Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Deciphering diabetes with "game-changing" human blood vessels from stem cells

17.01.2019

Changes in blood vessels are the major cause of death and morbidity in diabetes. For the first time, scientists managed to grow perfect human blood vessels as organoids in a petri dish. This breakthrough engineering technology dramatically advances research of vascular dysfunction in diseases like diabetes, identifying a key pathway that prevents diabetic vasculopathy, as reported in the current issue of Nature.

Diabetes is increasing at an alarming rate worldwide, already affecting at least 420 million people. Another 500 million people are estimated to be pre-diabetic.


Diabetic blood vessel changes in patients and human vascular organoids The basement membrane (green) around the blood vessels (red) is massively enlarged in diabetic patients (white arrows).

(c)IMBA


Vascular Organoid, illustration based on original data. These lab-made blood vessels recapitulate human capillaries.

(c)IMBA

The global costs of diabetes, which can lead to blindness, kidney failure, heart attacks, stroke or lower limb amputation, is estimated to be 825 billion dollars per year. Many of these diabetic symptoms are the consequence of changes in blood vessels, resulting in impaired blood circulation and oxygen supply of tissues.

Despite its prevalence, very little is known about the vascular changes arising from diabetes - in part because we lack human model systems that fully recapitulate these changes. This limitation has stymied the development of much needed therapeutics.

Engineering human blood vessels from stem cells

To tackle this problem, Josef Penninger and Reiner Wimmer at IMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, established a groundbreaking model: self-organizing, three-dimensional (3D) human blood vessel organoids grown in a Petri dish.

These so called vascular organoids can be robustly cultivated from induced pluripotent stem (iPS) cells in the lab, strikingly mimicking the structure and function of human blood vessels. ”What is so exciting about our work is that we were successful in making real human blood vessels out of stem cells.

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, “ says Reiner Wimmer, Postdoc at IMBA, the first and co-corresponding author of the paper.

Capillary blood vessels, the smallest branches of the vascular system, are in every organ of our body. These delicate vessels ,with a diameter of 5-10 micrometer, are coated by a structure called basement membrane that gives the blood vessels important physical support.

“Blood vessels are not just the smallest capillaries. Our entire body is nurtured by a huge vascular tree consisting of larger blood vessels that bring blood to organs, so called arteries, capillaries where blood flow slows down and oxygen exchange happens, and veins that recirculate the blood back to the lungs and heart”, says lead author Josef Penninger.

“To experimentally model such an intricate human vascular tree was in essence impossible, and many aspects of human blood vessel disease do not occur in our mouse models.”

When the researchers transplanted the human blood vessel organoids into immunodeficient mice, they gained access to their circulatory system and specified into perfectly functional human blood vessels including arteries, capillaries and venules in vivo. Thus, it is possible to not only engineer blood vessel organoids from human stem cells in a dish, but also to grow a functional human vascular tree in another species.

Mimicking diabetes in a dish with “vascular” organoids

One of the pathogenic feature of diabetes is that blood vessels show an abnormal thickening of the basement membrane. As a result, the delivery of oxygen and nutrients to cells and tissues is strongly impaired, causing a multitude of health problems, such as kidney failure, heart attacks, strokes, blindness, and peripheral artery disease, leading to amputations.

To recapitulate this pathological condition in a dish, the research team exposed the blood vessel organoids to a “diabetic” environment. “Surprisingly, we could observe a massive expansion of the basement membrane in the vascular organoids.

This typical thickening of the basement membrane is strikingly similar to the vascular damage seen in diabetic patients”, says Wimmer. “Such thickening of the blood vessel walls appears to only occur when there is an intricate and very close contact between the different cell types, endothelial cells and pericytes, that make up capillaries.”

As a next step, the scientists searched for chemical compounds that could block development of the pathological phenotype in the “diabetic” lab grown vessels. They screened current anti-diabetic medications, none of which had any positive effects on these blood vessel defects, as well as multiple small-molecule inhibitors of different signaling pathways.

They discovered that an inhibitor of γ-secretase could completely prevent the diabetic vasculopathies in organoids. They went on to show that the γ-secretase target Notch3 and its ligand Dll4 are key mediators of basement membrane thickening in diabetic organoids. The authors also found evidence of elevated Notch3 activity in skin blood vessel biopsies from diabetic patients.

Finally they modelled diabetic vasculopathy in diabetic mice, that where transplanted with stem cell-derived human vascular organoids and carry a functional human blood vessel tree. Intriguingly in diabetic mice, the human blood vessels showed prototypic pathologies, whereas the mouse blood vessels remained normal.

