Therapeutic Cell Repopulation of the Liver: From Fetal Rat Cells to Synthetic Human Tissues.
Therapeutic Cell Repopulation of the Liver: From Fetal Rat Cells to Synthetic Human Tissues.
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DOI：
10.3390/cells12040529
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发表时间：
2023-02-06
期刊：
影响因子：
6
通讯作者：
Oertel, Michael
中科院分区：
文献类型：
--
作者：
Shafritz, David A. A.;Ebrahimkhani, Mo R. R.;Oertel, Michael
从胎儿肝脏中分离出的祖细胞可以提供独特的细胞来源来产生新的健康组织块。大约 20 年前，研究表明，大鼠胎儿肝细胞通过类似于细胞竞争的机制重新进入正常的宿主肝脏环境。肝细胞产生的激活素 A 被认为是细胞竞争过程中的重要参与者。由于激活素受体表达减少，高度增殖的胎肝干/祖细胞对激活素 A 具有抗性，因此与肝细胞相比表现出生长优势。因此，移植的胎儿肝细胞能够重新填充正常肝脏。对于基于细胞的治疗很重要，可以使用细胞表面标记 δ-like 1 (Dlk-1) 将具有再生潜力的肝干/祖细胞与胎儿造血细胞分离。在患有晚期纤维化的肝脏中，胎儿上皮干/祖细胞分化为功能性肝细胞并在竞争中击败受损的内源性肝细胞，从而产生抗纤维化作用。尽管胎儿肝细胞可以有效地重新填充肝脏，但它们可能不会用于人类细胞移植。因此，利用再增殖的基本机制和开发的方法在体外产生类似的生长优势细胞，例如人类诱导多能干细胞（iPSC），这种方法在开发肝病患者的新型细胞疗法方面具有巨大潜力。本综述简要概述了经典的细胞移植模型和作为供体细胞候选物研究的各种细胞来源。讨论了胎儿肝脏来源的干/祖细胞的优点以及肝脏再生的机制。此外，本文回顾了体外开发的 iPSC 合成人胎肝脏的潜力及其治疗益处。
Progenitor cells isolated from the fetal liver can provide a unique cell source to generate new healthy tissue mass. Almost 20 years ago, it was demonstrated that rat fetal liver cells repopulate the normal host liver environment via a mechanism akin to cell competition. Activin A, which is produced by hepatocytes, was identified as an important player during cell competition. Because of reduced activin receptor expression, highly proliferative fetal liver stem/progenitor cells are resistant to activin A and therefore exhibit a growth advantage compared to hepatocytes. As a result, transplanted fetal liver cells are capable of repopulating normal livers. Important for cell-based therapies, hepatic stem/progenitor cells containing repopulation potential can be separated from fetal hematopoietic cells using the cell surface marker δ-like 1 (Dlk-1). In livers with advanced fibrosis, fetal epithelial stem/progenitor cells differentiate into functional hepatic cells and out-compete injured endogenous hepatocytes, which cause anti-fibrotic effects. Although fetal liver cells efficiently repopulate the liver, they will likely not be used for human cell transplantation. Thus, utilizing the underlying mechanism of repopulation and developed methods to produce similar growth-advantaged cells in vitro, e.g., human induced pluripotent stem cells (iPSCs), this approach has great potential for developing novel cell-based therapies in patients with liver disease. The present review gives a brief overview of the classic cell transplantation models and various cell sources studied as donor cell candidates. The advantages of fetal liver-derived stem/progenitor cells are discussed, as well as the mechanism of liver repopulation. Moreover, this article reviews the potential of in vitro developed synthetic human fetal livers from iPSCs and their therapeutic benefits.
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