Compound from Sully Putty Might Advance Neural Stem Cell Therapies


According to a University of Michigan engineering team, human pluripotent stem cells differentiate differently in response to the sponginess of the surface upon which they grow.

University of Michigan assistant professor of mechanical engineering, Jianping Fu, and his colleagues, efficiently directed human embryonic stem cells to differentiate into working spinal cord cells by growing the cells on a carpet of poly(dimethylsiloxane), which is one of the main ingredients in the toy known as “Silly Putty.” This study established the importance of physical signals in the control of stem cell differentiation.

According to Fu, these data could be the beginning of a series of investigations that uncovers the most efficient way to guide pluripotent stem cells to differentiate into nervous tissues that can be used to replace diseased cells in patients with Alzheimer’s disease, Huntington’s disease or amyotrophic lateral sclerosis (Lou Gehring’s disease).

In Fu’s system, he and his co-workers engineered the poly(dimethylsiloxane) carpets by using this compound to form fine threads that were strung between microscopic posts. By varying the height of the posts, Fu discovered that he could vary the stiffness of the surface. Shorter posts gave a more rigid, stiff carpet and longer posts gave softer more plush carpets.

When embryonic stem cells were grown on poly(dimethylsiloxane) carpet strung between tall posts, they differentiated into neurons much more quickly and at a higher percentage than when they were grown on the more rigid and stiffer poly(dimethylsiloxane) carpets.  After 23 days, colonies of spinal cord motor neurons that control how muscles move grew on the softer micropost carpets.  These cell assemblages were four times more pure and 10 times larger than those growing on either traditional plates or rigid carpets.

“To realize promising clinical applications of human embryonic stem cells, we need a better culture system that can reliably produce more target cells that function well,” said Fu.  He added: “Our approach is a big step in that direction, by using synthetic micro-engineered surfaces to control mechanical environmental signals.”

Fu is presently collaborating with U-M Medical School professor of neurology, Eva Feldman.  Dr. Feldman is an expert in amyotrophic lateral sclerosis (ALS), and firmly believes in the power of stem cells to help ALS patients grow new stem cells that can replace the diseased, death or damaged nerve cells.  Feldman is also applying Fu’s ingenious technique to make neurons from a patient’s own cells.  Mind you, these results are purely exploratory at this point, since Feldman simply wants to determine the feasibility of this procedure.

Even if this technique does not pan out for regenerative treatments, it provides a very workable model system to study the electrical behavior of neurons from ALS patients in comparison to neurons from non-ALS individuals.

Fu’s system also has identified a cell signaling pathway that is involved in the regulation of mechanically sensitive behaviors.  This signaling pathway – the Hippo/Yap pathway – is also involved in controlling organ size and suppression of tumor formation.

Corresponding proteins in Drosophila and mammals are shown in the same colours. When organs are growing (Hippo pathway OFF), nuclear Yki/Yap binds to unknown DNA-binding factor(s) X and regulates the transcription of growth targets. When organs have reached the correct size (ON), the Hippo signalling pathway is activated (unknown ligand Y–Fat– Merlin–Expanded–Hippo interactions, in the Drosophila case; ligand Y–FatJ–NF2–FDM6–Mst½–Lats½ in mammals), and Yki and YAP is inactivated by localizing to the cytoplasm in response to Wts phosphorylation and 14-3-3 binding. ? indicates regulatory relationships that still need to be investigated. Figure adapted from reference 2.
Corresponding proteins in Drosophila and mammals are shown in the same colors. When organs are growing (Hippo pathway OFF), nuclear Yki/Yap binds to unknown DNA-binding factor(s) X and regulates the transcription of growth targets. When organs have reached the correct size (ON), the Hippo signalling pathway is activated (unknown ligand Y–Fat– Merlin–Expanded–Hippo interactions, in the Drosophila case; ligand Y–FatJ–NF2–FDM6–Mst½–Lats½ in mammals), and Yki and YAP is inactivated by localizing to the cytoplasm in response to Wts phosphorylation and 14-3-3 binding. ? indicates regulatory relationships that still need to be investigated. Figure adapted from reference 2.

The work of Fu and Feldman could certainly provide significant advances in our understanding of how pluripotent stem cells differentiate in the body.  This work also suggests that physical signals are important in patterning the nervous system, especially since the cells of the nervous system become specialized for specific tasks according to their physical location within the body and nervous system in general.

Baby from Ohio Saved With An Airway Splint Made by A 3-D Printer


A baby boy from Ohio, Kaiba (KEYE’-buh) Gionfriddo, was born with a trachea (windpipe) that was fragile and kept collapsing. Without precious oxygen, he choked and passed out. Even though the physicians attending him thought about using an airway splint to open his airway, they had yet to implant it. Kaiba was not getting any better, and without a way to get him the oxygen that his little body desperately needed, he did not have much time. All he could do was lie in a hospital bed on a breathing machine.

Kaiba Gionfriddo

To solve this problem, the doctors used plastic particles and a 3-D laser printer to generate an airway splint to deliver oxygen to his lungs. This is a technological first and is the latest advance in the quickly advancing field of regenerative medicine that tries to make human body parts in the lab.

The even more stupendous aspect of this feat is that the production of the tracheal tube only too k one day. Yes, in a single day they “printed out” 100 tiny tubes by employing computer-guided lasers to stack and fuse thin layers of plastic to form various shapes and sizes. The next day, with special permission from the US Food and Drug Administration, they implanted one of these tubes in Kaiba. Needless to say, this is the first time such a treatment has even been done.

