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英国成功利用肝病患者皮肤细胞培育肝脏细胞

作者:

  英国剑桥大学25日发布公报说,该校研究人员成功利用肝病患者的皮肤细胞培育出肝脏细胞,这样得到的肝脏细胞与病人肝脏中的细胞高度相似,将有助于对特定肝病患者进行研究并开展治疗。

  公报说,研究人员从7名有遗传性肝脏疾病的患者身上提取了皮肤细胞,先将其改变为诱导多功能干细胞,然后培育成肝脏细胞。诱导多功能干细胞技术是2007年日美科学家的一项重大研究成果,它可以对皮肤细胞进行改造,使其具有与干细胞相似的功能。

  本次研究显示,利用这种方法得到的肝脏细胞在生理特征上与病人肝脏中的细胞高度相似,因此可用于试验各种药物,验之有效后再对病人进行治疗。

  研究人员泰米尔·拉希德(Tamir Rashid)说,过去很难直接培养出肝脏细胞,可用于研究的捐献肝脏也较少,本次研究成果提供了一种有效的替代手段,将有助于对肝病的研究和治疗。

  研究报告发表在新一期的《临床研究杂志》(Journal of Clinical Investigation)上。

J Clin Invest. 2010 Aug 25. [Epub ahead of print]

Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells.

Rashid ST, Corbineau S, Hannan N, Marciniak SJ, Miranda E, Alexander G, Huang-Doran I, Griffin J, Ahrlund-Richter L, Skepper J, Semple R, Weber A, Lomas DA, Vallier L.

Human induced pluripotent stem (iPS) cells hold great promise for advancements in developmental biology, cell-based therapy, and modeling of human disease. Here, we examined the use of human iPS cells for modeling inherited metabolic disorders of the liver. Dermal fibroblasts from patients with various inherited metabolic diseases of the liver were used to generate a library of patient-specific human iPS cell lines. Each line was differentiated into hepatocytes using what we believe to be a novel 3-step differentiation protocol in chemically defined conditions. The resulting cells exhibited properties of mature hepatocytes, such as albumin secretion and cytochrome P450 metabolism. Moreover, cells generated from patients with 3 of the inherited metabolic conditions studied in further detail (alpha1-antitrypsin deficiency, familial hypercholesterolemia, and glycogen storage disease type 1a) were found to recapitulate key pathological features of the diseases affecting the patients from which they were derived, such as aggregation of misfolded alpha1-antitrypsin in the endoplasmic reticulum, deficient LDL receptor-mediated cholesterol uptake, and elevated lipid and glycogen accumulation. Therefore, we report a simple and effective platform for hepatocyte generation from patient-specific human iPS cells. These patient-derived hepatocytes demonstrate that it is possible to model diseases whose phenotypes are caused by pathological dysregulation of key processes within adult cells.


Liver cells created from patients' skin cells

25 August 2010

Research paves way for new liver disease research and possibly cell-based therapy.

By creating diseased liver cells from a small sample of human skin, scientists have for the first time shown that stem cells can be used to model a diverse range of inherited disorders. The University of Cambridge researchers' findings, which will hopefully lead to new treatments for those suffering from liver diseases, were published today in The Journal of Clinical Investigation.

Because liver cells (hepatocytes) cannot be grown in the laboratory, researching liver disorders is extremely difficult. However, today's new research, which was funded by the Wellcome Trust and the Medical Research Council (MRC), demonstrates how to create diseased liver-like cells from patients suffering from a variety of liver disorders.

By replicating the organ's cells, researchers can not only investigate exactly what is happening in a diseased cell, they can also test the effectiveness of new therapies to treat these conditions. It is hoped that their discovery will lead to tailored treatments for specific individuals and eventually cell-based therapy - when cells from patients with genetic diseases are 'cured' and transplanted back. Additionally, as the process could be used to model cells from other parts of the body, their findings could have implications for conditions affecting other organs.

Dr Ludovic Vallier of the MRC Centre for Stem Cell Biology and Regenerative Medicine, University of Cambridge, principal investigator of the research, said: "Our work represents an important step towards delivering the clinical promises of stem cells. However, more work remains to be done and our group is dedicated to achieving this ultimate goal by increasing the knowledge necessary for the development of new therapies."

In the UK, liver disease is the fifth largest cause of death after cardiovascular, cancer, stroke, and respiratory diseases. Over the past 30 years mortality from liver disease in young and middle-aged people has increased over six times, with the number of individuals dying from the disease increasing at a rate of 8-10 per cent every year.

By 2012, the UK is expected to have the highest liver disease death rates in Europe and, without action to tackle the disease, it could overtake stroke and coronary heart disease as the leading cause of death within the next 10-20 years. In the United States, it accounts for approximately 25,000 deaths a year.

For their research, the scientists took skin biopsies from seven patients who suffered from a variety of inherited liver diseases and three healthy individuals (the control group). They then reprogrammed cells from the skin samples back into stem cells. These stem cells were then used to generate liver cells which mimicked a broad range of liver diseases - the first time patient-specific liver diseases have been modelled using stem cells - and to create 'healthy' liver cells from the control group. Importantly, the three diseases the scientists modelled covered a diverse range of pathological mechanisms, thereby demonstrating the potential application of their research on a wide variety of disorders.

Dr Tamir Rashid of the Laboratory for Regenerative Medicine, University of Cambridge, lead author of the paper, said: "We know that given the shortage of donor liver organs alternative strategies must urgently be sought. Our study improves the possibility that such alternatives will be found - either using new drugs or a cell-based therapeutic approach."

Professor Mark Thursz, a specialist in liver disease and Professor of Hepatology at Imperial College (who was not affiliated with the study), commented on the importance of the research: "Liver disease is the fifth most common cause of mortality in many developed countries and unlike the other leading causes of death, the rate of liver related mortality is increasing.

"The development of patient specific liver cell lines from stem cells is a significant advance in the battle against liver diseases. This technology holds promise in the short term by providing new tools to explore the biology of liver diseases and in the long term as a potential source of liver cells for patients with liver failure."