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Kasper C.D.R.,An Institute of the Royal Academy of Arts and science | Kasper C.D.R.,Harvard University | Kerstin T.S.W.,An Institute of the Royal Academy of Arts and science | Elske H.P.F.,An Institute of the Royal Academy of Arts and science | And 2 more authors.
PLoS ONE | Year: 2014

In their natural habitat, the peripheral nerve, Schwann cells (SCs) form nicely aligned pathways (also known as the bands of Bü ngner) that guide regenerating axons to their targets. Schwann cells that are implanted in the lesioned spinal cord fail to align in pathways that could support axon growth but form cellular clusters that exhibit only limited intermingling with the astrocytes and meningeal cells (MCs) that are present in the neural scar. The formation of cell clusters can be studied in cocultures of SCs and MCs. In these co-cultures SCs form cluster-like non-overlapping cell aggregates with well-defined boundaries. There are several indications that neuropilins (NRPs) play an important role in MC-induced SC aggregation. Both SCs and MCs express NRP1 and NRP2 and SCs express the NRP ligands Sema3B, C and E while MCs express Sema3A, C, E and F. We now demonstrate that in SC-MC co-cultures, siRNA mediated knockdown of NRP2 in SCs decreased the formation of SC clusters while these SCs maintained their capacity to align in bands of Büngner-like columnar arrays. Unexpectedly, knockdown of NRP1 expression resulted in a significant increase in SC aggregation. These results suggest that a reduction in NRP2 expression may enhance the capacity of implanted SCs to interact with MCs that invade a neural scar formed after a lesion of the spinal cord. ©2014 Roet et al. Source


Eggers R.,An Institute of the Royal Academy of Arts and science | de Winter F.,An Institute of the Royal Academy of Arts and science | de Winter F.,Leiden University | Hoyng S.A.,An Institute of the Royal Academy of Arts and science | And 9 more authors.
PLoS ONE | Year: 2013

Although the peripheral nerve is capable of regeneration, only a small minority of patients regain normal function after surgical reconstruction of a major peripheral nerve lesion, resulting in a severe and lasting negative impact on the quality of life. Glial cell-line derived neurotrophic factor (GDNF) has potent survival- and outgrowth-promoting effects on motoneurons, but locally elevated levels of GDNF cause trapping of regenerating axons and the formation of nerve coils. This phenomenon has been called the "candy store" effect. In this study we created gradients of GDNF in the sciatic nerve after a ventral root avulsion. This approach also allowed us to study the effect of increasing concentrations of GDNF on Schwann cell proliferation and morphology in the injured peripheral nerve. We demonstrate that lentiviral vectors can be used to create a 4 cm long GDNF gradient in the intact and lesioned rat sciatic nerve. Nerve coils were formed throughout the gradient and the number and size of the nerve coils increased with increasing GDNF levels in the nerve. In the nerve coils, Schwann cell density is increased, their morphology is disrupted and myelination of axons is severely impaired. The total number of regenerated and surviving motoneurons is not enhanced after the distal application of a GDNF gradient, but increased sprouting does result in higher number of motor axon in the distal segment of the sciatic nerve. These results show that lentiviral vector mediated overexpression of GDNF exerts multiple effects on both Schwann cells and axons and that nerve coil formation already occurs at relatively low concentrations of exogenous GDNF. Controlled expression of GDNF, by using a viral vector with regulatable GDNF expression, may be required to avoid motor axon trapping and to prevent the effects on Schwann cell proliferation and myelination. © 2013 Eggers et al. Source


Fagoe N.D.,An Institute of the Royal Academy of Arts and science | van Heest J.,An Institute of the Royal Academy of Arts and science | Verhaagen J.,An Institute of the Royal Academy of Arts and science | Verhaagen J.,VU University Amsterdam
NeuroMolecular Medicine | Year: 2014

Spinal cord injury (SCI) affects millions of people worldwide and causes a significant physical, emotional, social and economic burden. The main clinical hallmark of SCI is the permanent loss of motor, sensory and autonomic function below the level of injury. In general, neurons of the central nervous system (CNS) are incapable of regeneration, whereas injury to the peripheral nervous system is followed by axonal regeneration and usually results in some degree of functional recovery. The weak neuron-intrinsic regeneration-associated gene (RAG) response upon injury is an important reason for the failure of neurons in the CNS to regenerate an axon. This response consists of the expression of many RAGs, including regeneration-associated transcription factors (TFs). Regeneration-associated TFs are potential key regulators of the RAG program. The function of some regeneration-associated TFs has been studied in transgenic and knock-out mice and by adeno-associated viral vector-mediated overexpression in injured neurons. Here, we review these studies and propose that AAV-mediated gene delivery of combinations of regeneration-associated TFs is a potential strategy to activate the RAG program in injured CNS neurons and achieve long-distance axon regeneration. © 2014, Springer Science+Business Media New York. Source


Roet K.C.,An Institute of the Royal Academy of Arts and science | Wirz K.T.,An Institute of the Royal Academy of Arts and science | Franssen E.H.,An Institute of the Royal Academy of Arts and science | Verhaagen J.,An Institute of the Royal Academy of Arts and science
PloS one | Year: 2014

In their natural habitat, the peripheral nerve, Schwann cells (SCs) form nicely aligned pathways (also known as the bands of Büngner) that guide regenerating axons to their targets. Schwann cells that are implanted in the lesioned spinal cord fail to align in pathways that could support axon growth but form cellular clusters that exhibit only limited intermingling with the astrocytes and meningeal cells (MCs) that are present in the neural scar. The formation of cell clusters can be studied in co-cultures of SCs and MCs. In these co-cultures SCs form cluster-like non-overlapping cell aggregates with well-defined boundaries. There are several indications that neuropilins (NRPs) play an important role in MC-induced SC aggregation. Both SCs and MCs express NRP1 and NRP2 and SCs express the NRP ligands Sema3B, C and E while MCs express Sema3A, C, E and F. We now demonstrate that in SC-MC co-cultures, siRNA mediated knockdown of NRP2 in SCs decreased the formation of SC clusters while these SCs maintained their capacity to align in bands of Büngner-like columnar arrays. Unexpectedly, knockdown of NRP1 expression resulted in a significant increase in SC aggregation. These results suggest that a reduction in NRP2 expression may enhance the capacity of implanted SCs to interact with MCs that invade a neural scar formed after a lesion of the spinal cord. Source

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