在实验室中生长的功能人的肝细胞

StephenW

Functional human liver cells grown in the lab
Published: Thursday 26 November 2015 at 7am PST

Adapted media release

In new research appearing in the prestigious journal Nature Biotechnology, an international research team led by The Hebrew University of Jerusalem describes a new technique for growing human hepatocytes in the laboratory. This groundbreaking development could help advance a variety of liver-related research and applications, from studying drug toxicity to creating bio-artificial liver support for patients awaiting transplantations.

The liver is the largest internal organ in the human body, serving as the main site of metabolism. Human hepatocytes - cells that comprise 85% of the liver - are routinely used by the pharmaceutical industry for study of hepatotoxicity, drug clearance and drug-drug interactions. They also have clinical applications in cell therapy to correct genetic defects, reverse cirrhosis, or support patients with a liver-assist device.

Regrettably, while the human liver can rapidly regenerate in vivo, recognized by the ancient Greeks in the myth of Prometheus, this capability to proliferate is rapidly lost when human cells are removed from the body. Thus far, attempts to expand human hepatocytes in the laboratory resulted in immortalized cancer cells with little metabolic function. The scarce supply of human hepatocytes and this inability to expand them without losing function is a major bottleneck for scientific, clinical and pharmaceutical development.

To address this problem, Prof. Yaakov Nahmias, director of the Alexander Grass Center for Bioengineering at the Hebrew University of Jerusalem, partnered with leading German scientists at upcyte technologies GmbH (formerly Medicyte) to develop a new approach to rapidly expand the number of human liver cells in the laboratory without losing their unique metabolic function.

Based on early work emerging from the German Cancer Research Center (DKFZ) on the Human Papilloma Virus (HPV), the research team demonstrated that weak expression of HPV E6 and E7 proteins released hepatocytes from cell-cycle arrest and allowed them to proliferate in response to Oncostatin M (OSM), a member of the interleukin 6 (IL-6) superfamily that is involved in liver regeneration. Whereas previous studies caused hepatocytes to proliferate without control, turning hepatocytes into tumor cells with little metabolic function, the researchers carefully selected colonies of human hepatocytes that only proliferate in response to OSM. Stimulation with OSM caused cell proliferation, with doubling time of 33 to 49 hours. Removal of OSM caused growth arrest and hepatic differentiation within 4 days, generating highly functional cells. The method, described as the upcyte© process (upcyte technologies GmbH), allows expanding human hepatocytes for 35 population doubling, resulting in 1015 cells (quadrillion) from each liver isolation. By comparison, only 109 cells (billion) can be isolated from a healthy organ.

"The approach is revolutionary," said Dr. Joris Braspenning, who led the German group. "Its strength lies in our ability to generate liver cells from multiple donors, enabling the study of patient-to-patient variability and idiosyncratic toxicity." The team generated hepatocyte lines from ethnically diverse backgrounds that could be serially passaged, while maintaining CYP450 activity, epithelial polarization, and protein expression at the same level as primary human hepatocytes. Importantly, the proliferating hepatocytes showed identical toxicology response to primary human hepatocytes across 23 different drugs.

"This is the holy grail of liver research," said Prof. Nahmias, the study's lead author. "Our technology will enable thousands of laboratories to study fatty liver disease, viral hepatitis, drug toxicity and liver cancer at a fraction of the current cost." Nahmias noted that genetic modifications preclude using the cells for transplantation, "but we may have found the perfect cell source for the bio-artificial liver project."

The proliferating hepatocyte library was recently commercialized by upcyte technologies GmbH (Hamburg, Germany), which is expanding the scope of the technology. "upcyte© hepatocytes represent the next generation of cell technology", said Dr. Astrid Nörenberg, the company's managing director. "We are poised to become the leading cell supplier for pharmaceutical development and chemical toxicity testing."

Yissum, the Research and Development Company of the Hebrew University, and upcyte technologies GmbH submitted a joint patent application earlier this year and are actively seeking investment.

Collaborating researchers on this study are affiliated with the Alexander Grass Center for Bioengineering, The Hebrew University of Jerusalem; upcyte technologies GmbH; Tel Aviv Sourasky Medical Center and Tel-Aviv University.

