Accelerated senescence in skin in a murine model of radiation-induced multi-organ injury

Abstract

Accidental high-dose radiation exposures can lead to multi-organ injuries, including radiation dermatitis. The types of cellular damage leading to radiation dermatitis are not completely understood. To identify the cellular mechanisms that underlie radiation-induced skin injury in vivo, we evaluated the time-course of cellular effects of radiation (14, 16 or 17 Gy X-rays; 0.5 Gy/min) in the skin of C57BL/6 mice. Irradiation of 14 Gy induced mild inflammation, observed histologically, but no visible hair loss or erythema. However, 16 or 17 Gy radiation induced dry desquamation, erythema and mild ulceration, detectable within 14 days post-irradiation. Histological evaluation revealed inflammation with mast cell infiltration within 14 days. Fibrosis occurred 80 days following 17 Gy irradiation, with collagen deposition, admixed with neutrophilic dermatitis, and necrotic debris. We found that in cultures of normal human keratinocytes, exposure to 17.9 Gy irradiation caused the upregulation of p21/waf1, a marker of senescence. Using western blot analysis of 17.9 Gy–irradiated mice skin samples, we also detected a marker of accelerated senescence (p21/waf1) 7 days post-irradiation, and a marker of cellular apoptosis (activated caspase-3) at 30 days, both preceding histological evidence of inflammatory infiltrates. Immunohistochemistry revealed reduced epithelial stem cells from hair follicles 14–30 days post-irradiation. Furthermore, p21/waf1 expression was increased in the region of the hair follicle stem cells at 14 days post 17 Gy irradiation. These data indicate that radiation induces accelerated cellular senescence in the region of the stem cell population of the skin.

Residual γH2AX foci induced by low dose x-ray radiation in bone marrow mesenchymal stem cells do not cause accelerated senescence in the progeny of irradiated cells

“…Indeed, we did not observe increased rates of γН2АХ foci at passages 3 and 5 after irradiation, implying that irradiated MSCs (at least at the doses used here) do not transmit the residual γH2AX foci through the cell divisions, as described by Vaurijoux et al [ 71 ]. At the same time the observed high rates of γН2АХ foci in the progeny (passages 8 and 11) of 1000 mGy-exposed cells is consistent with radiation-induced genome instability [ 72 , 73 ] or accelerated cellular senescence [ 74 , 75 ]. Genome instability and senescence are not necessarily linked.…”

Biomarkers of Cellular Senescence and Skin Aging

“…Solar elastosis may be a consequence of impaired elastic and fibrillin production, elevated breakdown by MMPs secreted by senescent cells, or a direct consequence of UV exposure ( Sherratt, 2013 ; Quan and Fisher, 2015 ; Pittayapruek et al, 2016 ). In vitro , UVB-exposed skin cell types (fibroblasts, keratinocytes) exhibit DNA damage, cell cycle arrest and express senescence biomarkers such as increased SA-β-gal activity, p16 INK4a , p21 CIP1 , p53 activation and lamin B1 downregulation ( Chainiaux et al, 2002 ; Debacq-Chainiaux et al, 2005 ; Lewis et al, 2008 ; McCart et al, 2017 ; Wang et al, 2017 ). In vivo , chronic low dose exposure to UVB resulted in accumulation of DNA damage and lamin B1-low senescent cells within the mouse epidermis, but not the dermis ( Wang et al, 2017 ), a reduction in stem cell numbers in the hair follicle, and p21 CIP1 accumulation in epidermis and hair follicle stem cell region ( McCart et al, 2017 ).…”

Cellular Senescence and Inflammaging in the Skin Microenvironment

“…The acquired senescence-like phenotype in fibroblasts is indicated by the elevated levels of the cyclin-dependent kinases, p16 INK4a and p21, and the tumor protein p53, and the expression of senescence-associated β-galactosidase (SA-β-gal), which are critically influenced by UVR [ 2 ]. In vitro, ultraviolet B light (UVB)-exposed skin cell types, including fibroblasts and keratinocytes, exhibit DNA damage and cell cycle arrest evidenced by expression of senescence markers, such as increased SASPs, and decreased Lamin B1 [ 16 , 17 , 18 ]. On the contrary, in vivo experiments showed that chronic low-dose exposure to UVB resulted in the accumulation of DNA damage and reduced Lamin B1 expression in senescent cells within the mouse epidermis, explicitly in the basal and suprabasal layers, but not the dermis [ 19 ].…”