Stem-Like Progenitor Cell That Exclusively Forms Heart Muscle

Future therapies for failing hearts are likely to include stem-like cells and associated growth factors that regenerate heart muscle. Scientists from the Perelman School of Medicine at the University of Pennsylvania have just taken an important step towards that future by identifying a stem-like "progenitor" cell that produces only heart muscle cells.

"We've defined the progenitor cell that is committed to making heart muscle, and we've started to define the factors that make that cell grow and form heart muscle cells," says senior author Jonathan Epstein, MD, chair of the Cell and Developmental Biology Department.

Evolution has left the mammalian heart with relatively little self-repair capacity compared to skin, bone, and other tissues, possibly because an extensive repair process would compromise the heart's ability to keep working. Nevertheless, scientists have been trying to find ways to amplify the heart's limited regenerative potential and have looked for clues in the embryonic phase of life, when the heart forms itself from stem-like cardiac progenitor cells (CPCs).

A major goal has been to understand how CPCs give rise to the different cell types of the mature heart, which include muscle cells (cardiomyocytes) and endothelial cells that line cardiac chambers and valves. In particular, scientists have wanted to identify progenitor cells that have matured just beyond the "multipotent" CPC state, so that they are committed to making just one type of cardiac cell.

The Cardiomyoblast In the new study, Epstein and his colleagues identified a cardiac progenitor -- which they term a cardiomyoblast -- that gives rise exclusively to cardiomyocytes. The finding occurred somewhat unexpectedly, as researchers in Epstein's laboratory performed "lineage tracing" experiments on mouse CPCs by marking different cells with fluorescent beacons and observing their fates as they proliferated and matured. The scientists found that CPCs expressing a particular protein called Hopx always went on to form cardiomyocytes.

"We thought that Hopx would also mark a multipotent progenitor cell, and we were surprised to learn that it was marking only the cells that were going on to make heart muscle. It was an exciting moment in the laboratory when we realized that," says Epstein.

Hopx has been known as a marker of progenitor cells in other tissues, including the gut, hair follicles, and lungs. Epstein and colleagues first linked it to heart development in a study published in 2002, noting that its deletion leads to severe heart defects in mice and zebrafish.

To find out more about Hopx's role in heart development, co-first author Rajan Jain, MD, a cardiologist and instructor in the Department of Medicine, overexpressed it in embryonic mouse hearts and observed that at an early phase of development this overexpression led to an increase in the number of cardiomyocytes. He also found that Hopx exerts this effect by suppressing the activity of genes in the Wnt signaling pathway, which helps maintain some cells in a multipotent, stem-like state. By contrast, embryonic heart cells lacking Hopx showed higher levels of Wnt signaling and gave rise to far fewer myocytes.

Researchers have known that the suppression of Wnt signaling in multipotent progenitor cells typically induces them to move towards a more mature cell type. In the heart and other tissues, that process has been linked to the activity of another protein called Bmp. Jain and colleagues found that for heart cell development, Hopx is a critical go-between, associating with Smad proteins to work as Bmp's enforcers in the suppression of Wnt signaling.

Future Implications The findings expand the basic scientific knowledge of how the mammalian heart develops and should speed research in this area -- not least because scientists now have a definitive marker, Hopx, that they can use to isolate the cardiomyoblast progenitors that specifically make heart muscle cells.

The work also could accelerate the development of future cardiac therapies, which might include the injection of cardiomyoblasts into damaged hearts. Initial efforts to treat damaged heart muscle in animal models and people, using multipotent cardiac progenitors or stem-cell-derived myocytes, have met with some success, but also false starts and controversy, in part because so little has been known about how cardiomyocytes originate.

"We've really needed a cardiomyocyte-specific progenitor, and with this finding we can identify and purify those progenitors," says postdoctoral researcher and co-first author Deqiang Li, PhD, who performed the Hopx lineage-tracing studies.

"Understanding where commitment to the cardiomyocyte fate is occurring, what signals are involved, and how a cell can integrate all of them, will hopefully inform our ability to advance novel therapeutics," says Jain.

He notes that those novel therapeutics might include not just cell-based therapies but also implantable bioengineered patches of heart muscle.

