Back to Search Start Over

Hypoxia enhances anti-fibrotic properties of extracellular vesicles derived from hiPSCs via the miR302b-3p/TGFβ/SMAD2 axis.

Authors :
Paw M
Kusiak AA
Nit K
Litewka JJ
Piejko M
Wnuk D
Sarna M
Fic K
Stopa KB
Hammad R
Barczyk-Woznicka O
Cathomen T
Zuba-Surma E
Madeja Z
Ferdek PE
Bobis-Wozowicz S
Source :
BMC medicine [BMC Med] 2023 Oct 31; Vol. 21 (1), pp. 412. Date of Electronic Publication: 2023 Oct 31.
Publication Year :
2023

Abstract

Background: Cardiac fibrosis is one of the top killers among fibrotic diseases and continues to be a global unaddressed health problem. The lack of effective treatment combined with the considerable socioeconomic burden highlights the urgent need for innovative therapeutic options. Here, we evaluated the anti-fibrotic properties of extracellular vesicles (EVs) derived from human induced pluripotent stem cells (hiPSCs) that were cultured under various oxygen concentrations.<br />Methods: EVs were isolated from three hiPSC lines cultured under normoxia (21% O <subscript>2</subscript> ; EV-N) or reduced oxygen concentration (hypoxia): 3% O <subscript>2</subscript> (EV-H3) or 5% O <subscript>2</subscript> (EV-H5). The anti-fibrotic activity of EVs was tested in an in vitro model of cardiac fibrosis, followed by a detailed investigation of the underlying molecular mechanisms. Sequencing of EV miRNAs combined with bioinformatics analysis was conducted and a selected miRNA was validated using a miRNA mimic and inhibitor. Finally, EVs were tested in a mouse model of angiotensin II-induced cardiac fibrosis.<br />Results: We provide evidence that an oxygen concentration of 5% enhances the anti-fibrotic effects of hiPS-EVs. These EVs were more effective in reducing pro-fibrotic markers in activated human cardiac fibroblasts, when compared to EV-N or EV-H3. We show that EV-H5 act through the canonical TGFβ/SMAD pathway, primarily via miR-302b-3p, which is the most abundant miRNA in EV-H5. Our results show that EV-H5 not only target transcripts of several profibrotic genes, including SMAD2 and TGFBR2, but also reduce the stiffness of activated fibroblasts. In a mouse model of heart fibrosis, EV-H5 outperformed EV-N in suppressing the inflammatory response in the host and by attenuating collagen deposition and reducing pro-fibrotic markers in cardiac tissue.<br />Conclusions: In this work, we provide evidence of superior anti-fibrotic properties of EV-H5 over EV-N or EV-H3. Our study uncovers that fine regulation of oxygen concentration in the cellular environment may enhance the anti-fibrotic effects of hiPS-EVs, which has great potential to be applied for heart regeneration.<br /> (© 2023. The Author(s).)

Details

Language :
English
ISSN :
1741-7015
Volume :
21
Issue :
1
Database :
MEDLINE
Journal :
BMC medicine
Publication Type :
Academic Journal
Accession number :
37904135
Full Text :
https://doi.org/10.1186/s12916-023-03117-w