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Peripheral Nerve Transplantation Combined with Acidic Fibroblast Growth Factor and Chondroitinase Induces Regeneration and Improves Urinary Function in Complete Spinal Cord Transected Adult Mice.

DePaul MA, Lin CY, Silver J, Lee YS - PLoS ONE (2015)

Bottom Line: Cystometry analysis and external urethral sphincter electromyograms reveal that treatment with PNG+aFGF+ChABC reduced bladder weight, improved bladder and external urethral sphincter histology, and significantly enhanced LUT function, resulting in more efficient voiding.Regeneration of serotonin axons correlated with LUT recovery.These results suggest that our mouse model of LUT dysfunction recapitulates the results found in the rat model and may be used to further investigate genetic contributions to regeneration failure.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio, United States of America.

ABSTRACT
The loss of lower urinary tract (LUT) control is a ubiquitous consequence of a complete spinal cord injury, attributed to a lack of regeneration of supraspinal pathways controlling the bladder. Previous work in our lab has utilized a combinatorial therapy of peripheral nerve autografts (PNG), acidic fibroblast growth factor (aFGF), and chondroitinase ABC (ChABC) to treat a complete T8 spinal cord transection in the adult rat, resulting in supraspinal control of bladder function. In the present study we extended these findings by examining the use of the combinatorial PNG+aFGF+ChABC treatment in a T8 transected mouse model, which more closely models human urinary deficits following spinal cord injury. Cystometry analysis and external urethral sphincter electromyograms reveal that treatment with PNG+aFGF+ChABC reduced bladder weight, improved bladder and external urethral sphincter histology, and significantly enhanced LUT function, resulting in more efficient voiding. Treated mice's injured spinal cord also showed a reduction in collagen scaring, and regeneration of serotonergic and tyrosine hydroxylase-positive axons across the lesion and into the distal spinal cord. Regeneration of serotonin axons correlated with LUT recovery. These results suggest that our mouse model of LUT dysfunction recapitulates the results found in the rat model and may be used to further investigate genetic contributions to regeneration failure.

No MeSH data available.


Related in: MedlinePlus

5-HT regeneration correlates to LUT function recovery.Pearson correlation coefficient (r value) comparing bladder recovery to the number of regenerating (A-D) 5-HT and (E-H) TH fibers found in the caudal cord 200μm or 500μm from the PNG-cord interface. The number of regenerated 5-HT fibers below the lesion site shows a significant correlation with the improvement of CMG parameters. There is no significant correlation between regeneration of the TH fibers and CMG parameter analysis. Only animals whose spinal cord was processed and cut sagittally were included in the analysis. n = 7.
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pone.0139335.g005: 5-HT regeneration correlates to LUT function recovery.Pearson correlation coefficient (r value) comparing bladder recovery to the number of regenerating (A-D) 5-HT and (E-H) TH fibers found in the caudal cord 200μm or 500μm from the PNG-cord interface. The number of regenerated 5-HT fibers below the lesion site shows a significant correlation with the improvement of CMG parameters. There is no significant correlation between regeneration of the TH fibers and CMG parameter analysis. Only animals whose spinal cord was processed and cut sagittally were included in the analysis. n = 7.

Mentions: Since both 5-HT and TH tracts mediate LUT recovery in the rat, we sought to correlate bladder recovery with regeneration in the mouse model. At the individual animal level, 5-HT regeneration was significantly correlated with an improvement of CMG parameters including the decreasing of pressure difference from the baseline to post void, the increasing of bladder contraction interval, and the decreasing of residual volume (Fig 5A–5D). No such correlation was found with TH regeneration, however, the baseline pressure following a void showed a non-significant trend (Fig 5E–5H). These results suggest 5-HT regeneration may be more important than TH regeneration for bladder recovery in a mouse model of SCI.


Peripheral Nerve Transplantation Combined with Acidic Fibroblast Growth Factor and Chondroitinase Induces Regeneration and Improves Urinary Function in Complete Spinal Cord Transected Adult Mice.

DePaul MA, Lin CY, Silver J, Lee YS - PLoS ONE (2015)

5-HT regeneration correlates to LUT function recovery.Pearson correlation coefficient (r value) comparing bladder recovery to the number of regenerating (A-D) 5-HT and (E-H) TH fibers found in the caudal cord 200μm or 500μm from the PNG-cord interface. The number of regenerated 5-HT fibers below the lesion site shows a significant correlation with the improvement of CMG parameters. There is no significant correlation between regeneration of the TH fibers and CMG parameter analysis. Only animals whose spinal cord was processed and cut sagittally were included in the analysis. n = 7.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591338&req=5

pone.0139335.g005: 5-HT regeneration correlates to LUT function recovery.Pearson correlation coefficient (r value) comparing bladder recovery to the number of regenerating (A-D) 5-HT and (E-H) TH fibers found in the caudal cord 200μm or 500μm from the PNG-cord interface. The number of regenerated 5-HT fibers below the lesion site shows a significant correlation with the improvement of CMG parameters. There is no significant correlation between regeneration of the TH fibers and CMG parameter analysis. Only animals whose spinal cord was processed and cut sagittally were included in the analysis. n = 7.
Mentions: Since both 5-HT and TH tracts mediate LUT recovery in the rat, we sought to correlate bladder recovery with regeneration in the mouse model. At the individual animal level, 5-HT regeneration was significantly correlated with an improvement of CMG parameters including the decreasing of pressure difference from the baseline to post void, the increasing of bladder contraction interval, and the decreasing of residual volume (Fig 5A–5D). No such correlation was found with TH regeneration, however, the baseline pressure following a void showed a non-significant trend (Fig 5E–5H). These results suggest 5-HT regeneration may be more important than TH regeneration for bladder recovery in a mouse model of SCI.

Bottom Line: Cystometry analysis and external urethral sphincter electromyograms reveal that treatment with PNG+aFGF+ChABC reduced bladder weight, improved bladder and external urethral sphincter histology, and significantly enhanced LUT function, resulting in more efficient voiding.Regeneration of serotonin axons correlated with LUT recovery.These results suggest that our mouse model of LUT dysfunction recapitulates the results found in the rat model and may be used to further investigate genetic contributions to regeneration failure.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio, United States of America.

ABSTRACT
The loss of lower urinary tract (LUT) control is a ubiquitous consequence of a complete spinal cord injury, attributed to a lack of regeneration of supraspinal pathways controlling the bladder. Previous work in our lab has utilized a combinatorial therapy of peripheral nerve autografts (PNG), acidic fibroblast growth factor (aFGF), and chondroitinase ABC (ChABC) to treat a complete T8 spinal cord transection in the adult rat, resulting in supraspinal control of bladder function. In the present study we extended these findings by examining the use of the combinatorial PNG+aFGF+ChABC treatment in a T8 transected mouse model, which more closely models human urinary deficits following spinal cord injury. Cystometry analysis and external urethral sphincter electromyograms reveal that treatment with PNG+aFGF+ChABC reduced bladder weight, improved bladder and external urethral sphincter histology, and significantly enhanced LUT function, resulting in more efficient voiding. Treated mice's injured spinal cord also showed a reduction in collagen scaring, and regeneration of serotonergic and tyrosine hydroxylase-positive axons across the lesion and into the distal spinal cord. Regeneration of serotonin axons correlated with LUT recovery. These results suggest that our mouse model of LUT dysfunction recapitulates the results found in the rat model and may be used to further investigate genetic contributions to regeneration failure.

No MeSH data available.


Related in: MedlinePlus