Kullmann F Aura, Clayton Dennis R, Ruiz Wily G, Wolf-Johnston Amanda, Gauthier Christian, Kanai Anthony, Birder Lori A, Apodaca Gerard
University of Pittsburgh School of Medicine, Department of Medicine, Pittsburgh, Pennsylvania.
University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Pittsburgh, Pennsylvania; and.
Am J Physiol Renal Physiol. 2017 Jul 1;313(1):F85-F102. doi: 10.1152/ajprenal.00592.2016. Epub 2017 Mar 22.
The basal, intermediate, and superficial cell layers of the urothelium undergo rapid and complete recovery following acute injury; however, the effects of chronic injury on urothelial regeneration have not been well defined. To address this discrepancy, we employed a mouse model to explore urothelial changes in response to spinal cord injury (SCI), a condition characterized by life-long bladder dysfunction. One day post SCI there was a focal loss of umbrella cells, which are large cells that populate the superficial cell layer and normally express uroplakins (UPKs) and KRT20, but not KRT5, KRT14, or TP63. In response to SCI, regions of urothelium devoid of umbrella cells were replaced with small superficial cells that lacked KRT20 expression and appeared to be derived in part from the underlying intermediate cell layer, including cells positive for KRT5 and TP63. We also observed KRT14-positive basal cells that extended thin cytoplasmic extensions, which terminated in the bladder lumen. Both KRT14-positive and KRT14-negative urothelial cells proliferated 1 day post SCI, and by 7 days, cells in the underlying lamina propria, detrusor, and adventitia were also dividing. At 28 days post SCI, the urothelium appeared morphologically patent, and the number of proliferative cells decreased to baseline levels; however, patches of small superficial cells were detected that coexpressed UPKs, KRT5, KRT14, and TP63, but failed to express KRT20. Thus, unlike the rapid and complete restoration of the urothelium that occurs in response to acute injuries, regions of incompletely differentiated urothelium were observed even 28 days post SCI.
尿路上皮的基底细胞层、中间细胞层和表层细胞层在急性损伤后能迅速且完全恢复；然而，慢性损伤对尿路上皮再生的影响尚未明确界定。为解决这一差异，我们采用小鼠模型来探究尿路上皮对脊髓损伤（SCI）的反应变化，脊髓损伤是一种伴有终身膀胱功能障碍的疾病。脊髓损伤后一天，伞细胞出现局灶性缺失，伞细胞是位于表层细胞层的大细胞，通常表达尿血小板溶素（UPKs）和细胞角蛋白20（KRT20），但不表达细胞角蛋白5（KRT5）、细胞角蛋白14（KRT14）或p63蛋白（TP63）。作为对脊髓损伤的反应，缺乏伞细胞的尿路上皮区域被缺乏KRT20表达的小表层细胞所取代，这些小表层细胞似乎部分来源于下方的中间细胞层，包括KRT5和TP63阳性的细胞。我们还观察到KRT14阳性的基底细胞伸出细的细胞质延伸物，其终止于膀胱腔内。脊髓损伤后1天，KRT14阳性和KRT14阴性的尿路上皮细胞均增殖，到第7天，下方固有层、逼尿肌和外膜中的细胞也开始分裂。脊髓损伤后28天，尿路上皮在形态上看似完整，增殖细胞数量降至基线水平；然而，检测到一些小表层细胞斑块，它们共表达UPKs、KRT5、KRT14和TP63，但不表达KRT20。因此，与急性损伤后尿路上皮迅速且完全恢复不同，即使在脊髓损伤后28天仍观察到未完全分化的尿路上皮区域。
