Combined Effects of Neurotrophin Secreting Transplants, Exercise, and Serotonergic Drug Challenge Improve Function in Spinal Rats

Nothias, Jean Manuel; Mitsui, Takahiko; Shumsky, Jed S.; Fischer, Itzhak; Antonacci, M. Darryl; Murray, Marion

doi:10.1177/1545968305281209

Cited by 53 publications

(59 citation statements)

References 62 publications

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“…4B). Although we cannot exclude possibilities such as the re-extension of descending raphespinal axons, which are also important for the motor functional recovery of hind limbs [30,31], these results suggest that the regeneration of CST axons, if it occurs, cannot be a major contributing factor in the recovery induced by hiPS-lt-NES cell transplantation in our SCI model.…”

Section: Hips-lt-nes Cell Transplantation Does Not Promote Cst Axon Rmentioning

confidence: 78%

Treatment of a Mouse Model of Spinal Cord Injury by Transplantation of Human Induced Pluripotent Stem Cell-Derived Long-Term Self-Renewing Neuroepithelial-Like Stem Cells

et al. 2012

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Because of their ability to self-renew, to differentiate into multiple lineages, and to migrate toward a damaged site, neural stem cells (NSCs), which can be derived from various sources such as fetal tissues and embryonic stem cells, are currently considered to be promising components of cell replacement strategies aimed at treating injuries of the central nervous system, including the spinal cord. Despite their efficiency in promoting functional recovery, these NSCs are not homogeneous and possess variable characteristics depending on their derivation protocols. The advent of induced pluripotent stem (iPS) cells has provided new prospects for regenerative medicine. We used a recently developed robust and stable protocol for the generation of long-term, self-renewing, neuroepithelial-like stem cells from human iPS cells (hiPS-lt-NES cells), which can provide a homogeneous and well-defined population of NSCs for standardized analysis. Here, we show that transplanted hiPS-lt-NES cells differentiate into neural lineages in the mouse model of spinal cord injury (SCI) and promote functional recovery of hind limb motor function. Furthermore, using two different neuronal tracers and ablation of the transplanted cells, we revealed that transplanted hiPS-lt-NES cell-derived neurons, together with the surviving endogenous neurons, contributed to restored motor function. Both types of neurons reconstructed the corticospinal tract by forming synaptic connections and integrating neuronal circuits. Our findings indicate that hiPS-lt-NES transplantation represents a promising avenue for effective cell-based treatment of SCI. Disclosure of potential conflicts of interest is found at the end of this article.

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Section: Hips-lt-nes Cell Transplantation Does Not Promote Cst Axon Rmentioning

confidence: 78%

Treatment of a Mouse Model of Spinal Cord Injury by Transplantation of Human Induced Pluripotent Stem Cell-Derived Long-Term Self-Renewing Neuroepithelial-Like Stem Cells

et al. 2012

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“…Thus, the matrix persisted and filled the lesion cavity, providing a permissive substrate for axonal growth, as shown previously. 31,32 Catheter Site-The cervical spinal cord sections showed tissue damage from the catheter in all animals. Thus, the NEP1-40 or vehicle had access to the parenchyma in all experimental animals.…”

Section: Histological Analysismentioning

confidence: 97%

Nogo-66 Receptor Antagonist Peptide (NEP1-40) Administration Promotes Functional Recovery and Axonal Growth After Lateral Funiculus Injury in the Adult Rat

Cao

Shumsky

Sabol

et al. 2008

Neurorehabil Neural Repair

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Objective-The myelin protein Nogo inhibits axon regeneration by binding to its receptor (NgR) on axons. Intrathecal delivery of an NgR antagonist (NEP1-40) promotes growth of injured corticospinal axons and recovery of motor function following a dorsal hemisection. The authors used a similar design to examine recovery and repair after a lesion that interrupts the rubrospinal tract (RST).Methods-Rats received a lateral funiculotomy at C4 and NEP1-40 or vehicle was delivered to the cervical spinal cord for 4 weeks. Outcome measures included motor and sensory tests and immunohistochemistry.Results-Gait analysis showed recovery in the NEP1-40-treated group compared to operated controls, and a test of forelimb usage also showed a beneficial effect. The density of labeled RST axons increased ipsilaterally in the NEP1-40 group in the lateral funiculus rostral to the lesion and contralaterally in both gray and white matter. Thus, rubrospinal axons exhibited diminished dieback and/or growth up to the lesion site. This was accompanied by greater density of 5 HT and calcitonin gene-related peptide axons adjacent to and into the lesion/matrix site in the NEP1-40 group.Conclusions-NgR blockade after RST injury is associated with axonal growth and/or diminished dieback of severed RST axons up to but not into or beyond the lesion/matrix site, and growth of serotonergic and dorsal root axons adjacent to and into the lesion/matrix site. NgR blockade also supported partial recovery of function. The authors' results indicate that severed rubrospinal axons respond to NEP1-40 treatment but less robustly than corticospinal, raphe-spinal, or dorsal root axons. Keywords Spinal cord injury; Rubrospinal tract; NEP1-40Adult mammalian central nervous system (CNS) neurons do not spontaneously regenerate their axons. Contributors to this failure include the local environment of both the normal and injured adult CNS, which contains inhibitors that constitute a biochemical and physical barrier to regeneration. 1 Three molecules associated with myelin have been identified: NogoA, [2][3][4][5] Address correspondence to Yang Cao, Dept of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129. yc94@drexel.edu. NIH Public Access Author ManuscriptNeurorehabil Neural Repair. Author manuscript; available in PMC 2010 April 12. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript myelin-associated glycoprotein (MAG), 6,7 and oligodendrocyte-myelin glycoprotein (OMgp). 8,9 Nogo has 3 variants: NogoA, NogoB, and NogoC. NogoA is mainly expressed in the CNS, whereas the other 2 are more widely expressed outside the CNS. NogoA possesses a transmembrane loop region, Nogo66, which inhibits neurite outgrowth. 10,11 The Nogo-66 receptor, NgR1, 12 is a glycosylphosphatidylinositol-linked cell surface receptor that contains a leucine-rich repeat motif that also interacts with MAG [13][14][15] and OMgp. 15,16 All 3 myelin molecules bind to NgR1 in a complex with p75 neurotrophin receptor and a leucine-...

