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Fig. 6. HB-EGF expression in skin wound healing. The targeting vector contained the lacZ gene as a reporter for the expression of HB-EGF. When HB-EGF cDNA is deleted by Cre-recombinase, HB-EGF expression can be identified by X-gal staining in HB^+/– mice. (A) Double staining for X-gal and BrdU at the wound healing stage. Scale bar: 0.2 mm. Arrow, wound margin. (B-E) Distribution of ß-gal-positive [lacZ(+)] cells (B) and BrdU-positive cells (C) from day 2 to 7 in HB^+/– mice. HB-EGF is expressed predominantly at the tip of the leading edge, whereas BrdU-positive cells were distributed mainly at wound margin. Distribution of ß-gal-positive cells (D) and BrdU-positive cells (E) in HB^–/– mice. There was no significant difference in the number of BrdU-positive cells between HB^+/– and HB^–/– mice at any stage of wound healing. (F) A proposed schematic illustration of skin wound healing. After injury, keratinocytes at the wound margin begin to migrate and express HB-EGF without proliferation. Next, focal release of HB-EGF may signal further migration and up-regulate HB-EGF expression in an autocrine manner. Values in B-E are number of cells per indicated area.

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