Journal of Hepatology ( IF 26.8 ) Pub Date : 2022-09-09 , DOI: 10.1016/j.jhep.2022.08.037 Vincenzo Cardinale 1 , Guido Carpino 2 , Diletta Overi 3 , Samira Safarikia 4 , Wencheng Zhang 5 , Matt Kanke 6 , Antonio Franchitto 3 , Daniele Costantini 4 , Olga Riccioni 3 , Lorenzo Nevi 4 , Michele Chiappetta 4 , Paolo Onori 3 , Matteo Franchitto 4 , Simone Bini 4 , Yu-Han Hung 6 , Quirino Lai 7 , Ilaria Zizzari 8 , Marianna Nuti 8 , Carmine Nicoletti 3 , Saula Checquolo 1 , Laura Di Magno 9 , Maria Valeria Giuli 9 , Massimo Rossi 7 , Praveen Sethupathy 6 , Lola M Reid 5 , Domenico Alvaro 4 , Eugenio Gaudio 3
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Background & Aims
Common precursors for the liver, biliary tree, and pancreas exist at an early stage of development in the definitive endoderm forming the foregut. We have identified and characterised endodermal stem/progenitor cells with regenerative potential persisting in the adult human duodenum.
Methods
Human duodena were obtained from organ donors, and duodenal submucosal gland cells were isolated after removal of the mucosa layer. Cells were cultured on plastic or as organoids and were transplanted into severe combined immunodeficient (SCID) mouse livers.
Results
In situ studies of submucosal glands in the human duodenum revealed cells expressing stem/progenitor cell markers that had unique phenotypic traits distinguishable from intestinal crypt cells. Genetic signature studies indicated that the cells are closer to biliary tree stem cells and to definitive endodermal cells than to adult hepatocytes, supporting the interpretation that they are endodermal stem/progenitor cells. In vitro, human duodenal submucosal gland cells demonstrated clonal growth, capability to form organoids, and ability to acquire functional hepatocyte traits. In vivo, transplanted cells engrafted into the livers of immunocompromised mice and differentiated to mature liver cells. In an experimental model of fatty liver, human duodenal submucosal gland cells were able to rescue hosts from liver damage by supporting repopulation and regeneration of the liver.
Conclusions
A cell population with clonal growth and organoid formation capability, which has liver differentiation potency in vitro and in vivo in murine experimental models, is present within adult duodenal submucosal glands. These cells can be isolated, do not require reprogramming, and thus could potentially represent a novel cell source for regenerative medicine of the liver.
Impact and implications
Cell therapies for liver disease could represent an option to support liver function, but the identification of sustainable and viable cell sources is critical. Here, we describe a cell population with organoid formation capability and liver-specific regenerative potential in submucosal glands of the human duodenum. Duodenal submucosal gland cells are isolated from adult organs, do not require reprogramming, and could rescue hepatocellular damage in preclinical models of chronic, but not acute, liver injury. Duodenal submucosal gland cells could represent a potential candidate cell source for regenerative medicine of the liver, but the determination of cell dose and toxicity is needed before clinical testing in humans.
中文翻译：
人十二指肠粘膜下腺体含有明确的干细胞/祖细胞亚群，具有肝脏特异性再生潜能
背景与目标
肝脏、胆道树和胰腺的共同前体存在于形成前肠的定形内胚层的早期发育阶段。我们已经鉴定并表征了在成人十二指肠中持续存在的具有再生潜能的内胚层干/祖细胞。
方法
人十二指肠取自器官捐献者，去除粘膜层后分离十二指肠粘膜下腺细胞。细胞在塑料或类器官上培养，然后移植到严重联合免疫缺陷 (SCID) 小鼠肝脏中。
结果
对人十二指肠粘膜下腺体的原位研究表明，表达干细胞/祖细胞标记的细胞具有与肠隐窝细胞不同的独特表型特征。遗传特征研究表明，与成体肝细胞相比，这些细胞更接近于胆管树干细胞和定形内胚层细胞，这支持了它们是内胚层干细胞/祖细胞的解释。在体外，人十二指肠粘膜下腺细胞表现出克隆生长、形成类器官的能力以及获得功能性肝细胞特性的能力。体内，移植细胞植入免疫功能低下小鼠的肝脏并分化为成熟肝细胞。在脂肪肝的实验模型中，人十二指肠粘膜下腺细胞能够通过支持肝脏的再增殖和再生来拯救宿主免受肝损伤。
结论
具有克隆生长和类器官形成能力的细胞群存在于成人十二指肠粘膜下腺中，在小鼠实验模型中具有体外和体内的肝分化能力。这些细胞可以分离，不需要重新编程，因此可能代表肝脏再生医学的新型细胞来源。
影响和启示
肝病细胞疗法可能是支持肝功能的一种选择，但确定可持续和可行的细胞来源至关重要。在这里，我们描述了人类十二指肠粘膜下腺体中具有类器官形成能力和肝脏特异性再生潜能的细胞群。十二指肠粘膜下腺细胞是从成人器官中分离出来的，不需要重新编程，并且可以在慢性而非急性肝损伤的临床前模型中挽救肝细胞损伤。十二指肠粘膜下腺细胞可能是肝脏再生医学的潜在候选细胞来源，但在人体临床试验之前需要确定细胞剂量和毒性。
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