Exosomal RNF144A Derived From Mesenchymal Stem Cells Ameliorates LPS-induced Pneumonia in Experimental Models By Inducing TSHR Ubiquitination

Oct 22, 2025Applied biochemistry and biotechnology

Stem Cell Exosomes Carrying RNF144A May Improve Lung Inflammation by Targeting TSHR Protein

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Regenerative Health on OpenScience ↗PubMed ↗DOI ↗

Abstract

Exosomes derived from mesenchymal stem cells (MSC EXO) may protect against LPS-triggered injuries in WI-38 fibroblasts and pneumonia in mice.

MSCs EXO treatment improved cell viability and reduced apoptosis in WI-38 fibroblasts exposed to lipopolysaccharide (LPS).
Thyroid-stimulating hormone receptor (TSHR) levels were found to be elevated in both pneumonia serum samples and LPS-stimulated WI-38 fibroblasts.
Knocking down TSHR decreased LPS-induced apoptosis and inflammatory damage in WI-38 fibroblasts.
Ring finger protein 144A (RNF144A) was shown to destabilize TSHR through a process called ubiquitination.
MSC EXO treatment led to increased expression of RNF144A in LPS-stimulated WI-38 fibroblasts.
Reducing RNF144A levels weakened the protective effects of MSC EXO against LPS-induced damage.

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Exosomes derived from mesenchymal stem cells (MSC EXO) have emerged as promising therapeutic candidates for pneumonia. However, the molecular mechanisms underlying MSC EXO-mediated pneumonia protection remain incompletely elucidated. WI-38 fibroblasts were exposed to lipopolysaccharide (LPS) in vitro, while an animal model of pneumonia was generated through intratracheal LPS administration in mice. MSC EXO were isolated and used to treat the pneumonia models. The efficacy of MSC EXO was evaluated by detecting cell viability, proliferation, apoptosis, and pro-inflammatory cytokine secretion. Glutathione S-transferase (GST) pull-down, co-immunoprecipitation (Co-IP), and immunoprecipitation (IP) assays were performed to verify the RNF144A/thyroid-stimulating hormone receptor (TSHR) interaction. TSHR was upregulated in pneumonia serum samples and LPS-stimulated WI-38 fibroblasts. TSHR knockdown attenuated LPS-triggered apoptosis and inflammatory damage in WI-38 fibroblasts. Moreover, ring finger protein 144A (RNF144A) destabilized TSHR through ubiquitination in WI-38 cells. MSC EXO increased RNF144A expression in LPS-stimulated WI-38 fibroblasts. Downregulation of RNF144A diminished the protective effects of MSC EXO against LPS-triggered damage in WI-38 fibroblasts and LPS-induced pneumonia in mice. Additionally, re-expression of TSHR reversed the protective effects of MSC EXO against LPS-triggered injuries in WI-38 fibroblasts. Our findings suggest that MSC EXO protect against LPS-triggered injuries in WI-38 fibroblasts and LPS-evoked pneumonia in mice through RNF144A upregulation-mediated suppression of TSHR expression. This study provides a novel theoretical foundation for the application of MSC EXO in pneumonia treatment.

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Exosomal RNF144A Derived From Mesenchymal Stem Cells Ameliorates LPS-induced Pneumonia in Experimental Models By Inducing TSHR Ubiquitination

Abstract

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