A spatio-temporal analysis of motoneuron survival, axonal regeneration and neurotrophic factor expression after lumbar ventral root avulsion and implantation

Eggers, Ruben; Tannemaat, Martijn R.; Ehlert, Erich; Verhaagen, Joost

doi:10.1016/j.expneurol.2009.07.021

Cited by 114 publications

(145 citation statements)

References 66 publications

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“…After 4 weeks of re-implantation some motor axons were observed in the lumbar plexus, 4 cm distal to the spinal cord. However, the amount of motor fibers at 8 weeks at the same distance was similar to that at 4 weeks, as described previously [16]. The combination of re-implantation with MSC transplantation further increased MN survival and axonal regeneration compared to the group with reimplantation alone.…”

Section: Discussionsupporting

confidence: 86%

“…In fact, the beneficial effects of root reimplantation would be to provide neurotrophic action from the Schwann cells [17]. However, after prolonged periods of denervation, Schwann cells decrease their pro-regenerative capability, and there is a temporal decrease of neurotrophic factors, especially GDNF and BDNF [16], and an increase of inhibitory molecules in the denervated distal nerve stump [59]. Therefore, the rate of axonal growth declines markedly [16].…”

Section: Discussionmentioning

confidence: 99%

“…However, after prolonged periods of denervation, Schwann cells decrease their pro-regenerative capability, and there is a temporal decrease of neurotrophic factors, especially GDNF and BDNF [16], and an increase of inhibitory molecules in the denervated distal nerve stump [59]. Therefore, the rate of axonal growth declines markedly [16]. Thus, although an MSC transplant into the spinal cord enhances the regeneration of MN close to the transplant site, it can not compensate the reduced potential of long-time denervated nerves to sustain regeneration over longer time and distance.…”

Section: Discussionmentioning

confidence: 99%

“…However, the chances for functional recovery after lumbar VRA and surgery repair are very poor [14,15]. The lower capacity of lumbar MN to re-innervate distal target muscles may be due to the long distance that surviving neurons have to re-grow [16,17]. Besides the necessity of axons to reinnervate their target muscles, survival of the avulsed MN is fundamental.…”

Section: Introductionmentioning

confidence: 99%

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Neuroprotection and Axonal Regeneration After Lumbar Ventral Root Avulsion by Re-implantation and Mesenchymal Stem Cells Transplant Combined Therapy

et al. 2013

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Ventral spinal root avulsion causes complete denervation of muscles in the limb and also progressive death of segmental motoneurons (MN) leading to permanent paralysis. The chances for functional recovery after ventral root avulsion are very poor owing to the loss of avulsed neurons and the long distance that surviving neurons have to re-grow axons from the spinal cord to the corresponding targets. Following unilateral avulsion of L4, L5 and L6 spinal roots in adult rats, we performed an intraspinal transplant of mesenchymal stem cells (MSC) and surgical re-implantation of the avulsed roots. Four weeks after avulsion the survival of MN in the MSC-treated animals was significantly higher than in vehicle-injected rats (45 % vs 28 %). Re-implantation of the avulsed roots in the injured spinal cord allowed the regeneration of motor axons. By combining root re-implantation and MSC transplant the number of surviving MN at 28 days post-injury was higher (60 %) than in re-implantation alone animals (46 %). Electromyographic tests showed evidence of functional re-innervation of anterior tibialis and gastrocnemius muscles by the regenerated motor axons only in rats with the combined treatment. These results indicate that MSC are helpful in enhancing neuronal survival and increased the regenerative growth of injured axons. Surgical re-implantation and MSC grafting combined had a synergic neuroprotective effect on MN and on axonal regeneration and muscle re-innervation after spinal root avulsion.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neuroprotection and Axonal Regeneration After Lumbar Ventral Root Avulsion by Re-implantation and Mesenchymal Stem Cells Transplant Combined Therapy

et al. 2013

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“…Examples include the upregulation of neurotrophic factors, galectin-1, and cytoskeletal proteins, including actin and T-α-1 tubulin in the neurons [43][44][45][46], and neurotrophic factors and their receptors in the Schwann cells ( Fig. 3a) [31,41,42,[47][48][49]. A specific example of upregulation of T-α-1 tubulin in the neurons is shown in Fig.…”

