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

Denton, Christopher P., Khan, Korsa, Hoyles, Rachel K., Shiwen, Xu , Leoni, Patricia, Chen, Yunliang , Eastwood, Mark and Abraham, David J. (2009) Inducible lineage-specific deletion of T?RII in fibroblasts defines a pivotal regulatory role during adult skin wound healing. Journal of Investigative Dermatology, 129 (1). pp. 194-204. ISSN 0022-202X

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Previous attempts to delete type II TGF? receptor (T?RII) in fibroblasts have precluded examination of adult mice due to early mortality. We have selectively deleted T?RII 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 pro?2(I)collagen gene permitted deletion of floxed T?RII alleles. After postnatal deletion of T?RII 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 ? (TGF?) signalling in fibroblasts in regulating normal skin wound healing. Explanted dermal fibroblasts from T?RII-null-fib mice showed impaired migration and did not generate normal contractile biomechanical forces in fixed collagen gels nor develop ?-smooth muscle antigen-rich stress fibers in response to TGF?1. Surprisingly, some TGF?-regulated proteins, including connective tissue growth factor (CTGF), were basally upregulated in T?RII-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 TGF? signalling in fibroblasts. Together, our data confirm that expression of T?RII in differentiated dermal fibroblasts is essential for normal wound healing and demonstrate a critical role in the development and function of myofibroblasts.

Item Type: Article
Subjects: University of Westminster > Science and Technology > Life Sciences, School of (No longer in use)
Depositing User: Miss Nina Watts
Date Deposited: 14 Apr 2011 10:48
Last Modified: 14 Apr 2011 10:48

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