Transplantation of chemically induced liver progenitors in Nagase analbuminemic rats under liver regenerative stimulus

IF 3.4 3区环境科学与生态学 Q3 CELL & TISSUE ENGINEERING

Regenerative Therapy Pub Date : 2025-05-09 DOI:10.1016/j.reth.2025.04.015

Masayuki Fukumoto, Akihiko Soyama, Daisuke Miyamoto, Takanobu Hara, Hajime Matsushima, Hajime Imamura, Mampei Yamashita, Tomohiko Adachi, Kengo Kanetaka, Susumu Eguchi

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引用次数: 0

Abstract

We have explored chemically induced liver progenitors (CLiP) as a potential therapeutic agent for liver diseases because their proliferative capacity in vitro. Therefore, we hypothesized the potential treatment with CLiP transplantation (Tx) could be effective and be enhanced with liver regenerative stimulus for metabolic liver diseases.

Methods

Male Sprague Dawley rats were used for mature hepatocytes (HEP) isolation to induce CLiP using 3 small molecules cocktail (ROCK-inhibitor, TGF beta-1 inhibitor, GSK3 inhibitor). Harvested rat CLiP (1 × 10⁶) were transplanted to the posterior lobe of the liver (30 % of whole liver) of Nagase analbuminemic rats (NAR) through portal vein injection. One week later, portal venous branch to non-transplanted lobe was ligated to induce liver regeneration in CLiP bearing liver lobe (portal branch ligation: PBL). Only CLiP Tx or HEP Tx of same dose were used as control groups. Serial measurement of serum albumin level was measured by ELISA method. All NARs were subject to immunosuppression therapy using tacrolimus s.q. 3 days per week.

Results

After HEP Tx especially with PBL, serum albumin level was significantly elevated. However, even with PBL, CLiP Tx group did not show significant increase in serum albumin. CLiP were surrounded by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) positive cells in portal veins suggesting that CLiP were exposed to the risk of innate immunity.

Conclusion

Although CLiP respond to growth factors and proliferate better than HEP in vitro, their behavior in vivo in response to liver regenerative stimulus were not similar to in vitro probably because of less immaturity of receptors and/or high immunogenicity as compared to HEP.

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肝再生刺激下化学诱导的长酶无血血症大鼠肝祖细胞移植

化学诱导的肝祖细胞（CLiP）具有体外增殖能力，是一种潜在的肝脏疾病治疗药物。因此，我们假设CLiP移植（Tx）对代谢性肝病的潜在治疗可能是有效的，并且可以通过肝脏再生刺激来增强。方法采用3种小分子混合物（ROCK-inhibitor、TGF - β -1 inhibitor、GSK3 inhibitor）诱导成熟肝细胞（HEP）的克隆。将收获的大鼠CLiP （1 × 106）通过门静脉注射移植到长酶无血毒大鼠（NAR）肝脏后叶（占全肝的30%）。1周后，结扎门静脉分支至未移植肝叶，诱导带有CLiP的肝叶肝脏再生（门静脉分支结扎：PBL）。仅以相同剂量的CLiP Tx或HEP Tx为对照组。采用ELISA法连续测定血清白蛋白水平。所有NARs均接受免疫抑制治疗，使用他克莫司s.q，每周3天。结果乙型肝炎合并PBL患者血清白蛋白水平显著升高。然而，即使有PBL， CLiP Tx组也没有显示出血清白蛋白的显著增加。门静脉中，CLiP被肿瘤坏死因子相关凋亡诱导配体（TRAIL）阳性细胞包围，表明CLiP暴露于先天免疫风险中。结论尽管CLiP在体外对生长因子的反应和增殖能力优于HEP，但其在体内对肝脏再生刺激的反应与HEP不同，这可能是由于其受体的不成熟程度较低和/或免疫原性较HEP高。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Regenerative Therapy Engineering-Biomedical Engineering

CiteScore

6.00

自引率

2.30%

发文量

106

审稿时长

49 days

期刊介绍： Regenerative Therapy is the official peer-reviewed online journal of the Japanese Society for Regenerative Medicine. Regenerative Therapy is a multidisciplinary journal that publishes original articles and reviews of basic research, clinical translation, industrial development, and regulatory issues focusing on stem cell biology, tissue engineering, and regenerative medicine.