blood vessels

One day, scientists could grow the human cardiovascular system from stem cells

/ Karen Ring / Leave a comment

The human cardiovascular system is an intricate, complex network of blood vessels that include arteries, capillaries and veins. These structures distribute blood from the heart to all parts of the body, from our head to our toes, and back again.

This week, two groups of scientists published studies showing that they can create key components of the human cardiovascular system from human pluripotent stem cells. These technologies will not only be valuable for modeling the cardiovascular system, but also for developing transplantable tissues to treat patients with cardiovascular or vascular diseases.

Growing capillaries using 3D printers

Scientists from Rice University and the Baylor College of Medicine are using 3D printers to make functioning capillaries. These are tiny, thin vessels that transport blood from the arteries to the veins and facilitate the exchange of oxygen, nutrients and waste products between the blood and tissues. Capillaries are made of a single layer of endothelial cells stitched together by cell structures called tight junctions, which create an impenetrable barrier between the blood and the body.

In work published in the journal Biomaterials Science, the scientists discovered two materials that coax human stem cell-derived endothelial cells to develop into capillary-like structures. They found that adding mesenchymal stem cells to the process, improved the ability of the endothelial cells to form into the tube-like structures resembling capillaries. Lead author on the study, Gisele Calderon, explained their initial findings in an interview with Phys.org,

“We’ve confirmed that these cells have the capacity to form capillary-like structures, both in a natural material called fibrin and in a semisynthetic material called gelatin methacrylate, or GelMA. The GelMA finding is particularly interesting because it is something we can readily 3-D print for future tissue-engineering applications.”

Scientists grow capillaries from stem cells using 3D gels. (Image Credit: Jeff Fitlow/Rice University)

The team will use their 3D printing technology to develop more accurate models of human tissues and their vast network of capillaries. Their hope is that these 3D printed tissues could be used for more accurate drug testing and eventually as implantable tissues in the clinic. Co-senior author on the study, Jordan Miller, summarized potential future applications nicely.

“Ultimately, we’d like to 3D print with living cells … to create fully vascularized tissues for therapeutic applications. You could foresee using these 3D printed tissues to provide a more accurate representation of how our bodies will respond to a drug. The potential to build tissue constructs made from a particular patient represents the ultimate test bed for personalized medicine. We could screen dozens of potential drug cocktails on this type of generated tissue sample to identify candidates that will work best for that patient.”

Growing functioning arteries

In a separate study published in the journal PNAS, scientists from the University of Wisconsin-Madison and the Morgridge Institute reported that they can generate functional arterial endothelial cells, which are cells that line the insides of human arteries.

The team used a lab technique called single-cell RNA sequencing to identify important signaling factors that coax human pluripotent stem cells to develop into arterial endothelial cells. The scientists then used the CRISPR/Cas9 gene editing technology to develop arterial “reporter cell lines”, which light up like Christmas trees when candidate factors are successful at coaxing stem cells to develop into arterial endothelial cells.

Arterial endothelial cells derived from human pluripotent stem cells. (The Morgridge Institute for Research)

Using this two-pronged strategy, they generated cells that displayed many of the characteristic functions of arterial endothelial cells found in the body. Furthermore, when they transplanted these cells into mice that suffered a heart attack, the cells helped form new arteries and improved the survival rate of these mice significantly. Mice who received the transplanted cells had an 83% survival rate compared to untreated mice who only had a 33% survival rate.

In an interview with Genetic Engineering & Biotechnology News, senior author on the study James Thomson, explained the significance of their findings,

“Our ultimate goal is to apply this improved cell derivation process to the formation of functional arteries that can be used in cardiovascular surgery. This work provides valuable proof that we can eventually get a reliable source for functional arterial endothelial cells and make arteries that perform and behave like the real thing.”

In the future, the scientists have set their sights on developing a universal donor cell line that can treat large populations of patients without fear of immune rejection. With cardiovascular disease being the leading cause of death around the world, the demand for such a stem cell-based therapy is urgent.

Stem cell-derived blood-brain barrier gives more complete picture of Huntington’s disease

/ Todd Dubnicoff / Leave a comment

Like a sophisticated security fence, our bodies have evolved a barrier that protects the brain from potentially harmful substances in the blood but still allows the entry of essential molecules like blood sugar and oxygen. Just like in other parts of the body, the blood vessels and capillaries in the brain are lined with endothelial cells. But in the brain, these cells form extremely tight connections with each other making it nearly impossible for most things to passively squeeze through the blood vessel wall and into the brain fluid.

BloodBrainBarrier

Compared to blood vessels in other parts of the body, brain blood vessels form a much tighter seal to protect the brain.
Image source: Dana and Chris Reeve Foundation

Recent studies have shown defects in the brain-blood barrier are associated with neurodegenerative disorders like Huntington’s disease and as a result becomes leakier. Although the debilitating symptoms of Huntington’s disease – which include involuntary movements, severe mood swings and difficulty swallowing – are primarily due to the gradual death of specific nerve cells, this breakdown in the blood-brain barrier most likely contributes to the deterioration of the Huntington’s brain.

