Senescence in Normal Human Dermal Fibroblasts Induces Heterogeneous Fibril Orientation of Type I Collagen Through...

Considering that the body accumulates senescent fibroblasts during the progression of aging, the character of collagen fibrils secreted from the senescent cells associates with the skin condition. In this study, we examined the alteration of collagen fibrogenesis using groups of normal human dermal fibroblasts with different cumulative population doubling levels (PDLs). We found that the density of extracellular collagen fibrils in late PDLs was lower than that in early or middle PDLs, and their orientation was disturbed in late PDLs. Visualized type I procollagen imaging indicated that cells in late PDLs had a defect in the C-terminal propeptide (C-pp) cleavage of procollagen. Biochemical analyses confirmed decreases in intracellular C-pp and extracellular collagen accompanied by PDL progression. Cells in late PDLs downregulated BMP-1 and PCPE-1, and BMP-1 knockdown in cells of early PDLs decreased the amount of extracellular collagen and disturbed the fibril orientation. These fibrils contained more C-pp than the control fibrils. Our results showed that cell senescence decreases C-pp cleavage and secretion of type I collagen through downregulation of BMP-1, resulting in the accumulation of extracellular procollagen and loss of fibril orientation.