Abstract
After peripheral nerve injury, motor and sensory axons are able to regenerate but inaccuracy of target reinnervation leads to poor functional recovery. Extracellular matrix (ECM) components and neurotrophic factors (NTFs) exert their effect on different neuronal populations creating a suitable environment to promote axonal growth. Here, we assessed in vitro and in vivo the selective effects of combining different ECM components with NTFs on motor and sensory axons regeneration and target reinnervation. Organotypic cultures with collagen, laminin and nerve growth factor (NGF)/neurotrophin-3 (NT3) or collagen, fibronectin and brain-derived neurotrophic factor (BDNF) selectively enhanced sensory neurite outgrowth of DRG neurons and motor neurite outgrowth from spinal cord slices respectively. For in vivo studies, the rat sciatic nerve was transected and repaired with a silicone tube filled with a collagen and laminin matrix with NGF/NT3 encapsulated in poly(lactic-co-glycolic acid) (PLGA) microspheres (MP) (LM + MP.NGF/NT3), or a collagen and fibronectin matrix with BDNF in PLGA MPs (FN + MP.BDNF). Retrograde labeling and functional tests showed that LM + MP.NGF/NT3 increased the number of regenerated sensory neurons and improved sensory functional recovery, whereas FN + MP.BDNF preferentially increased regenerated motoneurons and enhanced motor functional recovery. Therefore, combination of ECM molecules with NTFs may be a good approach to selectively enhance motor and sensory axons regeneration and promote appropriate target reinnervation.
Highlights
After peripheral nerve injury, transected axons in the distal stump are disconnected from the neuronal body and undergo Wallerian degeneration, leading to denervation of peripheral organs [1]
The rat sciatic nerve was transected and repaired with a silicone tube filled with a collagen and laminin matrix with nerve growth factor (NGF)/NT3 encapsulated in poly(lactic-co-glycolic acid) (PLGA) microspheres (MP) (LM + MP.NGF/NT3), or a collagen and fibronectin matrix with brain-derived neurotrophic factor (BDNF) in PLGA MPs (FN + MP.BDNF)
In this study, we tested whether the combination of different neurotrophic factors (NTFs) and Extracellular matrix (ECM) components, that were previously shown to produce a selective limited stimulus for either sensory or motor axons regeneration [14,21], was able to produce a synergistic and selective pro-regenerative effect on motor and sensory neurons. Addition of both LM and NGF/NT3 or FN and BDNF increased the amount of sensory and motor neurite outgrowth, respectively, in culture models. These effects were maintained in vivo in adult animals as sensory and motor axonal regeneration as well as functional recovery was enhanced after treating nerve injuries with a nerve conduit prefilled with the same combinations of NTFs and ECM components
Summary
After peripheral nerve injury, transected axons in the distal stump are disconnected from the neuronal body and undergo Wallerian degeneration, leading to denervation of peripheral organs [1]. A pro-regenerative environment that selectively guides motor and sensory axons to regenerate into different branches of the injured nerve may be useful to increase the options of specific target reinnervation. The generation of a pro-regenerative environment involves the upregulation and secretion of extracellular matrix (ECM) components, such as collagen type IV, laminin and fibronectin, and the secretion of different neurotrophic factors (NTFs), such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and glial derived neurotrophic factor (GDNF), among others [10]. We found that NGF selectively promotes sensory neurite outgrowth, whereas BDNF or fibroblast growth factor (FGF) preferentially increase motor neurite outgrowth in vitro [15]
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