组织模型揭示了肝脏再生的关键参与者 通过追踪肝脏再生的

StephenW

组织模型揭示了肝脏再生的关键参与者
通过追踪肝脏再生的步骤，麻省理工学院的工程师希望利用肝脏的再生能力来帮助治疗慢性疾病。
安妮特拉夫顿 |麻省理工学院新闻办公室
发布日期：
2022 年 6 月 27 日

人类肝脏具有惊人的再生能力：即使切除了多达 70% 的肝脏，剩余的组织也可以在几个月内重新长出完整大小的肝脏。

利用这种再生能力可以为医生提供更多治疗慢性肝病的选择。麻省理工学院的工程师现在朝着这个目标迈出了一步，他们创建了一个新的肝组织模型，使他们能够比以前更精确地追踪肝脏再生所涉及的步骤。

研究小组的负责人 Sangeeta Bhatia 说，新模型可以产生无法从小鼠或其他动物的研究中收集到的信息，这些动物的生物学与人类不同。

“多年来，人们一直在识别似乎与小鼠肝脏再生有关的不同基因，其中一些似乎对人类很重要，但他们从未设法找出使人类肝细胞增殖的所有线索， ” Bhatia 说，他是麻省理工学院健康科学与技术、电气工程与计算机科学系 John 和 Dorothy Wilson 教授，也是麻省理工学院科赫综合癌症研究所和医学工程与科学研究所的成员。

本周发表在《美国国家科学院院刊》上的这项新研究已经确定了一种似乎发挥关键作用的分子，并且还产生了研究人员计划进一步探索的其他几个候选分子。

该论文的第一作者是前麻省理工学院研究生和博士后 Arnav Chhabra。

芯片再生

大多数需要肝移植的患者患有慢性疾病，例如病毒性肝炎、脂肪肝或癌症。然而，如果研究人员有一种可靠的方法来刺激肝脏自行再生，那么可以避免一些移植，Bhatia 说。或者，这种刺激可能被用来帮助捐赠的肝脏在移植后生长。

从对小鼠的研究中，研究人员对肝损伤或疾病后激活的一些再生途径有了很多了解。一个关键因素是肝细胞（肝脏中发现的主要细胞类型）和血管内皮细胞之间的相互关系。肝细胞产生有助于血管发育的因子，而内皮细胞产生有助于肝细胞增殖的生长因子。

研究人员发现的另一个因素是血管中的流体流动。在小鼠中，血流的增加可以刺激内皮细胞产生促进再生的信号。

为了模拟所有这些相互作用，Bhatia 的实验室与波士顿大学 William F. Warren 生物医学工程杰出教授 Christopher Chen 合作，他设计了具有模拟血管通道的微流体装置。为了创建这些“芯片上的再生”模型，研究人员沿着这些微流体通道之一生长血管，然后添加来自人体器官供体的肝细胞的多细胞球状聚集体。

该芯片的设计使得生长因子等分子可以在血管和肝球体之间流动。这种设置还允许研究人员轻松敲除特定细胞类型中感兴趣的基因，然后查看它如何影响整个系统。

使用该系统，研究人员表明，增加的流体流动本身并不会刺激肝细胞进入细胞分裂周期。然而，如果它们也传递炎症信号（细胞因子 IL-1-β），肝细胞确实进入了细胞周期。

当这种情况发生时，研究人员能够测量正在产生的其他因素。一些是基于早期的小鼠研究预期的，但其他一些以前在人类细胞中从未见过，包括一种称为前列腺素 E2 (PGE2) 的分子。

麻省理工学院的团队在他们的肝脏再生系统中发现了高水平的这种分子，这种分子也参与斑马鱼的再生。通过敲除内皮细胞中 PGE2 生物合成的基因，研究人员能够证明这些细胞是 PGE2 的来源，并且他们还证明了这种分子可以刺激人类肝细胞进入细胞周期。

人类特异性途径

研究人员现在计划进一步探索肝脏再生过程中芯片上产生的其他一些生长因子和分子。
“我们可以看看正在生产的蛋白质，然后问，这个名单上还有什么与刺激细胞分裂的其他分子具有相同的模式，但又是新的？”巴蒂亚说。 “我们认为我们可以利用它来发现新的人类特异性途径。”

在这项研究中，研究人员专注于刺激细胞进入细胞分裂的分子，但他们现在希望进一步跟踪这一过程并确定完成细胞周期所需的分子。他们还希望发现告诉肝脏何时停止再生的信号。

Bhatia 希望最终研究人员能够利用这些分子来帮助治疗肝功能衰竭患者。另一种可能性是，医生可以使用生物标志物等因素来确定患者肝脏自行再生的可能性。

“现在，当患者出现肝功能衰竭时，您必须将他们移植，因为您不知道他们是否会自行康复。但是，如果我们知道谁有强烈的再生反应，并且如果我们只需要让他们稳定一段时间，我们就可以让这些患者免于移植，”巴蒂亚说。

该研究部分由美国国立卫生研究院、美国国家科学基金会研究生研究奖学金计划、Wellcome Leap 以及保罗和黛西索罗斯奖学金计划资助。

StephenW

Tissue model reveals key players in liver regeneration
By tracing the steps of liver regrowth, MIT engineers hope to harness the liver’s regenerative abilities to help treat chronic disease.
Anne Trafton | MIT News Office
Publication Date:
June 27, 2022

The human liver has amazing regeneration capabilities: Even if up to 70 percent of it is removed, the remaining tissue can regrow a full-sized liver within months.

