一个强大的小鼠肝脏类器官平台能够从单个组织样本中实现持续的多细胞成熟和纤维化建模
A robust mouse liver organoid platform enables sustained multicellular maturation and fibrosis modeling from a single tissue sample.
摘要(中文译文)
高效分离和培养肝类器官对于研究肝纤维化、肝再生以及药物毒性和筛选至关重要。然而，在保留成熟肝胆特征的同时整合具有产生纤维化能力的肝星状细胞（HSCs）仍是一项重大挑战，往往阻碍了能够复制关键肝功能的大规模类器官生产。在此，我们报道了一种稳健的三维类器官培养系统，能够从单一来源的小鼠肝组织中同时分离并长期扩增原代肝细胞、胆管细胞和HSCs。通过在Hep-Med中补充Notch信号抑制剂和地塞米松，我们在多次传代培养中实现了类器官的持续成熟，包括稳定的白蛋白产生、代谢活性和肝脏特异性基因表达。该系统中的静息态HSCs保留脂滴，并可通过TGFβ刺激活化为肌成纤维细胞样表型，也称为活化HSCs。活化HSCs损害了Hep-Orgs和Cho-Orgs的增殖和干性，并诱导其发生上皮-间质转化（EMT），从而实现了体外肝纤维化建模。该平台经过优化可将组织用量降至最低，在最大化组织利用效率的同时保留了肝脏的异质性细胞结构。其多功能性支持在肝病建模、药物发现和再生医学中的多样化应用。
Abstract
Efficient isolation and culture of liver organoids are critical for studying liver fibrosis, liver regeneration and drug toxicity and screening. However, preserving mature hepatobiliary characteristics and concurrently incorporating fibrosis-producing hepatic stellate cells (HSCs) remains a significant challenge, often hindering the large-scale production of organoids capable of replicating key liver functions. Here, we report a robust 3D organoid culture system that enables simultaneous isolation and long-term propagation of primary hepatocytes, cholangiocytes, and HSCs from a single source of mouse liver tissue. By supplementing the Hep-Med with Notch signaling inhibitor and dexamethasone, we achieved sustained organoid maturity, including stable albumin production, metabolic activity, and liver-specific gene expression, over multiple passages in culture. Quiescent HSCs within the system retained lipid droplets and could be activated into a myofibroblast-like phenotype, also called activated HSCs, via TGFβ stimulation. Activated HSCs impaired the proliferation and stemness, and induced epithelial-mesenchymal transition (EMT) of Hep-Orgs and Cho-Orgs, enabling in vitro liver fibrosis modeling. Optimized for minimal tissue input, this platform maximizes tissue utilization efficiency while preserving the liver's heterogeneous cellular architecture. Its versatility supports diverse applications in liver disease modeling, drug discovery, and regenerative medicine.
如何引用
AMA
Yingyu Liang, Yongqin Ye, Hua Xie, Vincent Chi Hang Lui, Yan Chen, Paul Kwong Hang Tam. A robust mouse liver organoid platform enables sustained multicellular maturation and fibrosis modeling from a single tissue sample.. Scientific reports. 2026; doi:10.1038/s41598-026-42990-2.
APA
Yingyu Liang, Yongqin Ye, Hua Xie, Vincent Chi Hang Lui, Yan Chen, Paul Kwong Hang Tam (2026). A robust mouse liver organoid platform enables sustained multicellular maturation and fibrosis modeling from a single tissue sample.. Scientific reports. https://doi.org/10.1038/s41598-026-42990-2
GB/T 7714
Yingyu Liang, Yongqin Ye, Hua Xie, Vincent Chi Hang Lui, Yan Chen, Paul Kwong Hang Tam. A robust mouse liver organoid platform enables sustained multicellular maturation and fibrosis modeling from a single tissue sample.[J]. Scientific reports, 2026 doi:10.1038/s41598-026-42990-2.
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