Transplantation of chemically-induced liver progenitor cells ameliorates hepatic fibrosis in mice with diet-induced nonalcoholic steatohepatitis.
Transplantation of chemically-induced liver progenitor cells ameliorates hepatic fibrosis in mice with diet-induced nonalcoholic steatohepatitis.
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DOI：
10.1016/j.reth.2022.11.001
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发表时间：
2022-12
影响因子：
4.3
通讯作者：
Eguchi, Susumu
中科院分区：
文献类型：
--
作者：
Murakami, Shunsuke;Soyama, Akihiko;Miyamoto, Daisuke;Hara, Takanobu;Matsuguma, Kunihito;Imamura, Hajime;Matsushima, Hajime;Tanaka, Takayuki;Maruya, Yasuhiro;Adachi, Tomohiko;Miuma, Satoshi;Hidaka, Masaaki;Kanetaka, Kengo;Ochiya, Takahiro;Eguchi, Susumu
化学诱导的肝祖细胞（CLiP）在肝脏再生医学中具有广阔的应用前景。我们的目的是阐明 CLiP 在饮食诱导的非酒精性脂肪性肝炎大鼠模型中改善纤维化的功效，因为非酒精性脂肪肝病目前被认为是发达国家最常见的慢性肝病形式。方法：从7周龄雄性Wistar大鼠中分离出原代成熟肝细胞。为了建立 CLiP，将分离的肝细胞培养在由 Y-27632、A-83-01 和 CHIR99021（YAC 培养基）组成的分化培养基中。作为再现 NASH 病理生理学的动物模型，精心挑选和制备 6 周龄的严重联合免疫缺陷 (SCID) 小鼠，并用缺乏胆碱、L-氨基酸限定的高脂肪饮食 (HFD) 喂养。经过 12 周的 HFD 喂养后，小鼠被分配继续 HFD，给予或不给予大鼠 CLiP（分别为 HFD + CLiP 和 HFD-CLiP）。从脾脏给予大鼠 CLiP。根据组织学对肝纤维化进行半定量评估。收集肝实质和血液样本用于生化分析。结果：大鼠 CLiP CK19 呈阳性，EpCAM 成功递送至肝脏。 CLiPs 移植后 8 周，HFD + CLiPs 组的阳性染色明显少于 HFD-CLiPs 组。 Azan 染色和 αSMA 免疫染色证明，HFD + CLiPs 组的丙氨酸转氨酶显着改善。 RT qPCR 显示，HFD + CLiPs 组的肝脏 MMP2 和 9 表达趋于较高。结论：CLiPs 的抗纤维化作用在免疫缺陷 NASH 动物模型中得到证实，并且可能在人类中具有治疗应用。
Chemically-induced liver progenitors (CLiPs) have promising applications in liver regenerative medicine. We aimed to clarify the efficacy of CLiPs for ameliorating fibrosis in a diet-induced nonalcoholic steatohepatitis rat model, since nonalcoholic fatty liver disease is currently recognized as the most common form of chronic liver disease in developed countries. Methods: Primary mature hepatocytes were isolated from 7-week-old male Wistar rats. To establish CLiPs, isolated hepatocytes were cultured in differentiation medium composed of Y-27632, A-83-01, and CHIR99021 (YAC medium). As an animal model that reproduces NASH pathophysiology, 6-week-old severe combined immunodeficient (SCID) mice were carefully selected and prepared and fed with choline-deficient, L-amino acid-defined, high-fat diet (HFD). After 12 weeks’ HFD feeding, the mice were assigned to continue HFD with or without the administration of rat CLiPs (HFD + CLiPs and HFD-CLiPs, respectively). Rat CLiPs were administered from the spleen. Hepatic fibrosis was semi-quantitatively evaluated according to histology. Liver parenchyma and blood samples were collected for biochemical analyses. Results: Rat CLiPs were positive for CK19 and EpCAM were successfully delivered to the liver. At 8 weeks after CLiPs transplantation, the HFD + CLiPs group showed significantly less positive staining than the HFD-CLiPs group. Alanine aminotransferase significantly improved in the HFD + CLiPs group, as demonstrated by Azan staining and αSMA immunostaining. RT qPCR showed that the liver expression of MMP2 and 9 tended to be higher in the HFD + CLiPs group. Conclusions: The anti-fibrotic effect of CLiPs was demonstrated in the immunodeficient NASH animal model and may have therapeutic applications in humans.
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影响因子：
7.5
作者：
Rong, Xiaoli;Liu, Junzhi;Xie, Feng
通讯作者：
Xie, Feng
影响因子：
7.6
作者：
Hoofnagle JH;Van Natta ML;Kleiner DE;Clark JM;Kowdley KV;Loomba R;Neuschwander-Tetri BA;Sanyal AJ;Tonascia J;Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN)
通讯作者：
Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN)
影响因子：
6
作者：
Azuma YT;Fujita T;Izawa T;Hirota K;Nishiyama K;Ikegami A;Aoyama T;Ike M;Ushikai Y;Kuwamura M;Fujii H;Tsuneyama K
通讯作者：
Tsuneyama K
影响因子：
4.2
作者：
Huang, Yu;Miyamoto, Daisuke;Eguchi, Susumu
通讯作者：
Eguchi, Susumu
影响因子：
5.9
作者：
Kido T;Koui Y;Suzuki K;Kobayashi A;Miura Y;Chern EY;Tanaka M;Miyajima A
通讯作者：
Miyajima A