包被的人肝細胞類器官治療肝衰竭的臨床前療效和安全性

2024年4月，1.上海生物化學與細胞研究所CAS分子細胞科學英才中心細胞生物學國家重點實驗室中國科學院生物學，中國科學院大學，2.上海科技大學生命科學與技術學院，中國科學院上海營養與健康研究所計算生物學.3.CAS重點實驗室中國科學院，4上海交通大學醫學院仁濟醫院肝外科，5.英國倫敦國王學院醫院兒科肝臟胃腸和營養中心.6英國倫敦國王學院醫院倫敦國王學院肝臟研究所Mowat實驗室的Dhawan實驗室（1.State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China

2.School of Life Science and Technology, ShanghaiTech University, Shanghai, China

3.CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China

4.Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

5.Paediatric Liver GI and Nutrition Center, King’s College Hospital, London, UK

6Dhawan Lab at the Mowat Labs, Institute of Liver Studies, King’s College London at King’s College Hospital, London, UK）Ludi Zhang and Lijian Hui研究團隊在《Cell Stem Cell》上發表論文：

“Preclinical efficacy and safety of encapsulated proliferating human hepatocyte organoids in treating liver failure”

“囊化增殖的人肝細胞類器官治療肝衰竭的臨床前療效和安全性”

Abstract：

Alginate-encapsulated hepatocyte transplantation is a promising strategy to treat liver failure. However, its

clinical application was impeded by the lack of primary human hepatocytes and difficulty in controlling their quality. We previously reported proliferating human hepatocytes (ProliHHs). Here, quality-controlled ProliHHs were produced in mass and engineered as liver organoids to improve their maturity. Encapsulated ProliHHs liver organoids (eLO) were intraperitoneally transplanted to treat liver failure animals. Notably, eLO treatment increased the survival of mice with post-hepatectomy liver failure (PHLF) and ameliorated hyperammonemia and hypoglycemia by providing liver functions. Additionally, eLO treatment protected the gut from PHLF-augmented permeability and normalized the increased serum endotoxin and inflammatory

response, which facilitated liver regeneration. The therapeutic effect of eLO was additionally proved in acetaminophen-induced liver failure. Furthermore, we performed assessments of toxicity and biodistribution, demonstrating that eLO had no adverse effects on animals and remained non-tumorigenic.

摘要：

藻酸鹽包封肝細胞移植是治療肝衰竭的一種很有前途的策略。然而，由于缺乏原代人肝細胞和難以控制其質量，其臨床應用受到阻礙。我們之前報道了增殖的人肝細胞(ProliHHs)。在這里，質量控制的ProliHHs被大量生產，并被改造成肝類器官，以提高它們的成熟度。將包封的ProliHHs肝類器官(eLO)腹腔內移植治療肝衰竭動物。值得注意的是，eLO治療增加了肝切除術后肝衰竭(PHLF)小鼠的存活率，并通過提供肝功能改善高氨血癥和低血糖。此外，eLO治療可以保護腸道免受phlf增強的滲透性，并使血清內毒素和炎癥反應正常化，從而促進肝臟再生。eLO對對乙酰氨基酚所致肝衰竭的治療效果得到進一步證實。此外，我們進行了毒性和生物分布評估，證明eLO對動物沒有不良影響，并且仍然是非致瘤性的。

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