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标题: Scarring cells revert to inactive state as liver heals [打印本页]

作者: StephenW 时间: 2012-5-16 00:37 标题: Scarring cells revert to inactive state as liver heals

本帖最后由 StephenW 于 2012-5-16 00:39 编辑

Scarring cells revert to inactive state as liver heals May 7, 2012
in Medical research

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This is a photomicrograph of cirrhotic liver tissue, with extensive fibrotic scarring (stained blue). Credit: UC San Diego School of Medicine

An international team of scientists, led by researchers at the University of California, San Diego School of Medicine, report that significant numbers of myofibroblasts – cells that produce the fibrous scarring in chronic liver injury – revert to an inactive phenotype as the liver heals. The discovery in mouse models could ultimately help lead to new human therapies for reversing fibrosis in the liver, and in other organs like the lungs and kidneys.

The work is published in the May 7, 2012 online Early Edition of the Proceedings of the National Academy of Sciences.
"The take-away message is two-fold," said David A. Brenner, MD, vice chancellor for Health Sciences, dean of the UC San Diego School of Medicine and senior author of the paper. "First, we've shown that liver fibrosis is markedly reversible and we now better understand how it happens. Second, we can start looking for ways to direct active myofibroblasts to stop producing scar, and become inactive. We can focus on developing drugs that promote cell change and regression. It raises the bar for prospective treatment tremendously."
Liver fibrosis is the 12th leading cause of death in the United States. It is the result of chronic liver injury caused by such agents as the hepatitis B and C viruses, alcoholic liver disease and non-alcoholic steatohepatitis. The condition is manifested by extensive scarring of liver tissue and the organ's progressive inability to filter body toxins. Liver fibrosis precedes the development of liver cancer. Often, the only treatment for end-stage liver fibrosis is an organ transplant.
Fibrosis begins when infectious agents or excessive alcohol consumption trigger activation of hepatic stellate cells (HSCs), which normally act as quiescent storage units for nutrients like vitamin A in the liver. Once activated, these HSCs acquire characteristics of another cell type called myofibroblasts, which are characterized by their abundant production of extracellular matrix proteins such as collagen. These proteins accumulate as scar tissue, rendering the organ progressively dysfunctional.
However, if the source of the liver injury is successfully treated or eliminated, the liver can repair itself. In part, this is due to the activated HSCs undergoing apoptosis (programmed cell death) and being removed by other cells. But UC San Diego scientists say that, in tests using a mouse model, as many as half of all activated HSCs persist. They do not die, but rather revert to an inactive phenotype during fibrotic regression.
"After one month of regression, these cells have stopped producing collagen. They've upregulated some of the genes associated with quiescence and returned to their normal location in the liver," said Tatiana Kisseleva, MD, PhD, an assistant research scientist and first author of the study.
It's not clear why these myofibroblasts survive. Also, scientists note the reverted myofibroblasts do not completely return to their original quiescent state. "They're still more susceptible to repetitive injury than original quiescent HSCs," said Kisseleva, who noted future tests will investigate whether additional reversion occurs with more time.
Kisseleva suggested the findings present another avenue for treating liver fibrosis, especially in possibly reverting fibrosis and cirrhosis, which accounts for roughly 27,000 deaths in the United States annually.
Fibrosis occurs in other organs as well, such as the kidneys and lungs, with comparable deadly effect. Recent studies indicate fibrotic reversibility in these organs as well. "Our findings are applicable to other fibrosing organs," said Kisseleva. "Instead of killing damaged cells, we might be able to de-activate them and revert them to healthy originals."
Provided by University of California - San Diego (news : web)

作者: StephenW 时间: 2012-5-16 00:40

疤痕细胞，恢复肝医治无效状态
2012年5月7日，在医学研究
疤痕细胞，恢复肝医治无效状态

肝硬化肝组织的显微照片，这是一个广泛的纤维化疤痕（蓝染）。信用：加州大学圣地亚哥分校医学院

一个国际科学家小组的带领下，由研究人员在加州大学圣地亚哥医学院，报告，肌纤维母细胞显着 - 细胞产生慢性肝损伤的纤维疤痕 - 恢复到一个无效的表型肝治愈。在小鼠模型中发现可能最终帮助导致人类新疗法，逆转肝纤维化，肺和肾脏等其他器官。

这项工作发表在5月7日，2012年网上的早期版本的“国家科学院。

“外卖的消息是2倍，医学博士，副校长为健康科学，医学论文的资深作者，加州大学圣地亚哥分校的院长戴维·布伦纳说。”他说：“首先，我们已经表明，肝纤维化明显是可逆的，我们现在更好地理解它是如何发生的。其次，我们可以开始寻找方式直接主动肌纤维母细胞停止生产疤痕，变得不活跃，我们可以专注于开发药物，促进细胞的变化和回归。它极大地提高了预期治疗的酒吧。“

肝纤维化是在美国第12大死因。这是慢性乙肝和丙肝病毒，酒精性肝病和非酒精性脂肪性肝炎等药物引起的肝损伤的结果。表现为广泛的肝组织和器官的进步无法过滤体内毒素疤痕的条件。肝纤维化，肝癌的发展之前。通常情况下，为终末期肝病肝纤维化的唯一的治疗方法是器官移植。

当病原体或过量饮酒触发激活的肝星状细胞（造血干细胞），通常为静态存储单元作用的营养素如维生素A在肝纤维化开始。一旦被激活，这些造血干细胞获得另一个称为肌纤维母细胞的细胞类型，特点是其丰富的生产，如胶原蛋白的细胞外基质蛋白的特征。这些蛋白质积累的疤痕组织，逐步使器官功能失调。

然而，如果成功治疗或消除肝损伤的来源，肝脏可以自我修复。在某种程度上，这是由于激活造血干细胞发生凋亡（程序性细胞死亡）和其他细胞中删除。但加州大学圣迭戈分校的科学家说，在使用的小鼠模型，多达一半全部激活造血干细胞的试验，仍然存在。他们没有死，而是恢复到在纤维化回归无效型。

“塔蒂亚娜Kisseleva，博士，助理研究员和第一，说：”回归后一个月后，这些细胞已停止生产胶原蛋白。他们已经上调一些平静与相关的基因，并返回其在肝脏的正常位置作者的研究。

目前还不清楚为什么这些肌纤维母细胞的生存。此外，科学家们注意到，恢复肌纤维母细胞的不完全恢复其原来的静止状态。 “他们仍然比原来的静态造血干细胞更容易受到反复损伤，说：”Kisseleva，他指出，未来的测试将调查是否有更多的时间发生额外的回归。

kisseleva建议的调查结果提出了治疗肝纤维化，尤其是在可能恢复肝纤维化和肝硬化，占大约27000在美国的死亡人数每年另一种途径。

纤维化以及发生在其他器官，如肾脏和肺，具有可比性的致命的影响。最近的研究表明这些器官纤维化的可逆性以及。 Kisseleva“，说：”我们的研究结果适用于其他纤维化机关。 “而受损的细胞死亡，我们可能能够激活他们和他们恢复健康的原件。”

提供由加州大学 - 圣地亚哥（新闻：网络）

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