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 fibrogenic collagens during such injury. We further tested this notion by attempting to reduce the physiologic consequences of organ fibrosis through the selective killing of fibroblasts at sites of injury. Here, we report the conditional reduction of tissue fibroblasts using the coding sequence for herpesvirus thymidine kinase (DeltaTK) put under the control of a cell-specific promoter from the gene encoding fibroblast-specific protein 1 (FSP1). Transgenic fibroblasts from mice carrying FSP1.DeltaTK minigenes expressed thymidine kinase concordantly with native FSP1 and, compared to transgenic epithelium, were selectively susceptible to the lethal effects of nucleoside analogs either in culture or during experimental renal fibrosis. The numbers 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 fibrogenesis. Our findings convey a proof of principle regarding the importance of FSP1(+) fibroblasts in fibrosis as well as providing a new approach to treating the relentless scarification of tissue.
Iwano
M
M
Division of Nephrology and Hypertension, Vanderbilt University, Nashville, Tennessee 37232, USA.
Fischer
A
A
Okada
H
H
Plieth
D
D
Xue
C
C
Danoff
T M
TM
Neilson
E G
EG
D000818:Animals; D015152:Blotting, Northern; D015139:Blotting, Southern; D002135:Calcium-Binding Proteins / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D004261:DNA Replication; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis; D015774:Ganciclovir / Q000494:pharmacology; D020869:Gene Expression Profiling; D015316:Genetic Therapy / Q000379:methods*; D006564:Herpesviridae / Q000201:enzymology; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009705:Nucleosides / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D013937:Thymidine Kinase / Q000235:genetics; D013997:Time Factors; D014162:Transfection
D002135:Calcium-Binding Proteins; D009705:Nucleosides; D012333:RNA, Messenger; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D012313:RNA; D013937:Thymidine Kinase; D015774:Ganciclovir