Donor organ shortages for transplantation remain a serious global concern, and alternative treatment is in high demand. Fetal cells and tissues have considerable therapeutic potential as, for example, organoid technology that uses human induced pluripotent stem cells (hiPSCs) to generate unlimited human fetal-like cells and tissues. We previously reported the in vivo vascularization of early fetal liver–like hiPSC-derived liver buds (LBs) and subsquent improved survival of recipient mice with subacute liver failure. Here, we show hiPSC–liver organoids (LOs) that recapitulate midgestational fetal liver promote de novo liver generation when grafted onto the surface of host livers in chemical fibrosis models, thereby recovering liver function. We found that fetal liver, a hematopoietic tissue, highly expressed macrophage-recruiting factors and antifibrotic M2 macrophage polarization factors compared with the adult liver, resulting in fibrosis reduction because of CD163 + M2-macrophage polarization. Next, we created midgestational fetal liver–like hiPSC-LOs by fusion of hiPSC-LBs to induce static cell-cell interactions and found that these contained complex structures such as hepatocytes, vasculature, and bile ducts after transplantation. This fusion allowed the generation of a large human tissue suitable for transplantation into immunodeficient rodent models of liver fibrosis. hiPSC-LOs showed superior liver function compared with hiPSC-LBs and improved survival and liver function upon transplantation. In addition, hiPSC-LO transplantation ameliorated chemically induced liver fibrosis, a symptom of liver cirrhosis that leads to organ dysfunction, through immunomodulatory effects, particularly on CD163 + phagocytic M2-macrophage polarization. Together, our results suggest hiPSC-LO transplantation as a promising therapeutic option for liver fibrosis.

中文翻译：

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人 iPSC-肝类器官移植通过免疫调节减少纤维化


用于移植的供体器官短缺仍然是全球严重关注的问题，并且对替代治疗的需求很高。胎儿细胞和组织具有相当大的治疗潜力，例如，类器官技术利用人类诱导多能干细胞（hiPSC）产生无限的人类胎儿样细胞和组织。我们之前报道过早期胎儿肝脏样 hiPSC 衍生的肝芽 (LB) 的体内血管化，以及随后亚急性肝衰竭受体小鼠的存活率提高。在这里，我们展示了 hiPSC 肝脏类器官（LO），它可以概括妊娠中期胎儿肝脏，当移植到化学纤维化模型中的宿主肝脏表面时，可以促进肝脏从头生成，从而恢复肝功能。我们发现，与成人肝脏相比，胎儿肝脏作为造血组织，高表达巨噬细胞募集因子和抗纤维化M2巨噬细胞极化因子，导致CD163导致纤维化减少+ M2-巨噬细胞极化。接下来，我们通过融合 hiPSC-LB 来诱导静态细胞间相互作用，创建了类似妊娠中期胎儿肝脏的 hiPSC-LO，并发现移植后它们包含复杂的结构，如肝细胞、脉管系统和胆管。这种融合使得能够产生适合移植到免疫缺陷啮齿动物肝纤维化模型中的大型人体组织。与 hiPSC-LB 相比，hiPSC-LO 表现出更好的肝功能，并且移植后的存活率和肝功能得到改善。 此外，hiPSC-LO 移植通过免疫调节作用，特别是对 CD163 的作用，改善了化学诱导的肝纤维化，这是肝硬化的一种症状，会导致器官功能障碍。 +吞噬细胞 M2-巨噬细胞极化。总之，我们的结果表明 hiPSC-LO 移植作为肝纤维化的一种有前途的治疗选择。