Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.
Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome 'Foro Italico', Rome, Italy.
J Hepatol. 2023 Jan;78(1):165-179. doi: 10.1016/j.jhep.2022.08.037. Epub 2022 Sep 9.
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.
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.
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.
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.
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.
在形成前肠的固有内胚层中，肝脏、胆道和胰腺存在共同的早期前体细胞。我们已经鉴定和描述了具有再生潜能的内胚层干细胞/祖细胞，这些细胞存在于成人十二指肠中。
从器官捐献者中获得人十二指肠，并在去除黏膜层后分离十二指肠黏膜下腺细胞。细胞在塑料上或作为类器官培养，并移植到严重联合免疫缺陷（SCID）小鼠肝脏中。
对人十二指肠黏膜下腺的原位研究显示，表达干细胞/祖细胞标志物的细胞具有独特的表型特征，与肠隐窝细胞不同。遗传特征研究表明，这些细胞与胆管干细胞和固有内胚层细胞更接近，而与成体肝细胞更接近，支持其为内胚层干细胞/祖细胞的解释。在体外，人十二指肠黏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征的能力。在体内，移植细胞植入免疫缺陷小鼠的肝脏中并分化为成熟的肝细胞。在脂肪肝的实验模型中，人十二指肠黏膜下腺细胞能够通过支持肝脏的再定植和再生来拯救宿主免受肝损伤。
在体外和体内实验模型中，具有克隆生长和类器官形成能力、具有肝脏分化潜能的细胞群体存在于成人十二指肠黏膜下腺中。这些细胞可以被分离，不需要重编程，因此可能代表肝脏再生医学的一种新的细胞来源。
针对肝脏疾病的细胞疗法可能是支持肝脏功能的一种选择，但确定可持续和可行的细胞来源至关重要。在这里，我们描述了一种具有类器官形成能力和肝脏特异性再生潜能的细胞群体，存在于人十二指肠黏膜下腺中。从成人器官中分离出十二指肠黏膜下腺细胞，不需要重编程，可以在慢性（而非急性）肝损伤的临床前模型中拯救肝细胞损伤。十二指肠黏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。
