Mmp14-Dependent Remodeling of the Pericellular-Dermal Collagen Interface Governs Fibroblast Survival

Dermal fibroblasts deposit type I collagen, the dominant extracellular matrix molecule found in skin, during early postnatal development. Coincident with this biosynthetic program, fibroblasts proteolytically remodel pericellular collagen fibrils by mobilizing the membrane-anchored matrix metalloproteinase, Mmp14. Unexpectedly, dermal fibroblasts in Mmp14-/- mice commit to a large-scale apoptotic program that leaves skin tissues replete with dying cells. A requirement for Mmp14 in dermal fibroblast survival is recapitulated in vitro when cells are embedded within, but not cultured atop, 3-dimensional hydrogels of cross-linked type I collagen. In the absence of Mmp14-dependent pericellular proteolysis, dermal fibroblasts fail to trigger ß1 integrin activation and instead actuate a TGF-ß1/phospho-JNK stress response that leads to apoptotic cell death in vitro as well as in vivo. Taken together, these studies identify Mmp14 as a requisite cell survival factor that maintains dermal fibroblast viability in postnatal dermal tissues. Overall design: To assess changes in transcription between control and MT1-MMP-null mouse dermal fibroblasts in 3D collagen, samples of 1X10^5 cells were embedded in 3D, type I collagen hydrogels and cultured for 40 hours prior to RNA isolation and sequencing. Two control and two wild-type samples were prepared for analysis.