Department of Emergency and Critical Care Medicine, Shanghai Pudong New Area People's Hospital, No. 490 Chuansha South Road, Pudong New Area, 201299, Shanghai, China.
J Immunol Res. 2023 Oct 28;2023:3291137. doi: 10.1155/2023/3291137. eCollection 2023.
Acute lung injury (ALI) is a life-threatening disease that currently lacks a cure. Although stem cell-derived small extracellular vesicles (sEVs) have shown promising effects in the treatment of ALI, their underlying mechanisms and responsible components have yet to be identified. Proprotein convertase subtilisin/kexin type 6 (PCSK6) is a gene involved in inflammation and a potential target of miR-21-5p, a microRNA enriched in stem cell-derived sEVs. The current study investigated the role of PCSK6 in lipopolysaccharide (LPS)-induced ALI and its interaction with miR-21-5p. Notably, our results showed that PCSK6 expression was positively correlated with LPS stimulation. Knockdown of PCSK6 ameliorated LPS-induced inhibition of proliferation and upregulation of permeability in human BEAS-2B cells, whereas PCSK6 overexpression displayed the opposite effects. BEAS-2B cells were able to actively internalize the cocultured bone mesenchymal stem cell (MSC)-derived sEVs (BMSC-sEVs), which alleviated the cell damage caused by LPS. Overexpressing PCSK6, however, eliminated the therapeutic effects of BMSC-sEV coculture. Mechanistically, BMSC-sEVs inhibited PCSK6 expression via the delivery of miR-21-5p, which is directly bound to the PCSK6 gene. Our work provides evidence for the role of PCSK6 in LPS-induced ALI and identified miR-21-5p as a component of BMSC-derived sEVs that suppressed PCSK6 expression and ameliorated LPS-induced cell damage. These results reveal a novel molecular mechanism for ALI pathogenesis and highlight the therapeutic potential of using sEVs released by stem cells to deliver miR-21-5p for ALI treatment.
急性肺损伤（ALI）是一种危及生命的疾病，目前尚无治愈方法。虽然干细胞来源的小细胞外囊泡（sEVs）在治疗 ALI 方面显示出了有希望的效果，但它们的潜在机制和负责成分尚未确定。脯氨酸内切酶枯草溶菌素/凝血酶原激活物 6（PCSK6）是一种参与炎症的基因，也是 miR-21-5p 的潜在靶点，miR-21-5p 是一种在干细胞来源的 sEVs 中丰富的 microRNA。本研究探讨了 PCSK6 在脂多糖（LPS）诱导的 ALI 中的作用及其与 miR-21-5p 的相互作用。值得注意的是，我们的结果表明 PCSK6 表达与 LPS 刺激呈正相关。敲低 PCSK6 可改善 LPS 诱导的人 BEAS-2B 细胞增殖抑制和通透性上调，而过表达 PCSK6 则显示相反的效果。BEAS-2B 细胞能够主动内化共培养的骨髓间充质干细胞（MSC）来源的 sEVs（BMSC-sEVs），从而减轻 LPS 引起的细胞损伤。然而，过表达 PCSK6 消除了 BMSC-sEV 共培养的治疗效果。机制上，BMSC-sEVs 通过递送 miR-21-5p 抑制 PCSK6 表达，miR-21-5p 直接与 PCSK6 基因结合。我们的工作为 PCSK6 在 LPS 诱导的 ALI 中的作用提供了证据，并确定了 miR-21-5p 是 BMSC 来源的 sEVs 的一个组成部分，它抑制了 PCSK6 的表达，并改善了 LPS 诱导的细胞损伤。这些结果揭示了 ALI 发病机制的新分子机制，并强调了使用干细胞释放的 sEVs 传递 miR-21-5p 治疗 ALI 的治疗潜力。