What's more, knowing how Hopx and other factors help generate myocytes in the embryonic heart might lead to drugs that stimulate the adult heart to produce its own new myocytes, says Epstein. He notes that previous basic studies of how blood cells develop led to blockbuster medicines such as the red cell growth factor EPO, and the white cell booster GM-CSF.

A next step for the Epstein lab in this line of research is to see if the cardiomyoblasts and other factors that generate heart muscle cells in early life also do so to some extent in later life, after a heart attack or other injury. "We hope that by understanding how it happens in the embryo we'll be in a better position to find the cells that play a similar role in the adult heart," Epstein says.

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Stem Cells Show Promise as Treatment for Diabetic Neuropathy

A scientific team from the U.S. and Korea reports that laboratory rats models of diabetic neuropathy (DN) can experience both angiogenesis and nerve re-myelination following injections of mesenchymal stem cells derived from bone marrow (BM-MSCs). The study (“Bone marrow-derived mesenchymal stem cells improve diabetic neuropathy by direct modulation of both angiogenesis and myelination in peripheral nerves”), which will be published in a future issue of Cell Transplantation, is currently available online.

The researchers used mesenchymal stem cells, which can be easily isolated from a variety of sources, such as adipose tissues, tendons, peripheral blood, umbilical cord blood, and bone marrow. BM-MSCs have been among the most successfully transplanted cells, offering therapeutic benefits for a wide range of conditions, from serious burns to cardiovascular diseases, including heart attack and stroke.

In this study, the animals were randomly assigned to BM-MSC or saline injection groups 12 weeks after the induction of diabetes. The non-diabetic control group of rats was age- and sex-matched. DN was confirmed by latency in nerve conduction velocity tests.

"We investigated whether local transplantation of BM-MSCs could attenuate or reverse experimental DN by modulating angiogenesis and restoring myelin, the electrically insulating substance surrounding nerves that is reduced by DN," said study co-author Young-sup Yoon, M.D., professor at the department of medicine, division of cardiology at Emory University School of Medicine. "In this study we have provided the first evidence that intramuscular injected BM-MSCs migrate to nerves and can play a therapeutic role."

According to the researchers, their findings indicate that intramuscular injection of MSCs resulted in an increase of multiple angiogenic and neurotrophic factors associated with blood vessel growth and subsequently aided the survival of diabetic nerves, suggesting that BM-MSC transplantation restored both the myelin sheath and nerve cells in diabetic sciatic nerves.

"We identified several new mechanisms by which MSCs can improve DN," noted the researchers. "First, we demonstrated that numerous engraftments migrated to and survived in the diabetic nerves. Second, we demonstrated a robust increase in vascularity. Third, we found the first evidence that MSCs can directly modulate re-myelination and axonal regeneration."

The scientists concluded that DN, for which there is no other therapeutic option, can be an "initial target for cell therapy" and that transplantation of BM- MSCs "represents a novel therapeutic option for treating DN."

"Currently, the only treatment options available for DN are palliative  in nature, or are directed at slowing the progression of the disease by tightly controlling blood sugar levels," says John R. Sladek, Jr., Ph.D., professor of neurology, pediatrics, and neuroscience, department of neurology at the University of Colorado School of Medicine. "This study offers new insight into the benefits of cell therapy as a possible treatment option for a disease that significantly diminishes quality of life for diabetic patients. Safety and efficacy for human application must be evaluated to further determine the feasibility of BM-MSC transplantation for treatment of DN." 

Source : http://goo.gl/45IHrb

Protein Plays Unexpected Role in Embryonic Stem Cells

What if you found out that pieces of your front door were occasionally flying off the door frame to carry out chores around the house? That’s the kind of surprise scientists at the Salk Institute experienced with their recent discovery that nucleoporins–proteins that act as cellular “doorways” to help manage what goes in and out of a cell’s nucleus–are actually much bigger players in expressing genes than previously thought.

