Transitional epithelium of the urinary bladder can be damaged during, for example, catheterization, overstretching due to obstructed voiding, or partial resection. The subsequent repair process can be stimulated by specific
proteins such as
epidermal growth factor (
EGF) and
transforming growth factor-alpha (
TGFalpha). However, little is known about the role of
EGF-like
growth factors and their respective receptors in human urothelial repair. In this study, we examined the effects of
EGF,
TGFalpha,
amphiregulin and
heregulin-alpha (HRGalpha) on proliferation,
wound closure, and the expression of their receptors c-erbB1-c-erbB4 in primary cultures of human urothelial cells in vitro. Under conditions representing intact urothelium, all
EGF-like
growth factors except HRGalpha induced proliferation.
TGFalpha induced proliferation up to four times.
Amphiregulin increased expression of c-erbB1. Treatment with either
TGFalpha or
amphiregulin resulted in higher c-erbB1 activation and c-erbB3 levels. None of the
growth factors affected the constitutive expression of c-erbB2 and c-erbB4. In the repair model, both
EGF and
TGFalpha stimulated the
wound closure most strongly. This was mainly achieved by increased cellular migration. Receptor expression was not affected by the addition of exogenous
growth factor. The role of c-erbB2 in wound healing was further investigated with the use of
antisense DNA.
Wound closure could be delayed up to 50% by antisense c-erbB2 but not by mismatched or sense
oligonucleotides. Excessive production (e.g. in
bladder tumors) or application of
EGF,
TGFalpha or
amphiregulin, but not HRGalpha may lead to either
hyperplasia or a faster repair of damaged urothelium in vivo. These effects seem to be mediated not only via c-erbB1 but also via c-erbB2. Our results suggest that modified members of the
EGF-EGFR family are potential targets for future
therapies for bladder wound healing and
malignancy.