U of M News Wire
January 17 , 2008
University of Minnesota Researchers create a new heart in the lab
By Deane Morrison
U of M News Wire
In a medical first, University researchers have created a beating heart in the laboratory. Using detergents, they stripped away the cells from rat hearts until only the nonliving matrix was left; they then repopulated the matrix with fresh heart cells.
If perfected, the technique may be used someday to generate new hearts for patients. In the United States alone, about 5 million people live with heart failure, 550,000 new cases are diagnosed every year, and 50,000 die waiting for a donor heart. The work is published online in the January 13 issue of Nature Medicine.
"The results were a home run," says Doris Taylor, director of the University's Center for Cardiovascular Repair and a principal investigator on the study. "We knew that cell therapy--that is, transplanting cells into the heart--is not a panacea. So we started thinking, 'Is there a way to use cells to engineer heart tissue?'"
The idea, she says, is to create whole new blood vessels or organs by implanting a patient's own cells into a matrix derived from a donor organ. This approach ought to bypass the problem of organ rejection because the matrix, being devoid of cells, shouldn't provoke an immune response. Even if it did, the new cells would lay down a fresh matrix of their own, which would turn off the immune response and free patients from the need to take immunosuppressive drugs.
The process, called whole organ recellularization, can be done "with virtually any organ," Taylor says.
A simple plan
The main hurdle in creating new hearts wasn't finding the right cells, but recreating the vastly complex architecture of the heart, Taylor explains. In puzzling it over, she and Harald Ott, a research associate in the center (now a surgical resident at Harvard Medical School and first author of the study), hit on a way to get nature to solve the problem for them.
To remove cells from fresh rat hearts, the researchers pumped solutions of detergents through the network of blood vessels that normally nourish the organ. The treatment popped all the cells like balloons and washed away the debris, leaving the matrix of protein fibers that form the backbone of a living heart's connective tissue. It's called the extracellular matrix, or ECM.
"A huge amount of the heart structure is ECM," says Taylor. "Cells use the matrix to attach and take shape. The ECM also gives muscles something to pull against."
The naked ECM's looked strikingly like "ghost hearts": eerily white, rubbery "skeletons" that retained the organ's original 3-D structure. Among the surviving features was the tubing of blood vessels, which came in handy later.
Next, the team removed hearts from newborn rats and minced them, liberating a motley crew of adult and undifferentiated cells. The mix contained stem cells and progenitor cells--which have less potential than stem cells but can still become multiple cell types--along with adult heart muscle cells and many other types.
"Newborn tissue is rich in cells that are more hearty and more tolerant [than adult cells]," says Taylor.
The researchers then injected these cells into the left ventricles of the ECM hearts and began pumping a solution of oxygen and nutrients through the remnant blood vessels. After four days, they detected contractions in several hearts. In eight days, they had eight hearts beating normally enough to pump fluid out the aorta.
"We just took nature's own building blocks to build a new organ," says Ott. Still, "When we saw the first contractions we were speechless."
As the new hearts developed, the team coaxed them along by stimulating them with electrodes. The electrical signals propagated through the tissue and synchronized the beats. When stimulation was stopped, the hearts continued beating for various periods of time on their own. The best-performing hearts were kept beating for 40 days.
"We don't know yet, but the heart seems to get stronger over time as we pace it [with electrical stimulation] and increase the delivery of cells," says Taylor. "We're confident we can mimic the real heart."
The rat hearts she and her team created could contract with a force equal to about two percent of adult rat heart function and 25 percent of 16-week fetal human heart function. The next step is to optimize the mix of cells added to the ECM and the culture conditions for the maturing hearts so as to encourage optimal growth at each stage of maturity.
The team is also experimenting with pig hearts, which are about the same size as humans', and have successfully generated ECM's from them.
The hope
Someday, doctors may routinely extract cells from heart failure patients and use them to reseed a new organ from a cadaver-derived ECM. What types of cells those would be isn't known yet.
"It depends on what cells are best," says Taylor. "Bone marrow-derived stem cells are already used to treat hearts. It may be a mix of cells from bone marrow, hearts, and skeletal muscle. We'll use whatever cells we think are going to give us the best shot."
Surgeons already patch holes in the heart, or areas damaged by heart attacks, with pieces of heart muscle. Patches can be grown in the lab, but it's hard to get them anywhere near thick enough because of difficulties keeping the tissue oxygenated. The ECM technique, however, has good potential for overcoming this limitation because it uses the original circulatory system to oxygenate the growing hearts.
"The thickness of the ECM is key," Taylor explains. "If the matrix is there, we can recellularize its whole thickness."
While the ECM technique can supply heart patches, she says its main application is likely to be in patients who need a whole new heart. With too few donor hearts available, the ECM heart may fill the gap and help patients rid themselves of mechanical assist devices much earlier.
The potential is great, but "commercialization is not our goal," says Taylor. "It's getting this to patients safely and effectively.
"I'd like to think that these kinds of innovations will continue to happen at the U because the state realizes that we can change the world of medicine here in Minnesota."
