Loyola University Health System, Department of Urology, Maywood, Illinois, United States of America.
Developmental Biology, Stanley Manne Children's Research Institute, Anne and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States of America.
PLoS One. 2018 Nov 26;13(11):e0206436. doi: 10.1371/journal.pone.0206436. eCollection 2018.
Cystectomy is the removal of all or part of the urinary bladder. It has been observed that there is significant regrowth of the bladder after partial cystectomy and this has been proposed to be through regeneration of the organ. Regrowth of tissue in mammals has been proposed to involve compensatory mechanisms that share many characteristics of true regeneration, like the growth of specialized structures such as blood vessels or nerves. However, the overall structure of the normal organ is not achieved. Here we tested if bladder growth after subtotal cystectomy (STC, removal of 50% of the bladder) was compensatory or regenerative. To do this we subjected adult female mouse bladders to STC and assessed regrowth using several established cellular parameters including histological, gene expression, cytokine accumulation and cell proliferation studies. Bladder function was analyzed using cystometry and the voiding stain on paper (VSOP) technique. We found that STC bladders were able to increase their ability to hold urine with the majority of volume restoration occurring within the first two weeks. Regenerating bladders had thinner walls with less mean muscle thickness, and they showed increased collagen deposition at the incision as well as throughout the bladder wall suggesting that fibrosis was occurring. Cell populations differed in their response to injury with urothelial regeneration complete by day 7, but stromal and detrusor muscle still incomplete after 8wks. Cells incorporated EdU when administered at the time of surgery and tracing of EdU positive cells over time indicated that many newborn cells originate at the incision and move mediolaterally. Basal urothelial cells and bladder mesenchymal stem cells but not smooth muscle cells significantly incorporated EdU after STC. Since anti-inflammatory cytokines play a role in regeneration, we analyzed expressed cytokines and found that no anti-inflammatory cytokines were present in the bladder 1wk after STC. Our findings suggest that bladder regrowth after cystectomy is compensatory and functions to increase the volume that the bladder can hold. This finding sets the stage for understanding how the bladder responds to cystectomy and how this can be improved in patients after suffering bladder injury.
膀胱切除术是指全部或部分切除膀胱。人们观察到，部分膀胱切除术后膀胱有明显的再生，这被认为是通过器官再生实现的。哺乳动物组织的再生被认为涉及到许多与真正再生共享特征的补偿机制，例如血管或神经等特殊结构的生长。然而，正常器官的整体结构并未实现。在这里，我们测试了部分膀胱切除术后（切除 50%的膀胱）膀胱生长是补偿性的还是再生性的。为此，我们对成年雌性小鼠的膀胱进行了部分膀胱切除术，并通过几种已建立的细胞参数评估了再生，包括组织学、基因表达、细胞因子积累和细胞增殖研究。通过尿动力学和尿垫染色（VSOP）技术分析膀胱功能。我们发现，部分膀胱切除术后的膀胱能够增加其憋尿能力，大部分容量恢复发生在最初的两周内。再生的膀胱壁更薄，平均肌肉厚度更小，并且在切口处以及整个膀胱壁都有更多的胶原沉积，表明发生了纤维化。细胞群体对损伤的反应不同，上皮细胞在第 7 天即可完全再生，但基质和逼尿肌在 8 周后仍未完全再生。当在手术时给予 EdU 时，细胞会摄取 EdU，并且随着时间的推移追踪 EdU 阳性细胞表明，许多新生细胞起源于切口并向中侧移动。基底上皮细胞和膀胱间充质干细胞但不是平滑肌细胞在部分膀胱切除术后明显摄取 EdU。由于抗炎细胞因子在再生中起作用，我们分析了表达的细胞因子，发现部分膀胱切除术后 1 周膀胱内没有抗炎细胞因子。我们的研究结果表明，膀胱切除术后的膀胱再生是补偿性的，其功能是增加膀胱可以容纳的容量。这一发现为了解膀胱对膀胱切除术的反应以及如何在患者遭受膀胱损伤后改善这一反应奠定了基础。
