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Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment.

Sintusek P, Catapano F, Angkathunkayul N, Marrosu E, Parson SH, Morgan JE, Muntoni F, Zhou H - PLoS ONE (2016)

Bottom Line: We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON) designed to increase SMN protein expression.Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice.We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON.

View Article: PubMed Central - PubMed

Affiliation: Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, London, United Kingdom.

ABSTRACT
Gastrointestinal (GI) defects, including gastroesophageal reflux, constipation and delayed gastric emptying, are common in patients with spinal muscular atrophy (SMA). Similar GI dysmotility has been identified in mouse models with survival of motor neuron (SMN) protein deficiency. We previously described vascular defects in skeletal muscle and spinal cord of SMA mice and we hypothesized that similar defects could be involved in the GI pathology observed in these mice. We therefore investigated the gross anatomical structure, enteric vasculature and neurons in the small intestine in a severe mouse model of SMA. We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON) designed to increase SMN protein expression. Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice. After systemic AON treatment in neonatal mice, all the abnormalities observed were significantly restored to near-normal levels. We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON. This study on the histopathological changes in the gastrointestinal system in severe SMA mice provides further indication of the complex role that SMN plays in multiple tissues and suggests that at least in SMA mice restoration of SMN production in peripheral tissues is essential for optimal outcome.

No MeSH data available.


Related in: MedlinePlus

Histology of small intestine.H&E staining of (A) Control (B) SMA (C) SMA+PMO25 small intestine. Shortened and blunted villi (* asterisk) and intramural edema (^ arrow head) were present in the lamina propria layer in SMA mice, along with the distinct intestinal crypt architectural distortion (arrow). Quantification of the villus length (D) and crypt size (E) in mice. **P < 0.001, *P < 0.05. Scale bar = 100 μm.
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pone.0155032.g002: Histology of small intestine.H&E staining of (A) Control (B) SMA (C) SMA+PMO25 small intestine. Shortened and blunted villi (* asterisk) and intramural edema (^ arrow head) were present in the lamina propria layer in SMA mice, along with the distinct intestinal crypt architectural distortion (arrow). Quantification of the villus length (D) and crypt size (E) in mice. **P < 0.001, *P < 0.05. Scale bar = 100 μm.

Mentions: We next carried out a histological evaluation of the microstructure of duodenum in H&E stained transverse sections. Distinct histopathological abnormalities were present in SMA mice compared to controls (Fig 2A and 2B), and were dramatically improved after systemic PMO25 treatment (Fig 2C). Villi, the characteristic finger-like projections of the wall of the small intestine, in SMA mice were blunted (Fig 2B) and significantly reduced in length (139.6 ± 13.95 μm, N = 3) compared to control mice (215.7 ± 7.59 μm, N = 3; P<0.01) (Fig 2D). Diffused edema of the lamina propria, which underlies the epithelial layer of the gut tube, was also noted in SMA intestine (Fig 2B). These observations are consistent with previous findings in the Taiwanese SMA mouse model [32]. In addition the intestinal crypts (which lie between and at the base of projecting villi) were irregular in size, shape and distribution in SMA mice (Fig 2B). The depth of crypt in SMA mice (42.19 ± 7.60 μm, N = 3) was significantly greater than in control mice (24.36 ± 2.43 μm, N = 3; P<0.05) (Fig 2E). After systemic PMO25 treatment, all the histopathological alterations described above were significantly improved, with the length of villi (203.6 ± 16.48 μm, N = 3; P<0.05 vs SMA; no significance vs control; Fig 2D) and depth of crypts (30.55 ± 3.00 μm, N = 3; no significance vs control; Fig 2E) significantly improved to near-normal levels.


Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment.

Sintusek P, Catapano F, Angkathunkayul N, Marrosu E, Parson SH, Morgan JE, Muntoni F, Zhou H - PLoS ONE (2016)

Histology of small intestine.H&E staining of (A) Control (B) SMA (C) SMA+PMO25 small intestine. Shortened and blunted villi (* asterisk) and intramural edema (^ arrow head) were present in the lamina propria layer in SMA mice, along with the distinct intestinal crypt architectural distortion (arrow). Quantification of the villus length (D) and crypt size (E) in mice. **P < 0.001, *P < 0.05. Scale bar = 100 μm.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4862622&req=5

pone.0155032.g002: Histology of small intestine.H&E staining of (A) Control (B) SMA (C) SMA+PMO25 small intestine. Shortened and blunted villi (* asterisk) and intramural edema (^ arrow head) were present in the lamina propria layer in SMA mice, along with the distinct intestinal crypt architectural distortion (arrow). Quantification of the villus length (D) and crypt size (E) in mice. **P < 0.001, *P < 0.05. Scale bar = 100 μm.
Mentions: We next carried out a histological evaluation of the microstructure of duodenum in H&E stained transverse sections. Distinct histopathological abnormalities were present in SMA mice compared to controls (Fig 2A and 2B), and were dramatically improved after systemic PMO25 treatment (Fig 2C). Villi, the characteristic finger-like projections of the wall of the small intestine, in SMA mice were blunted (Fig 2B) and significantly reduced in length (139.6 ± 13.95 μm, N = 3) compared to control mice (215.7 ± 7.59 μm, N = 3; P<0.01) (Fig 2D). Diffused edema of the lamina propria, which underlies the epithelial layer of the gut tube, was also noted in SMA intestine (Fig 2B). These observations are consistent with previous findings in the Taiwanese SMA mouse model [32]. In addition the intestinal crypts (which lie between and at the base of projecting villi) were irregular in size, shape and distribution in SMA mice (Fig 2B). The depth of crypt in SMA mice (42.19 ± 7.60 μm, N = 3) was significantly greater than in control mice (24.36 ± 2.43 μm, N = 3; P<0.05) (Fig 2E). After systemic PMO25 treatment, all the histopathological alterations described above were significantly improved, with the length of villi (203.6 ± 16.48 μm, N = 3; P<0.05 vs SMA; no significance vs control; Fig 2D) and depth of crypts (30.55 ± 3.00 μm, N = 3; no significance vs control; Fig 2E) significantly improved to near-normal levels.

Bottom Line: We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON) designed to increase SMN protein expression.Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice.We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON.

View Article: PubMed Central - PubMed

Affiliation: Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, London, United Kingdom.

ABSTRACT
Gastrointestinal (GI) defects, including gastroesophageal reflux, constipation and delayed gastric emptying, are common in patients with spinal muscular atrophy (SMA). Similar GI dysmotility has been identified in mouse models with survival of motor neuron (SMN) protein deficiency. We previously described vascular defects in skeletal muscle and spinal cord of SMA mice and we hypothesized that similar defects could be involved in the GI pathology observed in these mice. We therefore investigated the gross anatomical structure, enteric vasculature and neurons in the small intestine in a severe mouse model of SMA. We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON) designed to increase SMN protein expression. Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice. After systemic AON treatment in neonatal mice, all the abnormalities observed were significantly restored to near-normal levels. We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON. This study on the histopathological changes in the gastrointestinal system in severe SMA mice provides further indication of the complex role that SMN plays in multiple tissues and suggests that at least in SMA mice restoration of SMN production in peripheral tissues is essential for optimal outcome.

No MeSH data available.


Related in: MedlinePlus