Section: The Window Of Opportunity For Nerve Regeneration Is Restrictedmentioning

confidence: 99%

Electrical Stimulation to Enhance Axon Regeneration After Peripheral Nerve Injuries in Animal Models and Humans

2016

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Injured peripheral nerves regenerate their lost axons but functional recovery in humans is frequently disappointing. This is so particularly when injuries require regeneration over long distances and/or over long time periods. Fat replacement of chronically denervated muscles, a commonly accepted explanation, does not account for poor functional recovery. Rather, the basis for the poor nerve regeneration is the transient expression of growth-associated genes that accounts for declining regenerative capacity of neurons and the regenerative support of Schwann cells over time. Brief low-frequency electrical stimulation accelerates motor and sensory axon outgrowth across injury sites that, even after delayed surgical repair of injured nerves in animal models and patients, enhances nerve regeneration and target reinnervation. The stimulation elevates neuronal cyclic adenosine monophosphate and, in turn, the expression of neurotrophic factors and other growth-associated genes, including cytoskeletal proteins. Electrical stimulation of denervated muscles immediately after nerve transection and surgical repair also accelerates muscle reinnervation but, at this time, how the daily requirement of long-duration electrical pulses can be delivered to muscles remains a practical issue prior to translation to patients. Finally, the technique of inserting autologous nerve grafts that bridge between a donor nerve and an adjacent recipient denervated nerve stump significantly improves nerve regeneration after delayed nerve repair, the donor nerves sustaining the capacity of the denervated Schwann cells to support nerve regeneration. These reviewed methods to promote nerve regeneration and, in turn, to enhance functional recovery after nerve injury and surgical repair are sufficiently promising for early translation to the clinic.

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Viral transduction of primary Schwann cells using a Cre‐lox system to regulate GDNF expression

Wu-Fienberg

Moore

Marquardt

et al. 2014

Biotech & Bioengineering

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Glial cell-line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor known to enhance motor nerve regeneration following its delivery. However, recent studies have determined that extended GDNF delivery to regenerating axons can entrap motor axons at the site of GDNF delivery. This entrapment leads to reduced motor axons available to reinnervate muscle. To address this issue, we designed a cell-based GDNF expression system that can temporally regulate protein expression using an inducible gene excision mechanism to prevent entrapment at the site of expression. To design this system for regulation of GDNF expression, we transduced two lentiviral vectors, one containing a constitutively active GDNF transgene flanked by two loxP sites, and the other containing a tetracycline-inducible cre transgene along with its constitutively active transactivator, into Schwann cells (SCs). These SCs over-express GDNF, but expression can be suppressed through the administration of tetracycline family antibiotics, such as doxycycline. The engineered SCs produced significantly more GDNF as compared to untransduced controls, as measured by enzyme-linked immunosorbent assay (ELISA). Following doxycycline treatment, these SCs produced significantly lower levels of GDNF and induced less neurite extension as compared to untreated SCs. Engineered SCs treated with doxycycline showed a marked increase in Cre recombinase expression, as visualized by immunohistochemistry (IHC), providing evidence of a mechanism for the observed changes in GDNF expression levels and biological activity. This cell-based GDNF expression system could have potential for future in vivo studies to provide a temporally-controlled GDNF source to promote axon growth.

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A spatio-temporal analysis of motoneuron survival, axonal regeneration and neurotrophic factor expression after lumbar ventral root avulsion and implantation

Cited by 114 publications

References 66 publications

Neuroprotection and Axonal Regeneration After Lumbar Ventral Root Avulsion by Re-implantation and Mesenchymal Stem Cells Transplant Combined Therapy

Neuroprotection and Axonal Regeneration After Lumbar Ventral Root Avulsion by Re-implantation and Mesenchymal Stem Cells Transplant Combined Therapy

Electrical Stimulation to Enhance Axon Regeneration After Peripheral Nerve Injuries in Animal Models and Humans

Viral transduction of primary Schwann cells using a Cre‐lox system to regulate GDNF expression

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