Blocking γ-secretase or, in first studies, Notch3, could prevent the diabetic vasculopathies of the human blood vessels in the chimeric mice. “Mouse genetics has taught us a lot about disease mechanisms, however some aspects of human disease, such as diabetic blood vessel changes, cannot be modelled well in mice” says Dontscho Kerjaschki, a pathologist of the Medical University of Vienna who was involved in the study.

“Now we can model it! This allows us to identify underlying disease mechanisms and hopefully develop and test new medicines for hundreds of millions of patients with diabetes.”

“Every single organ in our body is linked with the circulatory system, and the formation of new blood vessels is a key feature for cancers to grow. There are also many rare diseases that affect blood vessels and for instance lead to strokes and heart attacks in young people” says Penninger, founding director of IMBA, and recently appointed director of the Life Science Institute of the University of British Columbia, who is the lead author of the paper.

“Vascular organoids generated from iPS cells represent a game-changing model - allowing us to unravel etiologies and treatments for a broad spectrum of vascular diseases, ranging from diabetes, Alzheimer’s disease, cardiovascular diseases, wound healing, or stroke, to cancer”.

Video Abstract: https://youtu.be/MEKdEDcA2ok
Images: https://www.imba.oeaw.ac.at/about-imba/information-material-download/

Originalpublikation:

Reiner A. Wimmer, et. al. Human blood vessel organoids as a model of diabetic vasculopathy.
Nature 2019, DOI 10.1038/s41586-018-0858-8
https://doi.org/10.1038/s41586-018-0858-8

Weitere Informationen:

http://www.imba.oeaw.ac.at/research-highlights/deciphering-diabetes-with-game-ch...
https://www.imba.oeaw.ac.at/about-imba/information-material-download/

Mag. Evelyn Devuyst | idw - Informationsdienst Wissenschaft

More articles from Life Sciences:

nachricht Platinum nanoparticles for selective treatment of liver cancer cells
15.02.2019 | ETH Zurich

nachricht New molecular blueprint advances our understanding of photosynthesis
15.02.2019 | DOE/Lawrence Berkeley National Laboratory

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Regensburg physicists watch electron transfer in a single molecule

For the first time, an international team of scientists based in Regensburg, Germany, has recorded the orbitals of single molecules in different charge states in a novel type of microscopy. The research findings are published under the title “Mapping orbital changes upon electron transfer with tunneling microscopy on insulators” in the prestigious journal “Nature”.

The building blocks of matter surrounding us are atoms and molecules. The properties of that matter, however, are often not set by these building blocks...

Im Focus: University of Konstanz gains new insights into the recent development of the human immune system

Scientists at the University of Konstanz identify fierce competition between the human immune system and bacterial pathogens

Cell biologists from the University of Konstanz shed light on a recent evolutionary process in the human immune system and publish their findings in the...

Im Focus: Transformation through Light

Laser physicists have taken snapshots of carbon molecules C₆₀ showing how they transform in intense infrared light

When carbon molecules C₆₀ are exposed to an intense infrared light, they change their ball-like structure to a more elongated version. This has now been...

Im Focus: Famous “sandpile model” shown to move like a traveling sand dune

Researchers at IST Austria find new property of important physical model. Results published in PNAS

The so-called Abelian sandpile model has been studied by scientists for more than 30 years to better understand a physical phenomenon called self-organized...

Im Focus: Cryo-force spectroscopy reveals the mechanical properties of DNA components

Physicists from the University of Basel have developed a new method to examine the elasticity and binding properties of DNA molecules on a surface at extremely low temperatures. With a combination of cryo-force spectroscopy and computer simulations, they were able to show that DNA molecules behave like a chain of small coil springs. The researchers reported their findings in Nature Communications.

DNA is not only a popular research topic because it contains the blueprint for life – it can also be used to produce tiny components for technical applications.

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Global Legal Hackathon at HAW Hamburg

11.02.2019 | Event News

The world of quantum chemistry meets in Heidelberg

30.01.2019 | Event News

Our digital society in 2040

16.01.2019 | Event News

 
Latest News

Gravitational waves will settle cosmic conundrum

15.02.2019 | Physics and Astronomy

Spintronics by 'straintronics'

15.02.2019 | Physics and Astronomy

Platinum nanoparticles for selective treatment of liver cancer cells

15.02.2019 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>