(糖尿病新藥) 血管類器官 (vessel organoids ) 基底增厚 γ-secretase抑制劑

首次！科學家在實驗室中培育出人類血管「類器官」 北京新浪網 (2019-01-21 08:57) 新浪科技訊 日期:1月21日消息，據國外媒體報導，科學家首次成功在實驗室中培育出了「完美」的人類血管。這項突破將對多種血管疾病的研究產生重大影響，其中也包括糖尿病在內，可以讓研究人員更加輕鬆便捷地測試新型藥物。 「能夠從幹細胞逐步培育出人類血管具有重大意義。」該研究高級作者、英屬哥倫比亞大學生命科學研究所主任約瑟夫•佩寧格（Josef Penninger）指出，「人體中的每個器官都與循環系統息息相關。這一突破有望幫助研究人員找到多種血管疾病的原因和療法，如阿爾茨海默症、心血管疾病、傷口愈合問題、中風、癌症、當然還有糖尿病。」佩寧格和同事們研究出了一種方法，可以在培養皿中培育出三維人類血管「類器官」。類器官是指從幹細胞培育而來、模擬某種器官的三維結構，可以讓研究人員在培養皿中分析該人體器官的特定方面。這些所謂「血管類器官」也是用幹細胞在實驗室中培育得來的，與真正的人類血管的結構與功能驚人地相似。研究人員將這種血管類器官移植到小鼠體內后，這些人造血管成功發育成了功能完好的血管，包括動脈和毛細血管。這一發現說明，我們不僅能在培養皿中用人類幹細胞培育出血管類器官，還能讓其在另一種生物體內發育為一套功能正常的人體血管系統。這一突破性技術已被發表在期刊《自然》上。該發現還為我們預防血管變化指明了一條新途徑。血管變化是糖尿病患者的主要死亡原因和病變癥狀之一。研究人員讓培養皿中的血管類器官暴露在「糖尿病環境」之中。「我們驚訝地發現，這些血管類器官的基底膜明顯增厚。這與糖尿病患者體內的血管損傷極為相似。」研究人員指出。接著，研究人員試圖尋找能夠阻止血管壁增厚的化學物質。結果發現，在現有的糖尿病藥物中，沒有一種對這類血管問題有效，不過，他們發現人體內一種名叫γ-secretase的酶能夠阻止血管壁增厚，說明該物質或許有助於治療糖尿病。研究人員認為，此次發現將幫助他們找到血管疾病的內在根源，或許還有助於研發和測試糖尿病新療法，「我們此次工作最令人激動之處在於，我們成功用幹細胞造出了真正的人類血管，」該研究的第一作者雷納•維默（Reiner Wimmer）表示，「我們造出的血管類器官與人體毛細血管極為相似，相近度甚至達到了分子級，如今我們可以利用這些人造血管，直接在人體組織上研究血管疾病。」（葉子）

'Game Changer': Researchers Can Now Grow Stable Blood Vessel Mini-Organs In the Lab Fiona McMillan Researchers have developed a way to grow stable, viable human blood vessels from stem cells in the lab. The study, published in the journal Nature, significantly advances research into vascular diseases like diabetes. Indeed, the researchers used the new method to identify a human protein that contributes to diabetes-associated vascular damage, and showed that blocking its function could potentially prevent such damage. Diabetes affects more than 420 million people around the world and its most serious complications arise from the vascular damage it causes. Specifically, diabetes patients are prone to a range of blood vessel changes, including abnormal thickening of blood vessel walls, loss of vascular cells, and disrupted cellular communication in blood vessels. Over time, this impairs circulation and can ultimately cut off the supply of nutrients and oxygen to cells and tissues in the body. This, in turn, can lead to myriad problems including blindness, kidney failure, strokes, heart damage and the need for amputations. To address this, Josef Penninger at the University of British Colombia and Reiner Wimmer at the Institute for Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), together with their colleagues, developed a way to use human pluripotent stem cells to grow self-organizing three-dimensional human blood vessel 'organoids' that mimic the structure and function of human blood vessels. These organoids, which were grown in a Petri dish in the lab, were then transplanted into mice, where they developed into stable, functional blood vessels, including capillaries and even arteries."What is so exciting about our work is that we were successful in making real human blood vessels out of stem cells," says Wimmer. "Our organoids resemble human capillaries to a great extent, even on a molecular level, and we can now use them to study blood vessel diseases directly on human tissue."

Diabetes in a dish To better understand how diabetes alters blood vessels, the researchers mimicked diabetic conditions by exposing the organoids to a high level of glucose, thus simulating hyperglycemia. They also added diabetes-associated cytokines, which are signaling molecules that trigger inflammation. Sure enough, the blood vessel walls began to thicken in response. "Surprisingly, we could observe a massive expansion of the basement membrane in the vascular organoids," said Wimmer. "This typical thickening of the basement membrane is strikingly similar to the vascular damage seen in diabetic patients." To see if they could prevent this from happening, they tested a range of chemical compounds including a number of anti-diabetic medications. While the anti-diabetic medications did not prevent blood vessel thickening, they found something that did. They discovered that a compound called DAPT was able to prevent blood vessel thickening in the organoids. DAPT is a known inhibitor of the enzyme γ—secretase, so it seems that this enzyme is playing a critical role in diabetic vascular damage. The question, then, is what exactly is it doing? After all, γ-secretase interacts with a number of different proteins. Penninger, Wimmer and their colleagues discovered that in diabetes-linked blood vessel damage, γ-secretase is interfering with a protein called NOTCH3. DAPT is able to rescue NOTCH3 by blocking γ-secretase activity. Taken together, the research reveals how this NOTCH3 pathway plays an important role in vascular health and susceptibility to vascular damage in diabetes. By extension, this reveals potential drug targets for treating such vascular damage. Moreover, the study demonstrates how these blood vessel organoids can advance research of vascular diseases."Being able to build human blood vessels as organoids from stem cells is a game changer," says Penninger. "Every single organ in our body is linked with the circulatory system. This could potentially allow researchers to unravel the causes and treatments for a variety of vascular diseases, from Alzheimer's disease, cardiovascular diseases, wound healing problems, stroke, cancer and, of course, diabetes."

Original research: Wimmer, R et al (2019) Human blood vessel organoids as a model of diabetic vasculopathy. Nature https://doi.org/10.1038/s41586-018-0858-8