Scientists have managed to grow perfect human blood vessels as organoids in a petri dish for the first time. The breakthrough engineering technology dramatically advances research of vascular diseases like diabetes, identifying a key pathway to potentially prevent changes to blood vessels – A major cause of death and morbidity among those with diabetes.
An organoid is a three-dimensional structure grown from stem cells that mimics an organ and can be used to study aspects of that organ in a petri dish.
“Being able to build human blood vessels as organoids from stem cells is a game changer,” said the study’s senior author Josef Penninger, the Canada 150 Research chair in functional genetics, director of the Life Sciences Institute at the University of British Columbia (UBC) and founding director of the Institute for Molecular Biotechnology of the Austrian Academy of Sciences (IMBA).
“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.”
Diabetes affects an estimated 420m people worldwide. Many diabetic symptoms are the result of changes in blood vessels that result in impaired blood circulation and oxygen supply of tissues. Despite its prevalence, very little is known about the vascular changes arising from diabetes. This limitation has slowed the development of much-needed treatment.
To tackle this problem, Penninger and his colleagues developed a ground-breaking model: three-dimensional human blood vessel organoids grown in a petri dish. These so-called “vascular organoids” can be cultivated using stem cells in the lab, strikingly mimicking the structure and function of real human blood vessels.
When researchers transplanted the blood vessel organoids into mice, they found that they developed into perfectly functional human blood vessels including arteries and capillaries. The discovery illustrates that 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 system in another species.
“What is so exciting about our work is that we were successful in making real human blood vessels out of stem cells,” said Reiner Wimmer, the study’s first author and a postdoctoral research fellow at IMBA. “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.”
One 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.
The researchers then exposed the blood vessel organoids to a “diabetic” environment in a petri dish. “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.”
The researchers then searched for chemical compounds that could block thickening of the blood vessel walls. They found none of the current anti-diabetic medications had any positive effects on these blood vessel defects. However, they discovered that an inhibitor of ?-secretase, a type of enzyme in the body, prevented the thickening of the blood vessel walls, suggesting, at least in animal models, that blocking ?-secretase could be helpful in treating diabetes.
The researchers say the findings could allow them to identify underlying causes of vascular disease, and to potentially develop and test new treatments for patients with diabetes.
The increasing prevalence of diabetes has resulted in a global epidemic1. Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and amputation of lower limbs. These are often caused by changes in blood vessels, such as the expansion of the basement membrane and a loss of vascular cells2,3,4. Diabetes also impairs the functions of endothelial cells5 and disturbs the communication between endothelial cells and pericytes6. How dysfunction of endothelial cells and/or pericytes leads to diabetic vasculopathy remains largely unknown. Here we report the development of self-organizing three-dimensional human blood vessel organoids from pluripotent stem cells. These human blood vessel organoids contain endothelial cells and pericytes that self-assemble into capillary networks that are enveloped by a basement membrane. Human blood vessel organoids transplanted into mice form a stable, perfused vascular tree, including arteries, arterioles and venules. Exposure of blood vessel organoids to hyperglycaemia and inflammatory cytokines in vitro induces thickening of the vascular basement membrane. Human blood vessels, exposed in vivo to a diabetic milieu in mice, also mimic the microvascular changes found in patients with diabetes. DLL4 and NOTCH3 were identified as key drivers of diabetic vasculopathy in human blood vessels. Therefore, organoids derived from human stem cells faithfully recapitulate the structure and function of human blood vessels and are amenable systems for modelling and identifying the regulators of diabetic vasculopathy, a disease that affects hundreds of millions of patients worldwide.
Reiner A Wimmer, Alexandra Leopoldi, Martin Aichinger, Nikolaus Wick, Brigitte Hantusch, Maria Novatchkova, Jasmin Taubenschmid, Monika Hämmerle, Christopher Esk, Joshua A Bagley, Dominik Lindenhofer, Guibin Chen, Manfred Boehm, Chukwuma A Agu, Fengtang Yang, Beiyuan Fu, Johannes Zuber, Juergen A Knoblich, Dontscho Kerjaschki, Josef M Penninger