Abstract
Hepatic fibrosis is a wound healing response that results in excessive extracellular matrix (ECM) accumulation in response to chronic hepatic injury. Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor associated with the pathogenesis of liver fibrosis. Though a promising potential therapeutic target, there are no specific drug candidates for STAT3. Exosomes are extracellular vesicles generated by all cell types with a capacity to efficiently enter cells across different biological barriers. Here, we utilize exosomes as delivery conduit to specifically target STAT3 in liver fibrosis. Exosomes derived from clinical grade fibroblast-like mesenchymal stem cells (MSCs) were engineered to carry siRNA or antisense oligonucleotide (ASO) targeting STAT3 (iExosiRNA-STAT3 or iExomASO-STAT3). Compared to scrambled siRNA control, siRNA-STAT3, or ASO-STAT3, iExosiRNA-STAT3 or iExomASO-STAT3 showed enhanced STAT3 targeting efficiency. iExosiRNA-STAT3 or iExomASO-STAT3 treatments suppressed STAT3 levels and ECM deposition in established liver fibrosis in mice, and significantly improved liver function. iExomASO-Stat3 restored liver function more efficiently when compared to iExosiRNA-STAT3. Our results identify a novel anti-fibrotic approach for direct targeting of STAT3 with exosomes with immediate translational potential.
Original language | English (US) |
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Article number | e21557 |
Journal | FASEB Journal |
Volume | 35 |
Issue number | 5 |
DOIs | |
State | Published - May 2021 |
Keywords
- STAT3
- engineered exosomes
- liver fibrosis
- mesenchymal stromal cells
ASJC Scopus subject areas
- Biotechnology
- Biochemistry
- Molecular Biology
- Genetics
MD Anderson CCSG core facilities
- Research Animal Support Facility
- Small Animal Imaging Facility