CELLULAR SIGNALING IN THE BLADDER

Laurence S. Baskin^1,3, Simon W. Hayward^1,2, Ronald A. Sutherland¹, Michael S. DiSandro¹, Axel A.Thomson² and Gerald R. Cunha^1,2

Department of Urology1, Anatomy2 and Pediatrics3 University of California, San Francisco San Francisco, California, 94143-0738

Received 11/13/97 Accepted 11/25/97

4. BLADDER WOUND HEALING

Further evidence for cellular signaling via growth factors has been shown with our model of bladder wound healing (6). Again, using the rodent as a model, an incisional wound was created in the bladder and then sutured with primary closure. Histologic analysis revealed that the bladder epithelium regrew over the defect within 24 to 48 hours. RNase protection assays of growth factors showed an eightfold increase in the expression of KGF as compared to sham-operated and control animals (6). Interestingly, this increased expression occurred in the first 12 to 24 hours corresponding to the period of intense epithelial proliferation noted histologically. At 5 and 7 days, when the epithelium had completely regrown, the expression of KGF returned to normal. Another interesting finding is that when the bladder wall was sampled at a distance from the injury, there was still an up-regulation compared to sham and non-operated animals, suggesting that global signaling occurs throughout the bladder in response to injury which facilitates epithelial repair (figure 2). The proliferative activity of the urothelial cell is impressive as it is normallyquiescent with turnover every six months to a year (7). However, following bladder epithelial injury, KGF released by the stroma elicits receptors on the epithelial surface to cause the urothelium to proliferate (8). Further support for the direct effect of KGF in the bladder was tested by injecting human recombinant KGF subcutaneously into neonatal mice. In comparison to saline controls, urothelial proliferation was greatly enhanced as judged by 3H thymidine labeling 6. A similar finding has been reported for the monkey bladder by Ye, et al (9).

Figure 2. Keratinocyte Growth Factor is released from bladder stroma cells during bladder injury and directly acts through its urothelial located receptor to cause proliferation and regrowth of urothelial cells mending the bladder injury. (12) (Used with Permission) . One of the most clinically relevant areas of bladder signaling may occur at the border between native bladder and augmented intestinal segments (10). Here, the bladder urothelium is placed in an environment where it receives signals from the stroma of both the native bladder as well as the stroma of the gastrointestinal graft. Although the incidence of tumors in augmented bladders is low, tumors tend to occur exactly at this surgical juncture. We hypothesize that the abnormal signaling at this site leads to aberrant communication leading to cellular atypia. Further work is underway using tissue recombinations to assess the effects of intestinal stroma on bladder urothelium and vice versa.