Suddenly, Kaiba, whom doctors said would probably never leave the hospital alive, could breathe normally for the first time. Kaiba was 3 months old when the operation was done last year and is nearly 19 months old now. He is about to have his tracheotomy tube removed since it was placed in his throat when he was a couple of months old. He no longer needs a breathing machine and has had not had a single breathing crisis since coming home a year ago.

“He’s a pretty healthy kid right now,” says Dr. Glenn Green, a pediatric ear, nose and throat specialist at C.S. Mott Children’s Hospital of the University of Michigan in Ann Arbor, where the operation was done. This remarkable feat of tissue engineering is described in the New England Journal of Medicine.

Independent experts have highly praised this and the potential 3-D printing provides for creating and quickly manufacturing body parts to solve unmet medical needs.

“It’s the wave of the future,” says Dr. Robert Weatherly, a pediatric specialist at the University of Missouri in Kansas City. “I’m impressed by what they were able to accomplish.”

So far, only a few adults have had trachea, or windpipe transplants, and these are usually used to replace windpipes destroyed by cancer. The windpipes came from dead donors or were lab-made, sometimes using stem cells. Last month, a 2-year-old girl born without a windpipe received one grown from her own stem cells on a plastic scaffold at a hospital in Peoria, Ill.

Kaiba, however, had a different problem; namely an incompletely formed bronchus. The bronchi are the tubes that branch from the windpipe to the lungs. Approximately 2,000 babies are born with such defects each year in the United States and most outgrow them by age 2 or 3, as they grow and mature and their respiratory tract replaces the lost tissues.

In severe cases, parents learn of the defect when the child suddenly stops breathing and dies. That almost happened when Kaiba was 6 weeks old at a restaurant with his parents, April and Bryan Gionfriddo, who live in Youngstown, in northeast Ohio. “He turned blue and stopped breathing on us,” and his father did CPR to revive him, April Gionfriddo says.

More episodes followed, and Kaiba had to go on a breathing machine when he was 2 months old. Doctors told the couple his condition was grave. “Quite a few of them says he had a good chance of not leaving the hospital alive. It was pretty scary,” his mother says. “We pretty much prayed every night, hoping that he would pull through.”

Fortunately a physician at Akron Children’s Hospital named Dr. Marc Nelson suggested the experimental work in Michigan in which researchers were testing airway splints made from biodegradable polyester that are sometimes used to repair bone and cartilage.

Kaiba had the operation on Feb. 9, 2012. The splint was placed around his defective bronchus, which was stitched to the splint to keep it from collapsing. The splint has a slit along its length so it can expand and grow as the child does — something a permanent, artificial implant could not do.

The plastic from which the splint is made is designed to degrade and gradually be absorbed by the body over three years, as healthy tissue forms to replace it, according to the biomedical engineer who led the work, Scott Hollister.

Green and Scott Hollister have a patent pending on the device and Hollister has a financial interest in a company that makes scaffolds for implants.

Dr. John Bent, a pediatric specialist at New York’s Albert Einstein College of Medicine, says only time will tell if this proves to be a permanent solution, but he praised the researchers for persevering to develop it.

“I can think of a handful of children I have seen in the last two decades who suffered greatly … that likely would have benefited from this technology,” Bent says.

Sweat Glands Are A Source of Stem Cells for Healing Wounds


When I was a kid, I used to wish that I had no sweat glands. Sweating made me sticky, wet and miserable. Little did I now, that without sweat glands, my body would have quickly overheated to fatal levels. A new study now shows that sweat glands are also the source of healing for wounds.

Human skin contains millions of eccrine sweat glands. These glands are not connected to hair follicles and they function throughout our lives to regulate the temperature of the body. Sweat glands respond to elevated bodily temperatures by secreting a mixture of NaCl and water. The water cools the external bodily temperature and is used to secrete other unwanted molecules. This is the main reason our sweat can smell like the food we ate (garlic, onions, etc.).

A new study by from the University of Michigan Health System shows that sweat glands play a key role in providing cells for recovering skin wounds, such as scrapes, burns and ulcers. These results were recently published in the American Journal of Pathology.

“Skin ulcers – including those caused by diabetes or bed sores – and other non-healing wounds remain a tremendous burden on health services and communities around the world,” says lead author of this work, Laure Rittié, who is a research assistant professor of dermatology at the Univ. of Michigan Medical School. She continued, “Treating chronic wounds costs tens of billions of dollars annually in the U.S. alone, and this price tag just keeps rising. Something isn’t working.”

U of M researchers believe they have discovered one of the body’s most powerful secret healers.

“By identifying a key process of wound closure, we can examine drug therapies with a new target in mind: sweat glands, which are very under-studied,” Rittié says. “We’re hoping this will stimulate research in a promising, new direction.”

Previously, wound healing was thought to originate from cells that came from hair follicles and from intact skin at the edge of the wound. However, the findings from the U of M research group demonstrate that cells arise from beneath the wound, and suggest that human eccrine sweat glands are the source of an important reservoir of adult stem cells that can quickly be recruited to aid wound healing.

Rittié commented: “It may be surprising that it’s taken until now to discover the sweat glands’ vital role in wound repair. But there’s a good reason why these specific glands are under-studied – eccrine sweat glands are unique to humans and absent in the body skin of laboratory animals that are commonly used for wound healing research.” Rittié continued: “We have discovered that humans heal their skin in a very unique way, different from other mammals. The regenerative potential of sweat glands has been one of our body’s best-kept secrets. Our findings certainly advance our understanding of the normal healing process and will hopefully pave the way for designing better, targeted therapies.”