Stromal cell derived factor 1 plasmid to regenerate the anal sphincters.
Stromal cell derived factor 1 plasmid to regenerate the anal sphincters.
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DOI：
10.1002/term.3283
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发表时间：
2022-04
影响因子：
3.3
通讯作者：
Zutshi, Massarat
中科院分区：
文献类型：
--
作者：
Sun, Li;Billups, Alanna;Rietsch, Anna;Damaser, Margot S.;Zutshi, Massarat
本研究的目的是评估用编码基质细胞衍生因子-1（SDF-1）的质粒治疗后猪模型中慢性大肛门括约肌缺损的再生。根据伦理学批准的方案，对19只年龄/体重匹配的Sinclair小型猪切除肛门括约肌的后50%，并使其恢复6周。随机分配接受生理盐水治疗（生理盐水1 ml，n = 5），1次注射SDF-1质粒2 mg/ml（1次SDF-1，n = 9）或2次注射SDF-1，每次2 mg/ml，间隔2周（2次SDF-1，n = 5）。末次给药后8周实施安乐死。体内结果包括在麻醉下损伤前、注射前和安乐死前（治疗后8周）进行的肛门静息压。在损伤前和安乐死前进行肛门超声检查。保存组织用于组织学分析并进行定量分析。使用双因素ANOVA随后Holm-Sidak检验和单因素ANOVA随后Tukey检验进行数据分析，p < 0.05被认为是显著的。生理盐水组在3个时间点的后肛压无显著差异。相比之下，1 SDF-1组中的治疗后压力显著高于损伤前（p = 0.001）和治疗前时间点（p = 0.003）。在治疗后时间点，与生理盐水组相比，1个SDF-1（p = 0.01）和2个SDF-1（p = 0.01）组的平均压力显著更高。组织学显示对照组中正常解剖结构变形伴片状再生，而两个治疗组中肌肉组织化程度更高。在慢性肛门括约肌损伤中注射单次或两次SDF-1后8周，可改善静息肛门压力，并使整个缺损处的肌肉再生。SDF-1质粒在治疗大型动物肛门括约肌慢性缺损中是有效的，并且可以临床转化。
The aim of this study was to evaluate regeneration of a chronic large anal sphincter defect in a pig model after treatment with a plasmid encoding Stromal Cell Derived Factor-1(SDF-1). Under ethics approved protocol 19 age/weight matched Sinclair mini-pigs were subjected to excision of the posterior 50% of anal sphincter muscle and left to recover for 6 weeks. They were randomly allocated to receive either saline treatment (Saline 1 ml, n = 5), 1 injection of SDF-1 plasmid 2 mg/ml (1 SDF-1, n = 9) or 2 injections of SDF-1, 2 mg/ml each at 2 weeks intervals (2 SDF-1, n = 5). Euthanasia occurred 8 weeks after the last treatment. In vivo outcomes included anal resting pressures done under anesthesia pre-injury, pre-injection and before euthanasia (8 weeks after treatment). Anal ultrasound was done pre injury and pre-euthanasia. Tissues were saved for histology and analyzed quantitatively. Two way ANOVA followed by Holm-Sidak test and one way ANOVA followed by the Tukey test were used for data analysis, p < 0.05 was regarded as significant. Posterior anal pressures at the 3 time points were not significantly different in the saline group. In contrast, post-treatment pressures in the 1 SDF-1 group pressures were significantly higher than both pre-injury (p = 0.001) and pre-treatment time points (p = 0.003). At the post-treatment time point, both 1 SDF-1 (p = 0.01) and 2 SDF-1 (p = 0.01) groups had significantly higher mean pressures compared to the saline group. Histology showed distortion of normal anatomy with patchy regeneration in the control group while muscle was more organized in both treatment groups. Eight weeks after a single or two doses of SDF-1injected into a chronic anal sphincter injury improved resting anal pressures and regenerated muscle in the entire defect. SDF-1 plasmid is effective in treating chronic defects of the anal sphincter in a large animal and could be clinically translated.
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