Staff Writer

Mouse models are notoriously difficult to translate into a better understanding of disease mechanisms in humans. They haven't proven particularly useful in understanding diabetes and the vascular problems tied to it that result in serious complications in the limb and eye vasculature that can lead to pain, non-healing wounds, blindness and even amputation.

Now, researchers have been able to manipulate stem cells to grow into human blood vessels in a petri dish for the first time. They were then able to implant those blood vessels into mice and they became fully functional human blood vessels, including arteries and capillaries. They reported their results in the Jan. 16, 2019, issue of Nature.

First vessels

"One of the key tissues in our body, of course, are blood vessels which nurture everything and transport blood and oxygen to every tissue and are involved in basically every disease from Alzheimer's to dementia to cancer and diabetes," 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), explained to BioWorld MedTech.

"Many people tried, but no one could make perfect human blood vessels with the lumen, structural cells around it and the membrane around it. We set about to accomplish this and after many, many years of trying we finally succeeded, which we now reported in Nature. This was one of the big prizes left in tissue engineering in humans," he added.

Penninger noted that organoids, tiny versions of functioning human organs that are induced to grow in the petri dish, have made rapid advancements in recent years. His own prior work was to help create the first brain organoids. This human blood vessel achievement was the culmination of several teams at different academic institutions racing to reach the finish line first.

New diabetes model

The researchers exposed the blood vessels in the petri dish and in mice to an environment approximating diabetes that included hyperglycemia and inflammatory cytokines. The treatment induced a thickening of the vascular basement membrane that is characteristic in diabetes and results in impaired circulation and a reduced oxygen supply in tissue.

In the mice, microvascular changes that typically occur in diabetes patients were seen. The scientists were able to establish DLL4 and NOTCH3 proteins as causes of diabetic vasculopathy in these human blood vessels – and to identify an inhibitor of γ-secretase as potentially useful in preventing the thickening of the blood vessel walls.

Summed up the paper abstract, "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."

An estimated 420 million people globally have diabetes, with likely hundreds of millions more in a prediabetic state. This research could enable scientists to directly treat the most severe patients with vascular damage, as well as offer them a new model to develop preventative and treatment approaches.

The next steps for the research are to transplant human blood vessels into humans – and to continue to develop these organoid human blood vessels as models for drug development that can be used to better understand the wide variety of diseases involving the vasculature. Penninger expects that the former process will be more straightforward, while the latter likely will involve a longer timeline.

"We can use this to have a much, much better model for drug testing. Another thing we were thinking about is to take the blood vessel organs that we make in the petri dish and transplant them directly into non-healing wounds in humans," said Penninger. "To basically give patients with bad blood vessels, healthy young blood vessels back and maybe the wounds would heal faster. I would really like to see this translated into biotech and new medicines. Of course this will take awhile, but I am committed to doing it."

"I would really like to move this along, because it needs to do proper development drug testing in patients, obviously. I want to move fast," Penninger added. "Maybe this transplant in non-healing wounds of our organoids could be in patients relatively fast; drug development, of course, will take longer and needs proper and careful drug testing and clinical trials."

Factor stages

Until now, it was impossible to make a blood vessel that had precisely the right structures: a tube with an empty lumen in the middle, with endothelium around it, with structural support and a membrane around it to keep it all together.

These researchers took human stem cells, moved them along in embryonic development and at certain stages gave them particular growth factors to drive them into forming blood vessels. It took years to figure out the precise stages when to do so, said Penninger. He expects that the methodology developed in his lab will be easily reproducible elsewhere.

He estimated that about 60 percent to 70 percent of the pathology in diabetes is due to the thickening of blood vessel membranes, which then causes them to get leaky and leads to various complications including non-healing wounds, diabetic retinopathy, stroke and heart attack.

The researchers did not necessarily expect the blood vessels to develop into functional tissue within the mice – or to respond in a manner comparable to the state seen in patients with diabetes to similar conditions in the petri dish and in mice.

"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."

"Surprisingly, we could observe a massive expansion of the basement membrane in the vascular organoids," he added. "This typical thickening of the basement membrane is strikingly similar to the vascular damage seen in patients [with diabetes]."

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