The finding, published June 16, 2015 in the journal Genes & Development, shows that nucleoporins play an important role in maintaining embryonic stem cells before they begin to develop into specific tissues. This discovery gives a new understanding to genetic diseases that are caused by mutations in these proteins. One nucleoporin protein in particular has a dramatic–and unanticipated–function in the formation of neurons from stem cells.

“We’ve shone a new light on this class of proteins,” says Martin Hetzer, a professor in Salk’s Molecular and Cell Biology Laboratory and senior author of the new paper. “I hope people start to accept and realize that nucleoporins are more than just transport proteins.”

Nucleoporins–of which there are about 30 versions–are typically part of nuclear pore complexes, giant structures that connect the inside of a cell’s nucleus to the outer cytoplasm. In 2010, Hetzer’s team first uncovered hints that nucleoporins may also have a role in regulating the timing of when genes inside the nucleus are transcribed into proteins during a cell’s development. But exactly what that role might be was unclear.

In the new work, Hetzer and his colleagues focused on one particular nucleoporin called Nup153, which is known to rapidly move on and off of the nuclear pore complex, suggesting it might be doing something other than providing structural support to the pore.

The researchers turned to mouse embryonic stem cells–cells that have the potential to differentiate into any cell type in the body–and deleted Nup153. They expected that if Nup153 played a key role in cell differentiation, then removing it from stem cells would stop them from differentiating. Instead, the opposite happened.

“The big surprise was that when we took out this gene, the stem cells started to differentiate,” said Hetzer. “And not only did they start to differentiate, but they started to differentiate into neurons.”

Nup153, researchers discovered, put the brakes on certain genes that need to be turned on for stem cells to turn into brain cells. When the brakes are lifted, the stem cells start differentiating.

“This study not only revealed a critical function for nucleoporins in mediating the undifferentiated state of embryonic stem cells by silencing neural genes, but also introduced new mechanistic directions for elucidating the role of these proteins during mammalian development,” says Filipe Jacinto, a postdoctoral researcher in Hetzer’s lab and first author of the paper.

Hetzer suspects that other nucleoporins also have roles in gene expression control, but cautions that the roles could be very different–each nucleoporin, he says, likely targets a different set of genes, and some might activate the genes rather than repress them.

Mutations in many nucleoporin genes has been linked to human diseases and developmental disorders, including some forms of leukemia and inherited heart problems. Until now, Hetzer says, researchers have assumed the mutations led to disease by altering the transport of proteins in and out of a cell’s nucleus. “Now, we’re realizing this is probably not the only explanation,” he says. “Many of those diseases and developmental disorders might actually be caused by the ability of these genes to regulate gene expression programs.”

His lab is planning to follow up with studies on Nup153, and exactly how it’s recruited to genes, as well as investigating the developmental roles of other nucleoporins.

Chris Benner, director of the Integrative Genomics and Bioinformatics Core at the Salk Institute, also contributed to the work.

The work and the researchers involved were supported by grants from the National Institutes of Health and the National Cancer Institute.

Source : http://goo.gl/qMp0tL

Stem Cell Transplant Gives Redondo Beach Woman Reprieve From Aml Leukemia

Thanks to the generosity of an anonymous 19-year-old woman in Europe, Redondo Beach resident and single mom Devon Gilbreath-Smith will celebrate two birthdays each year: The day of her birth and the day she received a stem cell transplant.

“The nurses and doctors all came in with a cake and sang happy birthday to me,” said the 43-year-old about her “second birthday” on Feb. 20. She's been cancer-free for 100 days after battling AML leukemia since last August.

After making a miraculous recovery in September from cancer after rounds of chemotherapy killed off her stem cells, she's received a spanking new set. Now she's looking forward to getting all of the vaccinations that a baby needs.

Gilbreath-Smith and her 6-year-old son Ryder and family are indebted to the 19-year-old who signed up for Be The Match, a Pasadena organization that makes becoming a stem cell donor as simple as taking an oral swab and placing the package in the mail.

Program director at Be The Match, Jill Kendall said the chances of being selected to actually donate are extremely slim, but if it does happen, the donation procedure is not as invasive as it used to be. In fact, now it's simple, yet does come with a little pain.

“It's really exciting for people who do get matched to donate. It really gives people a great feeling to know that you are saving a life and making a difference,” Kendall said.

