Senescent Human Lung Fibroblasts Produce Lung Fibrosis when Transplanted into Mice
From the evidence accumulated to date in animal models and studies of human tissue, it seems clear that senescent cells play an important role in the development of fibrosis in a variety of tissues. Fibrosis is a dysfunction of normal tissue maintenance processes, an excessive deposition of collagen extracellular matrix that is disruptive to tissue structure and function. Senescent cells secrete signals that encourage both growth and inflammation, and that sort of signaling sustained for the long term may be necessary for the development of fibrosis. Many age-related fibrotic diseases exist, in lungs, liver, and heart for example, and at present there is little that can be done to even effectively slow the progression of fibrosis once it is identified in a patient.
A number of animal studies of senolytic therapies, those capable of selectively clearing senescent cells from tissues, have resulted in reversal of fibrosis. This gives researchers the hope that targeting cellular senescence will prove fruitful as a treatment for fibrotic conditions, and there is a growing focus on the biochemistry and clearance of senescent cells in this context. As a part of this ongoing research, in today's open access paper the authors show that transplantation of senescent cells into the lung is sufficient to produce pulmonary fibrosis, a fairly compelling demonstration.
One might recall that researchers have similarly demonstrated that transplantation of senescent cells into joint tissue is sufficient to produce osteoarthritis. Interestingly, it has also been shown that in naturally occurring age-related osteoarthritis, locally clearing senescent cells from joint tissue isn't sufficient to improve the condition. It is plausible that the burden of senescent cells elsewhere in the body provides sufficient harmful signaling to make it necessary to remove senescent cells throughout the body rather than targeting only those present in evidently diseased tissue.
Human senescent fibroblasts trigger progressive lung fibrosis in mice
Fibrosing interstitial lung diseases (f-ILDs) constitute a complex and heterogeneous group of diseases characterized by non-resolving pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is the most frequent and representative f-ILD. The pathogenesis of f-ILD is complex and still incompletely understood but cell senescence has recently emerged as a potentially relevant pathogenic player. Cell senescence is an adaptation of cells to circumstances of unrepairable cellular damage. The entry in senescence involves a profound rewiring of cellular biology that is largely irreversible, with a permanent exit from the cell cycle (in the case of proliferating cells), the acquisition of stable epigenetic changes, the expansion of the lysosomal compartment and a vigorous Senescence Associated Secretory Phenotype (SASP). The SASP includes multiple pro-inflammatory and tissue remodelling mediators that can foster a fibrogenic cascade and propagate the senescent phenotype to the surrounding cells.
We hypothesized that senescent human fibroblasts may suffice to trigger a progressive fibrogenic reaction in the lung. To address this, senescent human lung fibroblasts, or their secretome (SASP), were instilled into the lungs of immunodeficient mice. We found that: (1) human senescent fibroblasts engraft in the lungs of immunodeficient mice and trigger progressive lung fibrosis associated to increasing levels of mouse senescent cells, whereas non-senescent fibroblasts do not trigger fibrosis; (2) the SASP of human senescent fibroblasts is pro-senescence and pro-fibrotic both in vitro when added to mouse recipient cells and in vivo when delivered into the lungs of mice, whereas the conditioned medium (CM) from non-senescent fibroblasts lacks these activities; and, (3) navitoclax, nintedanib, and pirfenidone ameliorate lung fibrosis induced by senescent human fibroblasts in mice, albeit only navitoclax displayed senolytic activity.
We conclude that human senescent fibroblasts, through their bioactive secretome, trigger a progressive fibrogenic reaction in the lungs of immunodeficient mice that includes the induction of paracrine senescence in the cells of the host, supporting the concept that senescent cells actively contribute to disease progression in patients with f-ILDs.