RESUMO
The urothelium of the bladder functions as a waterproof barrier between tissue and outflowing urine. Largely quiescent during homeostasis, this unique epithelium rapidly regenerates in response to bacterial or chemical injury. The specification of the proper cell types during development and injury repair is crucial for tissue function. This Review surveys the current understanding of urothelial progenitor populations in the contexts of organogenesis, regeneration and tumorigenesis. Furthermore, we discuss pathways and signaling mechanisms involved in urothelial differentiation, and consider the relevance of this knowledge to stem cell biology and tissue regeneration.
Assuntos
Transformação Celular Neoplásica , Urotélio , Diferenciação Celular/fisiologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Humanos , Células-Tronco , Bexiga Urinária , Urotélio/fisiologiaRESUMO
Pparg, a nuclear receptor, is downregulated in basal subtype bladder cancers that tend to be muscle invasive and amplified in luminal subtype bladder cancers that tend to be non-muscle invasive. Bladder cancers derive from the urothelium, one of the most quiescent epithelia in the body, which is composed of basal, intermediate, and superficial cells. We find that expression of an activated form of Pparg (VP16;Pparg) in basal progenitors induces formation of superficial cells in situ, that exit the cell cycle, and do not form tumors. Expression in basal progenitors that have been activated by mild injury however, results in luminal tumor formation. We find that these tumors are immune deserted, which may be linked to down-regulation of Nf-kb, a Pparg target. Interestingly, some luminal tumors begin to shift to basal subtype tumors with time, down-regulating Pparg and other luminal markers. Our findings have important implications for treatment and diagnosis of bladder cancer.
Assuntos
PPAR gama/metabolismo , Transdução de Sinais , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia , Animais , Biomarcadores Tumorais/metabolismo , Carcinogênese , Carcinógenos/toxicidade , Diferenciação Celular , Proliferação de Células , Proteína Vmw65 do Vírus do Herpes Simples/genética , Proteína Vmw65 do Vírus do Herpes Simples/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , PPAR gama/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/metabolismo , Urotélio/efeitos dos fármacos , Urotélio/imunologia , Urotélio/patologiaRESUMO
The urothelium is an epithelial barrier lining the bladder that protects against infection, fluid exchange and damage from toxins. The nuclear receptor Pparg promotes urothelial differentiation in vitro, and Pparg mutations are associated with bladder cancer. However, the function of Pparg in the healthy urothelium is unknown. Here we show that Pparg is critical in urothelial cells for mitochondrial biogenesis, cellular differentiation and regulation of inflammation in response to urinary tract infection (UTI). Superficial cells, which are critical for maintaining the urothelial barrier, fail to mature in Pparg mutants and basal cells undergo squamous-like differentiation. Pparg mutants display persistent inflammation after UTI, and Nf-KB, which is transiently activated in response to infection in the wild type urothelium, persists for months. Our observations suggest that in addition to its known roles in adipogegnesis and macrophage differentiation, that Pparg-dependent transcription plays a role in the urothelium controlling mitochondrial function development and regeneration.