Taking advantage of this regenerative capability could give doctors many more options for treating chronic liver disease. MIT engineers have now taken a step toward that goal, by creating a new liver tissue model that allows them to trace the steps involved in liver regeneration more precisely than has been possible before.

The new model can yield information that couldn’t be gleaned from studies of mice or other animals, whose biology is not identical to that of humans, says Sangeeta Bhatia, the leader of the research team.

“For years, people have been identifying different genes that seem to be involved in mouse liver regeneration, and some of them seem to be important in humans, but they have never managed to figure out all of the cues to make human liver cells proliferate,” says Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science.

The new study, which appears this week in the Proceedings of the National Academy of Sciences, has identified one molecule that appears to play a key role, and also yielded several other candidates that the researchers plan to explore further.

The lead author of the paper is Arnav Chhabra, a former MIT graduate student and postdoc.

Regeneration on a chip

Most of the patients who need liver transplants suffer from chronic illnesses such as viral hepatitis, fatty liver disease, or cancer. However, if researchers had a reliable way to stimulate the liver to regenerate on its own, some transplants could be avoided, Bhatia says. Or, such stimulation might be used to help a donated liver grow after being transplanted.

From studies in mice, researchers have learned a great deal about some of the regeneration pathways that are activated after liver injury or illness. One key factor is the reciprocal relationship between hepatocytes (the main type of cell found in the liver) and endothelial cells, which line the blood vessels. Hepatocytes produce factors that help blood vessels develop, and endothelial cells generate growth factors that help hepatocytes proliferate.

Another contributor that researchers have identified is fluid flow in the blood vessels. In mice, an increase in blood flow can stimulate the endothelial cells to produce signals that promote regeneration.

To model all of these interactions, Bhatia’s lab teamed up with Christopher Chen, the William F. Warren Distinguished Professor of Biomedical Engineering at Boston University, who designs microfluidic devices with channels that mimic blood vessels. To create these models of “regeneration on a chip,” the researchers grew blood vessels along one of these microfluidic channels and then added multicellular spheroid aggregates derived from liver cells from human organ donors.

The chip is designed so that molecules such as growth factors can flow between the blood vessels and the liver spheroids. This setup also allows the researchers to easily knock out genes of interest in a specific cell type and then see how it affects the overall system.

Using this system, the researchers showed that increased fluid flow on its own did not stimulate hepatocytes to enter the cell division cycle. However, if they also delivered an inflammatory signal (the cytokine IL-1-beta), hepatocytes did enter the cell cycle.

When that happened, the researchers were able to measure what other factors were being produced. Some were expected based on earlier mouse studies, but others had not been seen before in human cells, including a molecule called prostaglandin E2 (PGE2).

The MIT team found high levels of this molecule, which is also involved in zebrafish regeneration, in their liver regeneration system. By knocking out the gene for PGE2 biosynthesis in endothelial cells, the researchers were able to show that those cells are the source of PGE2, and they also demonstrated that this molecule stimulates human liver cells to enter the cell cycle.

Human-specific pathways

The researchers now plan to further explore some of the other growth factors and molecules that are produced on their chip during liver regeneration.

“We can look at the proteins that are being produced and ask, what else on this list has the same pattern as the other molecules that stimulate cell division, but is novel?” Bhatia says. “We think we can use this to discover new human-specific pathways.”

In this study, the researchers focused on molecules that stimulate cells to enter cell division, but they now hope to follow the process further along and identify molecules needed to complete the cell cycle. They also hope to discover the signals that tell the liver when to stop regenerating.

Bhatia hopes that eventually researchers will be able to harness these molecules to help treat patients with liver failure. Another possibility is that doctors could use such factors as biomarkers to determine how likely it is that a patient’s liver will regrow on its own.

“Right now when patients come in with liver failure, you have to transplant them because you don’t know if they’re going to recover on their own. But if we knew who had a robust regenerative response, and if we just needed to stabilize them for a little while, we could spare those patients from transplant,” Bhatia says.

The research was funded in part by the National Institutes of Health, the National Science Foundation Graduate Research Fellowship Program, Wellcome Leap, and the Paul and Daisy Soros Fellowship Program.

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