ProPath Laboratory, and Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9032, USA.
Obstet Gynecol. 2012 Jan;119(1):134-44. doi: 10.1097/AOG.0b013e3182397009.
To understand the endogenous process of wound healing after anal sphincter injury and to determine possible mechanisms by which mesenchymal stem cells (MSCs) exert their regenerative potential.
Virginal female rats (n=204) underwent anal sphincter laceration and repair. Thereafter, animals were randomly assigned to control injection, injection with intravenous MSCs, or direct injection of MSCs into the injured sphincter. Twenty uninjured animals served as baseline controls. Sphincters were analyzed for contractile function and parameters of wound healing 24 hours, 48 hours, 7 days, and 21 days after injury.
Direct injection of MSCs into the injured anal sphincter resulted in improved contractile function 21 days after injury compared with controls. Although expression of both proinflammatory (cyclooxygenase-2 and interleukin-6) and anti-inflammatory (interleukin-10 and tumor necrosis factor-α-stimulated gene-6) genes were increased dramatically and transiently after injury, MSCs did not alter this response. In contrast, transforming growth factor (TFG)-β1 (an important mediator of matrix deposition by mesenchymal cells) and lysyl oxidase (an enzyme important for synthesis of collagen and elastin) expression increased dramatically at earlier time points in the direct MSC injection group compared with controls. Increased expression of TFG-β1 and lysyl oxidase in directly injected sphincters was associated with increased collagen deposition and engraftment of MSCs in the sphincter.
In this preclinical animal model, direct, but not intravenous, injection of MSCs into the injured anal sphincter at the time of repair resulted in improved contractile function of the sphincter after injury, increased matrix deposition in the external anal sphincter, and increased expression of TFG-β1 and lysyl oxidase in the acute phase after injury.
了解肛门括约肌损伤后内源性愈合过程，并确定间充质干细胞（MSCs）发挥其再生潜能的可能机制。
处女雌性大鼠（n=204）进行肛门括约肌裂伤和修复。此后，动物随机分为对照组、静脉注射 MSCs 组或直接注射 MSCs 至损伤的括约肌。20 只未受伤的动物作为基线对照。在损伤后 24 小时、48 小时、7 天和 21 天，分析括约肌的收缩功能和愈合参数。
与对照组相比，直接将 MSCs 注射到损伤的肛门括约肌中可改善 21 天后的收缩功能。尽管损伤后促炎（环氧化酶-2 和白细胞介素-6）和抗炎（白细胞介素-10 和肿瘤坏死因子-α刺激基因-6）基因的表达均显著且短暂地增加，但 MSCs 并未改变这种反应。相比之下，转化生长因子-β1（间充质细胞沉积基质的重要介质）和赖氨酰氧化酶（合成胶原和弹性蛋白的重要酶）在直接 MSC 注射组中的表达在损伤后更早的时间点显著增加，而在对照组中则没有。直接注射的括约肌中 TFG-β1 和赖氨酰氧化酶的表达增加与胶原沉积增加和 MSCs 在括约肌中的植入有关。
在这个临床前动物模型中，在修复时直接而非静脉注射 MSCs 到损伤的肛门括约肌中，可改善损伤后括约肌的收缩功能，增加外括约肌的基质沉积，并增加损伤后急性期的 TFG-β1 和赖氨酰氧化酶的表达。