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Autism up close
By Jack El-Hai
U of M News Wire
Autism now affects one in every 166 children born. Scott Selleck and his colleagues in the College of Biological Sciences' Department of Genetics, Cell Biology and Development have spent several years trying to find out whether a specific genetic mutation might play a role in this disorder that changes the lives of so many kids.
Selleck entered this investigation by chance, but his continued involvement is decidedly deliberate.
Three years ago, when University of Minnesota pediatric clinics separately evaluated two families that included children with autism and other developmental problems, Selleck had no idea that he would soon be drawn into a new field of research. His lab studies the ways in which various proteins stimulate the growth and differentiation of cells, most often focusing on the fruitfly, Drosophila melanogaster, as a vehicle for understanding genetic development.
The two families in question, however, entered his scientific purview when the pediatric clinics sent their genetic samples to Selleck's lab. "We found that they shared a chromosomal anomaly, one so small that if we didn't have a terrific cytogenetics lab, it would have gone unnoticed," Selleck says.
It turned out that members of both families had deletions, or missing genetic material, in Chromosome 10. Could this genetic mutation play a role in the autism that affects many of the children? The answer could be crucial in efforts to halt the growing incidence of autism. Selleck was intrigued by the possibilities.
Autistic children often have large heads or abnormal patterns in brain growth. That suggested to Selleck the value of investigating the molecular signaling pathways within genes that control growth. His colleague Tom Neufeld, associate professor in Selleck's department, has expertise in those particular pathways. Selleck and Neufeld devised fruitfly studies to find out if those pathways are involved in the growth and development of the brain. The answer was yes.
Selleck also enlisted another colleague, professor Mike O'Connor, to work with laboratory mice to determine if there is a link between a protein important in nervous system development, BMP, and the kinds of neural signaling that may play a role in childhood cognitive abnormalities such as autism.
"Within two to five years we should have a better understanding of how BMP growth factors affect autism spectrum disorders," O'Connor says. "They've already been shown to have a role in learning, so it's possible."
As a newcomer to autism-related research, Selleck initially relied on funds available through his endowed chair to jumpstart his work with O'Connor and Neufeld. "That shows how critical seed-money funds are for new science," he says. "In the current climate it's very hard to get money for new projects outside of your published area of expertise."
Selleck has grown so involved in autism-related research that he is helping to lead an effort to raise $2 million for medical care for patients and continuing research into the causes of the disorder. Says Selleck: "We want to inspire others to get into this research."
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Growing Concerns
A parenting column with Dr. Martha Farrell Erickson of the University of Minnesota
Editor’s note: Dr. Erickson's regular column will be back next week. This column is from the Growing Concerns archive.
Question: Our 3-year-old son Chris has always been a champion sleeper. Usually all we have to do is tell him it's time for bed and he walks upstairs, gets a book to read and hops into bed. He shares a room with our 1-year-old and they have been great roommates. However, for the last few weeks, Chris has been climbing into the baby's crib. Initially they would play and jump around. This was not good at 3 a.m. That has subsided now, but Chris is still climbing into the crib after we've put the two kids down for the night. When we check on them before we go to sleep, there is Chris sleeping with the baby in the crib, pillow, blanket and all. How do we stop this?
Answer: For starters, it may be helpful to think about why Chris is doing this -- what purpose it serves for him. Does he long for the coziness of snuggling up with baby brother, especially on these cold winter nights? Does he feel more safe and secure in the confines of the crib and with someone close by? Or might Chris be jealous of the attention the 1-year-old receives with his antics and cuteness? If so, does he want to show you by crawling into the crib that he's a cute little toddler too, rather than a boring 3-year-old? I know that sounds awfully analytical, but it happens.
Whatever the reasons, the following steps should help put a stop to the behavior:
• Tell Chris clearly and firmly that it's not OK to get in the crib. He needs to sleep in his own bed.
• Depending on what he can tell you (with words or behavior) about his reasons for getting in the crib, suggest an alternative. For example, some possibilities might include sleeping with a big teddy bear; moving the crib closer to Chris's bed so he can feel close to his brother without getting in the crib; or coming to get you if he feels scared in the night.
• Praise Chris profusely (or even use a sticker chart) for staying in his own big-boy bed. Initially check on him at 15-minute intervals after bedtime and reinforce him each time for staying in bed. Give him a big hug and praise when you find him in his own bed in the morning.
• If you find Chris in the crib at any point, move him swiftly and firmly back to his own bed without talking a lot about it. Simply say, "You need to sleep in your own bed."
If these steps don't solve the problem, you may even want to tell Chris there will be a consequence if he keeps getting into the crib. This could be loss of a privilege, or perhaps moving the baby's crib into another room until Chris learns to stay in his own bed. Just knowing that could happen might be an incentive for him to stay in his own bed.
Dr. Erickson is a senior fellow and director of the Harris Programs in the Center for Early Childhood Education at the University of Minnesota.
Want to hear more parenting advice?
Dr. Erickson and her daughter can be heard every Sunday, from 2 - 4 pm, on “Good Enough Moms,” on FM107.1 radio in the Twin Cities or via Webcast at www.FM1071.com
