Conditional abatement of tissue fibrosis using nucleoside analogs to selectively corrupt DNA replication in transgenic fibroblasts

Progressive tissue fibrosis can compromise epithelial function resulting in organ failure. Appreciating evidence suggests that fibroblasts provide fib rogenic collagens during such injury. We further tested this notion by atte mpting to reduce the physiologic consequences of organ fibrosis through the selective killing of fibroblasts at sites of injury. Here, we report the c onditional reduction of tissue fibroblasts using the coding sequence for he rpesvirus thymidine kinase (Delta TK) put under the control of a cell-speci fic promoter from the gene encoding fibroblast-specific protein 1 (FSP1). T ransgenic fibroblasts from mice carrying FSP1.Delta TK minigenes expressed thymidine kinase concordantly with native FSP1 and, compared to transgenic epithelium, were selectively susceptible to the lethal effects of nucleosid e analogs either in culture or during experimental renal fibrosis. The numb ers of fibroblasts in fibrogenic kidney tissue were reduced on exposure to nucleoside analogs as was the degree of type I collagen deposition and the extent of fibrosis. Fibroblast reduction following the stress of DNA chain termination highlights the important contribution of cell division during f ibrogenesis. Our findings convey a proof of principle regarding the importa nce of FSP1(+) fibroblasts in fibrosis as well as providing a new approach to treating the relentless scarification of tissue.