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“…In a contusion model, a modified moderate contusion injury was created using the impact rod of the MASCIS device dropped from a height of 25 mm and allowed to rest on the spinal cord for 5 s. 2,3 In a complete transection model, the spinal cord was cut with microscissors at T8/9 as previously described. 8 Muscle and skin were closed in layers after SCI.…”

Section: Sci Proceduresmentioning

confidence: 99%

“…Transections of the spinal cord were complete and contusion injuries were similar to those described previously. [2][3][4]8 Projection patterns at the L6 spinal cord Coronal sections at the L6 level were immersed in 0.1 M, pH 7.6, phosphatebuffered saline for free floating staining using the avidin-biotin complex method. Sections were permeabilized with 10% goat serum in phosphatebuffered saline for 2 h, then incubated with the appropriate primary antibody (serotonin (5-hydroxytryptamine; 1:50 000, ImmunoStar Inc., Hudson, WI, USA), dopamine-beta-hydroxylase (DbH; 1:1000, Protos Biotech Corporation, New York, NY, USA) for noradrenergic fibers, CGRP for small diameter primary afferents (1:6000, Peninsula Laboratories Inc., San Carlos, CA, USA)) and 2% goat serum in phosphate-buffered saline containing 0.3% Triton X-100 at 4 1C for 24-48 h, and finally reacted with a species-specific biotinylated secondary antibody and the ABC reagent (Vector, Burlingame, CA, USA), each for 2 h at room temperature.…”

Section: Cystometry In Conscious Ratsmentioning

confidence: 99%

Lower urinary tract function in spinal cord-injured rats: midthoracic contusion versus transection

2014

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Objectives: To compare changes in lower urinary tract (LUT) function with modifications in pathways that regulate LUT function using two different animal models (incomplete and complete) of spinal cord injury (SCI). Methods: Female Sprague-Dawley rats were used. SCI was made at Th8/9 by a contusion injury (contusion, n ¼ 9) or a complete transection (transection, n ¼ 9). Unoperated rats were used as normal controls (normal, n ¼ 6). LUT function was evaluated by micturition behavior in metabolic cages for 24 h and cystometry in awake animals. Immunocytochemical staining at the L6 spinal cord, spinal areas associated with LUT, was performed to identify descending modulatory fibers and dorsal root afferents that project to the L6 spinal cord. Results: Volume/micturition in metabolic cages gradually increased in both contusion and transection groups compared with normals, and operated groups did not differ from each other. Urodynamic parameters from cystometry were significantly different in contusion and transection groups compared with normals, but again there was no significant difference between contusion and transection groups. Immunocytochemical analyses at the L6 spinal cord showed no serotonergic or noradrenergic fibers in transection group, but some descending fibers remained in contusion group, indicating sparing. Small dorsal root afferents were denser in both contusion and transection groups than in normals, indicating sprouting. Conclusions: Although differences were not found in LUT function in operated animals, supraspinal and dorsal root projections to the L6 spinal cord responded differently to contusion and transection. This suggests that the benefits of pharmacologic treatments may be different in two lesion models. Spinal Cord (2014) 52, 658-661; doi:10.1038/sc.2014.114; published online 15 July 2014 INTRODUCTION Spinal cord injury (SCI) is classified clinically into complete injuries,where function below the level of a injury is lost, and incomplete injuries where some sensory and/or motor function is retained. Nevertheless, it is known that some descending pathways are spared in many cases of clinically complete injuries. 1 Lower urinary tract (LUT) dysfunction in SCI results from damage to descending modulatory pathways and increased sensory input through sprouting of primary afferent pathways. A contusion injury that we use destroys the dorsal spinal cord in the thoracic region, including the dorsal columns, the corticospinal tract and the dorsolateral (DL) funiculus, damages the dorsal horn (DH) and impinges on the intermediolateral column. 2-4 Thus, the ventral funiculi and the ventral portions of the lateral funiculi, which contain descending modulatory pathways, were partially spared in contusion injuries, but not in transection injuries.Serotonergic axons project to the DL nucleus in the spinal cord, which has been implicated in the central control of the bladder and the urethra and recovery of bladder-external urethral sphincter coordination in SCI rats. 5,6 Brainstem-spinal noradrenerg...

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Combined Effects of Neurotrophin Secreting Transplants, Exercise, and Serotonergic Drug Challenge Improve Function in Spinal Rats

Abstract: Combined treatments, but not individual treatments, improved hindlimb function.

Cited by 53 publications

References 62 publications

Treatment of a Mouse Model of Spinal Cord Injury by Transplantation of Human Induced Pluripotent Stem Cell-Derived Long-Term Self-Renewing Neuroepithelial-Like Stem Cells

Treatment of a Mouse Model of Spinal Cord Injury by Transplantation of Human Induced Pluripotent Stem Cell-Derived Long-Term Self-Renewing Neuroepithelial-Like Stem Cells

Nogo-66 Receptor Antagonist Peptide (NEP1-40) Administration Promotes Functional Recovery and Axonal Growth After Lateral Funiculus Injury in the Adult Rat

Lower urinary tract function in spinal cord-injured rats: midthoracic contusion versus transection

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