The expression of fibrosis-related genes is elevated in doxorubicin-induced senescent human dermal fibroblasts, but their secretome does not trigger a paracrine fibrotic response in non-senescent cells

Abstract

Tissue fibrosis is associated with the aging process of most of our organs, and organ aging correlates with the chronic accumulation of senescent cells. Fibrosis occurs when fibroblasts proliferate and deposit pathological amounts of extracellular matrix (ECM), leading to progressive tissue scarring and organ dysfunction. Fibroblasts play a key role in fibrosis, especially in the skin where fibroblasts are the most abundant cell type in the dermis and are mainly responsible for the synthesis of ECM. This study aims to investigate how senescent fibroblasts and their secretome influence dermal fibrosis. Here we used human dermal fibroblasts (HDFs) treated with doxorubicin (doxo) to induce senescence. The senescent phenotype of these stress-induced premature senescent (SIPS) cells was confirmed with several markers. The expression of pro-fibrotic genes was quantified and finally, the impact of their secretome on the fibrotic response of non-senescent fibroblasts was assessed. Doxorubicin treatment, induced senescence in fibroblasts which has been confirmed with elevated senescence-associated β- galactosidase (SA-β-gal) activity, absence of BrdU incorporation, upregulation of p21, and loss of Lamin b1. Expression levels of the pro-fibrotic genes ACTA2 and FN1 increased in SIPS cells, but in contrast to studies using lung fibroblasts the secretome of these cells failed to induce a paracrine fibrotic response in non-senescent cells. In general, these results suggest that these senescent cells are potentially profibrotic, and their accumulation can trigger fibrosis in organs.

Generation of a p21 Reporter Mouse and Its Use to Identify and Eliminate p21high Cells In Vivo

“…The main alteration in the lung observed in our results after DOXO administration was fibrosis. Elevated p21, as a characteristic of fibroblast senescence resulting in fibrotic lesions, has been extensively studied [ 37 , 38 ], especially in chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) [ 39 , 40 ]. We hypothesize that the better outcome achieved in the lungs in our results is also related to this point.…”

Mechanism and role of nuclear laminin B1 in cell senescence and malignant tumors

“…Changes in senescent cells can be specific to chromatin remodeling, metabolic switching, and altered gene expression and regulate the secretion of inflammatory cytokines and growth factors and production of proteases and other senescence-related secretory phenotype (SASP) molecules [ 12 ]. In general, senescent cells exert a potential profibrotic effect, resulting in organ fibrosis and eventually leading to disease development [ 13 ]. Therefore, it is crucial to assess the factors related to LMNB1-associated cell aging (Table 1 ).…”