What hasn’t been clear is if mutations in Huntingtin, the gene that is linked to Huntington’s disease, directly impact the specialized endothelial cells within the blood-brain barrier or if these specialized cells are just innocent bystanders of the destruction that occurs as Huntington’s progresses. It’s an important question to answer. If the mutations in Huntingtin directly affect the blood-brain barrier then it could provide a bigger picture of how this incurable, fatal disease works. More importantly, it may provide new avenues for therapy development.

A UC Irvine research team got to the bottom of this question with the help of induced pluripotent stem cells (iPSCs) derived from the skin cells of individuals with Huntington’s disease. Their CIRM-funded study was published this week in Cell Reports.

In a first for a neurodegenerative disease, the researchers coaxed the Huntington’s disease iPSCs in a lab dish to become brain microvascular endothelial cells (BMECs), the specialized cells responsible for forming the blood-brain barrier. The researchers found that the Huntington’s BMECs themselves were indeed dysfunctional. Compared to BMECs derived from unaffected individuals, the Huntington’s BMECs weren’t as good at making new blood vessels, and the vessels they did make were leakier. So the Huntingtin mutation in these BMECs appears to be directly responsible for the faulty blood-brain barrier.

The team dug deeper into this new insight by looking for possible differences in gene activity between the healthy and Huntington’s BMECs. They found that the Wnt group of genes, which plays an important role in the development of the blood-brain barrier, are over active in the Huntington’s BMECs. This altered Wnt activity can explain the leaky defects. In fact, the use of a drug inhibitor of Wnt fixed the defects. Dr. Leslie Thompson, the team lead, described the significance of this finding in a press release:

“Now we know there are internal problems with blood vessels in the brain. This discovery can be used for possible future treatments to seal the leaky blood vessels themselves and to evaluate drug delivery to patients with HD.”

151117_lesliethompson_05_sz-1080x720

Study leader, Leslie Thompson. Steve Zylius / UCI

A companion Cell Stem Cell report, also published this week, used the same iPSC-derived blood-brain barrier system. In that study, researchers at Cedars-Sinai pinpointed BMEC defects as the underlying cause of Allan-Herndon-Dudley syndrome, another neurologic condition that causes mental deficits and movement problems. Together these results really drive home the importance of studying the blood-brain barrier function in neurodegenerative disease.

Dr. Ryan Lim, the first author on the UC Irvine study, also points to a larger perspective on the implications of this work:

“These studies together demonstrate the incredible power of iPSCs to help us more fully understand human disease and identify the underlying causes of cellular processes that are altered.”

Scientists use cotton candy to make artificial blood vessels

/ Karen Ring / Leave a comment

Cotton candy gets a bad rap. The irresistible, brightly colored cloud of sugar is notorious for sending kids into hyperactive overdrive and wreaking havoc on teeth. While it’s most typically found at a state fair or at a sports stadium, cotton candy is now popping up at the lab bench and is re-branding itself into a useful tool that will help scientists develop artificial blood vessels for lab-grown organs.Pink_and_blue_cotton_candy

How is this sticky, sweet substance transitioning from stomachs to the lab? The answer comes from a Professor at Vanderbilt University, Dr. Leon Bellan. He develops 3D microfluidic materials for biomedical applications. Recently he and his students have tackled an obstacle that has plagued the fields of tissue engineering and 3D organ modeling – making enough blood vessels to keep engineered organs alive. The story was covered by the blog Inhabitat.

Scientists are using 3D organoids or “mini-organs” derived from stem cells to model organ development and human disease in a dish. While methods to make organoids have advanced to the point where various cell types of an organ are generated, these organoids do not develop a proper capillary system – a distribution of blood vessels that allows blood to bring water, oxygen and nutrients to tissue cells. Inevitably, cells located in the center of organoids die because they don’t have access to life-saving nutrients that the cells at the surface do.

Spinning cotton candy in the lab.

Bellan lab member spins cotton candy in the lab.

Bellan came up with a sweet solution to this problem. His team discovered that you can use cotton candy to make an artificial capillary system. Conveniently, the strands of cotton candy are similar in size to human blood vessels. Bellan and his team “spin” cotton candy fibers to generate a network of sugar strands that are held in place with a special polymer. Then, they pour a gelatinous mold over the strands, let that harden, and dissolve the sugar with an enzyme solution. What’s left is an intricate network of channels that are similar to the human capillary system.

Free of cotton candy, these artificial channels are now ready to be turned into functioning human capillaries. Bellan and his team were able to grow human endothelial cells (the cells that line your blood vessels) in these channels. The cells in these artificial blood vessels are able to survive for over a week.

cotton-candy-capillaries01-889x430

Gelatin mold with cotton candy made channels.

Their work is still preliminary but Bellan is excited about their technology’s potential for tissue engineering applications. In a video interview, he explained:

Leon Bellan. Photo by Joe Howell

Leon Bellan.
(Photo by Joe Howell)

“We’re really try to attack a fundamental hurdle for the entire field. The sci-fi version would be that you would like to be able to build an organ from scratch.”

 

Hopefully, Bellan and his group will be able to turn their sweet dream into a reality and help scientists develop properly functioning artificial organs that can be transplanted into humans.

To learn more about this fascinating technique, check out this video:

Related links: