Human senescent fibroblasts trigger progressive lung fibrosis in mice

Area of Science:

• Cellular biology
• Pulmonary medicine
• Fibrosis research

Background:

• Cell senescence is implicated in fibrosing interstitial lung diseases (f-ILDs).
• Idiopathic pulmonary fibrosis is a key f-ILD where senescence may play a role.
• The hypothesis is that senescent fibroblasts can initiate lung fibrotic reactions.

Purpose of the Study:

• To investigate if senescent human fibroblasts can induce progressive lung fibrosis.
• To determine the role of the senescent cell secretome (SASP) in fibrosis.
• To evaluate potential therapeutic interventions for senescent cell-induced lung fibrosis.

Main Methods:

• Instillation of senescent or non-senescent human lung fibroblasts into immunodeficient mice.
• Administration of the secretome of senescent fibroblasts (SASP) or conditioned medium (CM) from non-senescent cells.
• Treatment with navitoclax, nintedanib, and pirfenidone to assess amelioration of lung fibrosis.

Main Results:

• Senescent human fibroblasts engrafted and induced progressive lung fibrosis, increasing mouse senescence.
• The SASP from senescent fibroblasts was pro-senescence and pro-fibrotic both in vitro and in vivo.
• Navitoclax, nintedanib, and pirfenidone reduced fibrosis; navitoclax also showed senolytic activity.

Conclusions:

• Human senescent fibroblasts, via their SASP, drive progressive lung fibrosis and paracrine senescence in host cells.
• These findings support the role of senescent cells in the progression of f-ILDs.
• Targeting senescent cells may offer a therapeutic strategy for fibrotic lung diseases.