Inducible lineage-specific deletion of TβRII in fibroblasts defines a pivotal regulatory role during adult skin wound healing

Denton, C.P., Khan, K., Hoyles, R.K., Shiwen, X., Leoni, P., Chen, Y., Eastwood, M. and Abraham, D.J. 2009. Inducible lineage-specific deletion of TβRII in fibroblasts defines a pivotal regulatory role during adult skin wound healing. Journal of Investigative Dermatology. 129 (1), pp. 194-204.

TitleInducible lineage-specific deletion of TβRII in fibroblasts defines a pivotal regulatory role during adult skin wound healing
AuthorsDenton, C.P., Khan, K., Hoyles, R.K., Shiwen, X., Leoni, P., Chen, Y., Eastwood, M. and Abraham, D.J.
Abstract

Previous attempts to delete type II TGFβ receptor (TβRII) in fibroblasts have precluded examination of adult mice due to early mortality. We have selectively deleted TβRII postnatally in differentiated connective tissue fibroblasts using an inducible Cre-Lox strategy. Tamoxifen-dependent Cre recombinase linked to a fibroblast-specific regulatory sequence from the proα2(I)collagen gene permitted deletion of floxed TβRII alleles. After postnatal deletion of TβRII in fibroblasts, healing of excisional skin wounds in adults showed markedly attenuated dermal scar formation, defective wound contraction and enhanced epidermal proliferation. These findings support a pivotal role for transforming growth factor β (TGFβ) signalling in fibroblasts in regulating normal skin wound healing. Explanted dermal fibroblasts from TβRII-null-fib mice showed impaired migration and did not generate normal contractile biomechanical forces in fixed collagen gels nor develop α-smooth muscle antigen-rich stress fibers in response to TGFβ1. Surprisingly, some TGFβ-regulated proteins, including connective tissue growth factor (CTGF), were basally upregulated in TβRII-null fibroblasts and this was dependent on extracellular signal-regulated kinase 1/2 activity in these cells. This suggests that other intracellular pathways regulating CTGF expression may partially compensate for disruption of TGFβ signalling in fibroblasts. Together, our data confirm that expression of TβRII in differentiated dermal fibroblasts is essential for normal wound healing and demonstrate a critical role in the development and function of myofibroblasts.

JournalJournal of Investigative Dermatology
Journal citation129 (1), pp. 194-204
ISSN0022-202X
YearJan 2009
PublisherNature Publishing Group
Digital Object Identifier (DOI)doi:10.1038/jid.2008.171
Publication dates
PublishedJan 2009

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