Zarifpour Mona, Andersson Karl-Erik, Kelkar Sneha S, Mohs Aaron, Mendelsohn Cathy, Schneider Kerry, Marini Frank, Christ George J
Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina.
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska.
Biores Open Access. 2017 May 1;6(1):35-45. doi: 10.1089/biores.2017.0011. eCollection 2017.
Previous work demonstrated restoration of a bioequivalent bladder within 8 weeks of removing the majority of the bladder (subtotal cystectomy or STC) in rats. The goal of the present study was to extend our investigations of bladder repair to the murine model, to harness the power of mouse genetics to delineate the cellular and molecular mechanisms responsible for the observed robust bladder regrowth. Female C57 black mice underwent STC, and at 4, 8, and 12 weeks post-STC, bladder repair and function were assessed via cystometry, pharmacologic organ bath studies, and -weighted magnetic resonance imaging (MRI). Histology was also performed to measure bladder wall thickness. We observed a time-dependent increase in bladder capacity (BC) following STC, such that 8 and 12 weeks post-STC, BC and micturition volumes were indistinguishable from those of age-matched non-STC controls and significantly higher than observed at 4 weeks. MRI studies confirmed that bladder volume was indistinguishable within 3 months (11 weeks) post-STC. Additionally, bladders emptied completely at all time points studied (i.e., no increases in residual volume), consistent with functional bladder repair. At 8 and 12 weeks post-STC, there were no significant differences in bladder wall thickness or in the different components (urothelium, lamina propria, or smooth muscle layers) of the bladder wall compared with age-matched control animals. The maximal contractile response to pharmacological activation and electrical field stimulation increased over time in isolated tissue strips from repaired bladders but remained lower at all time points compared with controls. We have established and validated a murine model for the study of organ repair that will allow for further mechanistic studies of this phenomenon after, for example, genetic manipulation.
先前的研究表明，在大鼠切除大部分膀胱（次全膀胱切除术或STC）后的8周内，可恢复生物等效的膀胱。本研究的目的是将我们对膀胱修复的研究扩展到小鼠模型，利用小鼠遗传学的力量来阐明导致观察到的膀胱强劲再生的细胞和分子机制。雌性C57黑小鼠接受了STC，在STC后4周、8周和12周，通过膀胱测压、药理学器官浴研究和加权磁共振成像（MRI）评估膀胱修复和功能。还进行了组织学检查以测量膀胱壁厚度。我们观察到STC后膀胱容量（BC）呈时间依赖性增加，因此在STC后8周和12周，BC和排尿量与年龄匹配的非STC对照无异，且显著高于4周时观察到的值。MRI研究证实，STC后3个月（11周）内膀胱体积无差异。此外，在所有研究时间点膀胱均完全排空（即残余尿量无增加），这与功能性膀胱修复一致。与年龄匹配的对照动物相比，STC后8周和12周时，膀胱壁厚度或膀胱壁的不同组成部分（尿路上皮、固有层或平滑肌层）无显著差异。在来自修复膀胱的离体组织条中，对药理学激活和电场刺激的最大收缩反应随时间增加，但在所有时间点均低于对照。我们已经建立并验证了一种用于器官修复研究的小鼠模型，这将允许在例如基因操作后对这一现象进行进一步的机制研究。
