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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

PNG+aFGF+ChABC treatment improves bladder and EUS morphology.(A-C) Gross observation of the bladder at 18 weeks after SCI in naïve (A), TX-only (B), and PNG+aFGF+ChABC animals (C). (D-F) Photomicrographs of transverse bladder sections stained with Masson’s trichrome from naïve (D), TX-only (E), and PNG+aFGF+ChABC animals (F). Scale bar, 500μm. (G-I) Higher magnification of photomicrographs from boxed area (D-F) shows details of the bladder structure. Note that PNG+aFGF+ChABC animals showed improved bladder morphology. Sale bar, 250μm. (J-L) Photomicrographs of transverse EUS sections stained with Masson’s trichrome from naïve(J), TX-only (K), and PNG+aFGF+ChABC animals (L). The TX-only animals show swelling as well as short and discontinuous muscle fibers (arrow), while the PNG+aFGF+ChABC animals show continuous and long muscle fibers (arrow), similar in morphology to naïve animals (arrow). Scale bar, 500μm.
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pone.0139335.g002: PNG+aFGF+ChABC treatment improves bladder and EUS morphology.(A-C) Gross observation of the bladder at 18 weeks after SCI in naïve (A), TX-only (B), and PNG+aFGF+ChABC animals (C). (D-F) Photomicrographs of transverse bladder sections stained with Masson’s trichrome from naïve (D), TX-only (E), and PNG+aFGF+ChABC animals (F). Scale bar, 500μm. (G-I) Higher magnification of photomicrographs from boxed area (D-F) shows details of the bladder structure. Note that PNG+aFGF+ChABC animals showed improved bladder morphology. Sale bar, 250μm. (J-L) Photomicrographs of transverse EUS sections stained with Masson’s trichrome from naïve(J), TX-only (K), and PNG+aFGF+ChABC animals (L). The TX-only animals show swelling as well as short and discontinuous muscle fibers (arrow), while the PNG+aFGF+ChABC animals show continuous and long muscle fibers (arrow), similar in morphology to naïve animals (arrow). Scale bar, 500μm.

Mentions: We next examined the anatomical changes that may underlie the improvements seen in LUT physiology. Comparing gross observations of the bladder 18 weeks after SCI, mice in the PNG+aFGF+ChABC group had smaller bladders that weighed significantly less than those in the TX-only group (Figs 1H,2B and 2C), although both injury groups had larger and heavier bladders than naïve mice (Figs 1H and 2A). Masson's trichrome stain of the bladder revealed preserved architecture and less bladder distension with greater organization of the muscle and lamina propria in PNG+aFGF+ChABC animals compared to the TX-only group (Fig 2D–2I).


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)

PNG+aFGF+ChABC treatment improves bladder and EUS morphology.(A-C) Gross observation of the bladder at 18 weeks after SCI in naïve (A), TX-only (B), and PNG+aFGF+ChABC animals (C). (D-F) Photomicrographs of transverse bladder sections stained with Masson’s trichrome from naïve (D), TX-only (E), and PNG+aFGF+ChABC animals (F). Scale bar, 500μm. (G-I) Higher magnification of photomicrographs from boxed area (D-F) shows details of the bladder structure. Note that PNG+aFGF+ChABC animals showed improved bladder morphology. Sale bar, 250μm. (J-L) Photomicrographs of transverse EUS sections stained with Masson’s trichrome from naïve(J), TX-only (K), and PNG+aFGF+ChABC animals (L). The TX-only animals show swelling as well as short and discontinuous muscle fibers (arrow), while the PNG+aFGF+ChABC animals show continuous and long muscle fibers (arrow), similar in morphology to naïve animals (arrow). Scale bar, 500μm.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0139335.g002: PNG+aFGF+ChABC treatment improves bladder and EUS morphology.(A-C) Gross observation of the bladder at 18 weeks after SCI in naïve (A), TX-only (B), and PNG+aFGF+ChABC animals (C). (D-F) Photomicrographs of transverse bladder sections stained with Masson’s trichrome from naïve (D), TX-only (E), and PNG+aFGF+ChABC animals (F). Scale bar, 500μm. (G-I) Higher magnification of photomicrographs from boxed area (D-F) shows details of the bladder structure. Note that PNG+aFGF+ChABC animals showed improved bladder morphology. Sale bar, 250μm. (J-L) Photomicrographs of transverse EUS sections stained with Masson’s trichrome from naïve(J), TX-only (K), and PNG+aFGF+ChABC animals (L). The TX-only animals show swelling as well as short and discontinuous muscle fibers (arrow), while the PNG+aFGF+ChABC animals show continuous and long muscle fibers (arrow), similar in morphology to naïve animals (arrow). Scale bar, 500μm.
Mentions: We next examined the anatomical changes that may underlie the improvements seen in LUT physiology. Comparing gross observations of the bladder 18 weeks after SCI, mice in the PNG+aFGF+ChABC group had smaller bladders that weighed significantly less than those in the TX-only group (Figs 1H,2B and 2C), although both injury groups had larger and heavier bladders than naïve mice (Figs 1H and 2A). Masson's trichrome stain of the bladder revealed preserved architecture and less bladder distension with greater organization of the muscle and lamina propria in PNG+aFGF+ChABC animals compared to the TX-only group (Fig 2D–2I).

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