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间充质基质细胞衍生的细胞外囊泡用于逆转三维肝球体中的肝纤维化

Mesenchymal Stromal Cell-Derived Extracellular Vesicles for Reversing Hepatic Fibrosis in 3D Liver Spheroids.

作者信息

Chiabotto Giulia, Semnani Armina, Ceccotti Elena, Guenza Marco, Camussi Giovanni, Bruno Stefania

机构信息

Department of Medical Sciences, University of Torino, 10126 Torino, Italy.

出版信息

Biomedicines. 2024 Aug 14;12(8):1849. doi: 10.3390/biomedicines12081849.

DOI:10.3390/biomedicines12081849
PMID:39200313
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11351945/
Abstract

Hepatic fibrosis, arising from prolonged liver injury, entails the activation of hepatic stellate cells (HSCs) into myofibroblast-like cells expressing alpha-smooth muscle actin (α-SMA), thereby driving extracellular matrix deposition and fibrosis progression. Strategies targeting activated HSC reversal and hepatocyte regeneration show promise for fibrosis management. Previous studies suggest that extracellular vesicles (EVs) from mesenchymal stromal cells (MSCs) can suppress HSC activation, but ensuring EV purity is essential for clinical use. This study investigated the effects of MSC-derived EVs cultured in chemically defined conditions on liver spheroids and activated HSCs. Umbilical cord- and bone marrow-derived MSCs were expanded in chemically defined media, and EVs were isolated using filtration and differential ultracentrifugation. The impact of MSC-EVs was evaluated on liver spheroids generated in Sphericalplate 5D™ and on human HSCs, both activated by transforming growth factor beta 1 (TGF-β1). MSC-EVs effectively reduced the expression of profibrotic markers in liver spheroids and activated HSCs induced by TGF-β1 stimulation. These results highlight the potential of MSC-EVs collected under chemically defined conditions to mitigate the activated phenotype of HSCs and liver spheroids, suggesting MSC-EVs as a promising treatment for hepatic fibrosis.

摘要

肝纤维化源于长期的肝脏损伤，会导致肝星状细胞（HSCs）激活成为表达α平滑肌肌动蛋白（α-SMA）的肌成纤维细胞样细胞，从而推动细胞外基质沉积和纤维化进展。针对激活的肝星状细胞逆转和肝细胞再生的策略在纤维化治疗方面显示出前景。先前的研究表明，间充质基质细胞（MSCs）来源的细胞外囊泡（EVs）可以抑制肝星状细胞激活，但确保细胞外囊泡的纯度对于临床应用至关重要。本研究调查了在化学成分明确的条件下培养的间充质基质细胞来源的细胞外囊泡对肝球体和激活的肝星状细胞的影响。脐带和骨髓来源的间充质基质细胞在化学成分明确的培养基中扩增，细胞外囊泡通过过滤和差速超速离心法分离。评估了间充质基质细胞来源的细胞外囊泡对在Sphericalplate 5D™中生成的肝球体以及对由转化生长因子β1（TGF-β1）激活的人肝星状细胞的影响。间充质基质细胞来源的细胞外囊泡有效降低了肝球体和由TGF-β1刺激诱导的激活的肝星状细胞中促纤维化标志物的表达。这些结果突出了在化学成分明确的条件下收集的间充质基质细胞来源的细胞外囊泡减轻肝星状细胞和肝球体激活表型的潜力，表明间充质基质细胞来源的细胞外囊泡有望成为肝纤维化的治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/485a/11351945/6846e3903083/biomedicines-12-01849-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/485a/11351945/e4962c01cc2f/biomedicines-12-01849-g001a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/485a/11351945/a8214f810e67/biomedicines-12-01849-g002a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/485a/11351945/e23a26f54452/biomedicines-12-01849-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/485a/11351945/656d4d70d9f3/biomedicines-12-01849-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/485a/11351945/6846e3903083/biomedicines-12-01849-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/485a/11351945/e4962c01cc2f/biomedicines-12-01849-g001a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/485a/11351945/a8214f810e67/biomedicines-12-01849-g002a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/485a/11351945/e23a26f54452/biomedicines-12-01849-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/485a/11351945/656d4d70d9f3/biomedicines-12-01849-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/485a/11351945/6846e3903083/biomedicines-12-01849-g005.jpg

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J Extracell Vesicles. 2024 Feb;13(2):e12404. doi: 10.1002/jev2.12404.
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Extracellular vesicles as tools and targets in therapy for diseases.细胞外囊泡作为疾病治疗的工具和靶点
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Liver fibrosis: pathological features, clinical treatment and application of therapeutic nanoagents.
肝纤维化：病理特征、临床治疗及治疗纳米制剂的应用。
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