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Extracellular vesicles stimulate smooth muscle cell migration by presenting collagen VI.

ABSTRACT: The extracellular matrix (ECM) supports blood vessel architecture and functionality and undergoes active remodelling during vascular repair and atherogenesis. Vascular smooth muscle cells (VSMCs) are essential for vessel repair and, via their secretome, are able to invade from the vessel media into the intima to mediate ECM remodelling. Accumulation of fibronectin (FN) is a hallmark of early vascular repair and atherosclerosis and here we show that FN stimulates VSMCs to secrete small extracellular vesicles (sEVs) by activating the β1 integrin/FAK/Src pathway as well as Arp2/3-dependent branching of the actin cytoskeleton. Spatially, sEV were secreted via filopodia-like cellular protrusions at the leading edge of migrating cells. We found that sEVs are trapped by the ECM in vitro and colocalise with FN in symptomatic atherosclerotic plaques in vivo . Functionally, ECM-trapped sEVs induced the formation of focal adhesions (FA) with enhanced pulling forces at the cellular periphery. Proteomic and GO pathway analysis revealed that VSMC-derived sEVs display a cell adhesion signature and are specifically enriched with collagen VI. In vitro assays identified collagen VI as playing the key role in cell adhesion and invasion. Taken together our data suggests that the accumulation of FN is a key early event in vessel repair acting to promote secretion of collage VI enriched sEVs by VSMCs. These sEVs stimulate migration and invasion by triggering peripheral focal adhesion formation and actomyosin contraction to exert sufficient traction forces to enable VSMC movement within the complex vascular ECM network.

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SUBMITTER: Kapustin A

PROVIDER: S-EPMC10462164 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Extracellular vesicles stimulate smooth muscle cell migration by presenting collagen VI.

Kapustin Alexander A Tsakali Sofia Serena SS Whitehead Meredith M Chennell George G Wu Meng-Ying MY Molenaar Chris C Kutikhin Anton A Bogdanov Leo L Sinitsky Maxim M Rubina Kseniya K Clayton Aled A Verweij Frederik J FJ Pegtel Dirk Michiel DM Zingaro Simona S Lobov Arseniy A Zainullina Bozhana B Owen Dylan D Parsons Maddy M Cheney Richard E RE Warren Derek D Humphries Martin James MJ Iskratsch Thomas T Holt Mark M Shanahan Catherine M CM

bioRxiv : the preprint server for biology 20230822

The extracellular matrix (ECM) supports blood vessel architecture and functionality and undergoes active remodelling during vascular repair and atherogenesis. Vascular smooth muscle cells (VSMCs) are essential for vessel repair and, via their secretome, are able to invade from the vessel media into the intima to mediate ECM remodelling. Accumulation of fibronectin (FN) is a hallmark of early vascular repair and atherosclerosis and here we show that FN stimulates VSMCs to secrete small extracellu ...[more]

PMID: 37645762

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Project description:BackgroundHuman bronchial epithelial cell-derived extracellular vesicles have demonstrated the ability to attenuate fibroblasts activation. However, the specific key effector cell populations mediating this inhibitory effect remain unidentified. Airway basal stem cells (BSCs), which serve as progenitor cells for bronchial epithelial cells, play a critical role in fibrotic remodeling processes and possess significant therapeutic potential. This study aimed to characterize BSC-derived extracellular vesicles (BSC-EVs) and investigate their regulatory influence on fibroblasts behavior.MethodsAirway BSCs were collected through bronchoscopic brushing and differential centrifugation. Fibroblasts were subsequently treated with BSC-EVs at various concentrations to evaluate their dose- and time-dependent effects in vitro. The proteomic composition of BSC-EVs was analyzed using four-dimensional data-independent acquisition quantitative mass spectrometry (4D-DIA). Moreover, a bleomycin-induced pulmonary fibrosis model was established to evaluate the safety and preliminary efficacy of BSC-EVs.ResultsWe successfully isolated and identified BSC-EVs, which expressed the nucleus-specific marker TP63, indicative of BSCs, but lacked the BSC marker KRT5. Our findings demonstrated that BSC-EVs enhanced fibroblasts proliferation and migration in a dose-dependent manner. Importantly, BSC-EVs significantly attenuated fibroblasts activation and promoted fibroblasts senescence. Utilizing 4D-DIA quantitative proteomics, we revealed that BSC-EVs modulate extracellular matrix remodeling processes and regulate the expression of key proteins, including collagen I/III and matrix metalloproteinases. Animal models utilizing intratracheal administration of BSC-EVs demonstrate efficient reduction of collagen deposition.ConclusionThis study offers an extensive characterization of BSC-EVs, adhering to the guidelines set forth by MISEV2023. The findings underscore the significant therapeutic potential of BSC-EVs in the management of fibrotic diseases.

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Extracellular vesicles stimulate smooth muscle cell migration by presenting collagen VI.

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Publications

Extracellular vesicles stimulate smooth muscle cell migration by presenting collagen VI.

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