Inducible Lineage-Specific Deletion of TβRII in Fibroblasts Defines a Pivotal Regulatory Role during Adult Skin Wound Healing

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