Adapted by MNT from original media release
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StephenW

在实验室中生长的功能人的肝细胞
发布时间：周四2015年26月在太平洋标准时间上午7点

适应媒体发布

在新的研究中出现的久负盛名的杂志自然生物技术，一个国际研究小组领导的耶路撒冷希伯来大学描述了在实验室中培养的人类肝细胞的新技术。这一突破性的发展将有助于推动各种肝脏相关的研究和应用，从研究药物的毒性，以创造为患者等待移植的生物人工肝支持。

肝脏是人体中最大的内部器官，作为新陈代谢的主要部位。人肝细胞 - 细胞，其包含肝的85％ - 常规用于制药工业的肝毒性，药物清除和药物 - 药物相互作用的研究。它们也具有在细胞疗法的临床应用纠正的遗传缺陷，反向肝硬化，或支持患者肝脏辅助装置。

令人遗憾的是，当人的肝可以在体内，在普罗米修斯的神话认可古希腊迅速再生，这种能力增殖迅速当人细胞从人体取出丢失。迄今为止，试图扩大的人肝细胞在实验室中导致永生化癌细胞很少代谢功能。人肝细胞的供应稀缺，这不能将其展开，而不会失去功能的科学，临床和医药发展的一大瓶颈。

为了解决这个问题，教授雅各布·纳米亚斯，亚历山大芳草中心生物工程在耶路撒冷希伯来大学的主任，合作与领先的德国科学家在upcyte技术有限公司（原Medicyte）开发一种新的方法来迅速扩大人类的数量肝细胞在实验室中，而不会失去其独特的代谢功能。

基于早期的作品摆脱了德国癌症研究中心（DKFZ）对人类乳头状瘤病毒（HPV），研究小组证实，HPV E6和E7蛋白弱表达释放出细胞周期阻滞肝细胞，​​并允许他们在应对激增到制瘤素M（OSM），是参与肝再生的白介素-6（IL-6）超家族的成员。虽然以前的研究引起肝细胞增殖无控制，把肝细胞进入肿瘤细胞很少代谢功能，研究人员精心挑选的人肝细胞的增殖只在响应OSM的殖民地。刺激OSM引起细胞增殖，与加倍的33到49小时的时候。 OSM去除造成生长停滞和肝分化4天之内，生成功能强大的细胞。该方法，描述为upcyte©进程（upcyte技术有限公司），允许扩大人类肝细胞对35人口倍增，导致各肝隔离1015细胞（万亿）。相比之下，只有109个细胞（十亿）可以从健康的器官被隔离。

“这种方法是革命性的，”里斯Braspenning博士，谁领导的德国小组说。 “它的优势在于我们来从多个供体的肝细胞的能力，使病人与病人的变异与异质性毒性的研究。”该小组从可连续传代，同时保持CYP450活性，上皮细胞极化和蛋白表达在同一水平作为主要的人类肝细胞不同种族背景的生成肝细胞系。重要的是，增殖肝细胞表现出相同毒理学响应于跨23种不同的药物的原代人肝细胞。

“这是神圣的肝脏研究大盘，”教授纳米亚斯，该研究报告的主要作者。 “我们的技术将使数以千计的实验室研究脂肪肝疾病，病毒性肝炎，药物毒性和肝癌在当前成本的一小部分。”纳米亚斯指出，遗传修饰排除使用细胞移植，“但我们可能已经找到了完美的细胞源生物人工肝项目。”

增殖肝细胞库最近被upcyte技术GmbH公司（德国汉堡），它是扩展技术的范围商品化。 “upcyte©肝细胞代表了下一代电池技术”，说阿斯特丽德Nörenberg博士，该公司的常务董事。 “我们正准备成为药物开发和化学毒性测试的主要电池供应商。”

Yissum，本公司希伯来大学的研究和开发，并upcyte技术有限公司提交了一份共有的专利申请在今年早些时候，正在积极寻求投资。

这项研究的研究人员合作是附属于亚历山大草中心的生物工程，耶路撒冷希伯来大学; upcyte技术有限公司;特拉维夫Sourasky医疗中心和特拉维夫大学。

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