged in circumferential, longitudinal, and oblique orientations.[6,9]
To start to address this issue, we recently showed that Schwann cells and neurons are highly sensitive to the stiffness of the nerve microenvironment[23,24] and found that this mechanosensitivity is important for PNS development, physiology, and pathophysiology.[25]
Summary
During the development and maturation of the peripheral nervous system (PNS), nerve fibers are exposed to mechanical forces imposed by the surrounding tissue microenvironment and the musculoskeletal system. Mechanical stresses such as tension, shear, or compression associated with limb movement and locomotion permanently act on peripheral nerves[1] and, under certain circumstances, may compromise nerve function[2,3,4] and alter the nerve microstructure.[5] To maintain nerve function and ensure the physiologically crucial propagation of action potentials, the body provides biomechanical protection via three different connective tissue layers: the epineurium, perineurium, and endoneurium. The structure of peripheral nerves is well known, as described authoritatively elsewhere.[1,6,7] Briefly, the outermost peripheral nerve layer, the epineurium, holds together the nerve fascicles and is made up of a dense irregular layer of connective tissue (collagens and elastin fibers) that helps disperse compressive forces.[6,8] Within each fascicle, the nerve fibers (axons surrounded by nonmyelinating and myelinating Schwann cells) are bundled together by the perineurium, which is composed of multiple concentric layers of flattened epithelial-like perineurial cells embedded in yet another layer of connective tissue made of collagens and elastin fibers arranged in circumferential, longitudinal, and oblique orientations.[6,9] the innermost connective tissue, which occupies the space between the nerve fibers, is the endoneurium, typically made up of collagen type I and type II fibrils[10] as well as collagen type IV fibrils in close association with the Schwann
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