Preferential Enhancement of Sensory and Motor Axon Regeneration by Combining Extracellular Matrix Components with Neurotrophic Factors

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.

Optogenetically enhanced axon regeneration: motor versus sensory neuron‐specific stimulation

“…After nerve transection and repair, Schwann cells occupying endoneurial tubes in the denervated distal nerve stump express differential neurotrophic factors dependent upon their former occupation by either motor or sensory axons (Brushart, ; Hoke et al ., ; Santos et al ., ). This phenotypic distinction preferentially supports modality‐specific axon regeneration.…”

A novel technique for decellularization of allogenic nerves and in vivo study of their use for peripheral nerve reconstruction

“…During the last years, considerable effort has been placed into the development of solutions considering different kinds of nerve repair [5][6][7]. When larger nerve gaps exist (20 mm or longer in humans), the current clinical gold standard for peripheral nerve reconstruction is an autologous sensitive nerve graft (autograft); even if it offers a cell-rich material through which axons can regenerate, its use is not ideal because of limited availability [8], and mismatch of donor nerve size with the recipient site [9].…”

Segregation of motor and sensory axons regenerating through bicompartmental tubes by combining extracellular matrix components with neurotrophic factors

“…Therefore, we have evaluated here if the addition of a different combinations of ECM molecules and NTFs into a collagen matrix was able to selectively promote the regeneration of MN and SN towards different distal fascicles. We chose the two matrix combinations based on previous in vitro findings using organotypic cultures that demonstrated a preferential effect of fibronectin and BDNF to promote neurite growth from MNs and of laminin and NGF/NT‐3 to promote neurite growth of SNs (González‐Pérez et al, ; Santos, González‐Pérez, Giudetti, Micera, Udina, Del Valle, & Navarro, ). The distal insert was selected to accommodate the size of the distal nerve with the number of axons of each type.…”

“…In the present study, a sciatic nerve transection was repaired with a bicompartmental tube containing a different combination of ECM and neurotrophic factors in each distal branch. Based on our previous results (Santos, González‐Pérez, et al, ; Santos, Giudetti, et al, ; Santos, González‐Pérez, et al, ), each compartment was filled prior to implantation with a collagen matrix containing either fibronectin with poly‐lactic co‐glycolic acid (PLGA) microspheres releasing BDNF (FN + MP.BDNF) in one side in contact with the distal peroneal nerve (P), or laminin with PLGA microspheres releasing NGF and NT‐3 (LM + MP.NGF/NT‐3) at the other side in contact with the tibial and sural nerves (T + S). We assessed whether regenerated motor axons preferentially grew in the first branch and sensory axons in the second branch, compared with control condition in which both branches contained the same collagen matrix and PLGA microspheres filled with PBS (Col + MP.PBS).…”