The two methods are both out-patient. The first and more traditional method is a marrow harvest from the bone. The physicians use anesthesia and still a needle in the bone to access enough marrow.

“It's safe, but donors are sore, but can return to normal activities right away,” she said. “These days most donors choose to do apheresis. It's a fancy word for blood collection that is a lot like dialysis. They collect the blood, extract the stem cells or platelets and then return the blood to the donor.”

In February, Gilbreath-Smith was admitted to UCLA Medical Center-Santa Monica and given six more rounds of chemotherapy which killed off her damaged stem cells. She then received the new stem cells through an IV, a lot like when she received many blood transfusions.

She remained in the hospital for 30 days after the transplant so that doctors could keep a close watch on her progress. Now 118 days later she is finally going back to work part-time as an administrator for local businessman Tony Turtanich.

“It's a miracle that I'm even alive. I just want to take my son with me to meet my donor to say 'thank you for saving this 6-year-old boy's mom,'” Gilbreath-Smith said. “The donors remain anonymous for the first year because it's possible that a body will reject the transplant, but after that, if we want to meet, we can.”

Meanwhile, she can send care packages to the donor through Be The Match. Gilbreath-Smith has sent several packages that contained items such as seashells, her favorite candy (turtles), her favorite book, (“Tuesdays with Morrie”), a letter to thank her, a photo of her and her son, a copy of the October article in The Beach Reporter and a map of the South Bay.

“I am so grateful. I just would never imagine that a 19-year-old would be so giving. Usually 19-year-olds are into partying and thinking about themselves. I used to be down on the world, but when I learned that she was donating stem cells to me, a complete stranger, that really changed how I view the world. I will never see it the same way again,” Gilbreath-Smith said. “I want people to understand how easy it is to save someone's life.

“We need to get as many people as possible to join Be The Match. It saves lives, children, babies and people like me. It's so sad, there are so many people waiting to find a match. If I hadn't found one, I would have died.”

The beach cities community rallied around Gilbreath-Smith and raised $20,000 for medical bills and living expenses.

“We have such an amazing community here in the South Bay. People I don't even know have given so much to me. I haven't been able to work, so if it weren't for the generous people in the community, I wouldn't have been able to pay my rent and bills,” she said.

After a year passes, she will be able to enjoy some of her favorite foods and resume normal activities. She can't wait to take her first bite of sushi and have a glass of wine. She looks forward to being able to attend award ceremonies like the one she had to miss at her son's school.

“I'm not able to go into large crowds, I can't be exposed to a lot of germs and I'm sad that I can't go to my son's awards ceremony this week because of the germ exposure at the school. And so I feel like a bad mom, but they all know what I'm dealing with,” she said. “I'm just happy that I can be here for my son.”

Every day she takes a walk at the beach and always thinks about how close she came to death and how grateful she is for the generosity of people.

Gilbreath-Smith's odyssey began last August when she was feeling fatigued and noticed she was bruising too easily. She was in the emergency room at Little Company of Mary Hospital in Torrance when the doctor told her she had acute myelogenous leukemia, an aggressive cancer that attacks the blood and bone marrow.

Doctors immediately began an aggressive treatment and after three days of blood transfusions she was transferred to UCLA where she began chemotherapy treatment. In September, after a second round of chemotherapy, her organs began to shut down and doctors told her parents it was time to gather family and friends to say goodbye.

“I don't remember any of that. I was on my deathbed, they said my feet and hands had started to turn black,” Gilbreath-Smith said.

She was given only two days to live, but the next day, her platelet numbers began to rise, however the prognosis remained grimly the same. The doctors were hesitant to give her family hope. Three days after being handed the medical death sentence, Gilbreath-Smith's heart function started to improve. Doctors were confused, saying this never happens.

She bounced back as fast as she declined and seven days later she was released from the hospital. Ultimately, the stem cell transplant is the only cure of ALM leukemia.

Since Gilbreath-Smith had herself signed up with Be The Match as a potential donor in 2008, she knew exactly where to turn.

Source : http://goo.gl/CZMrgF

Dunnellon Woman To Receive Stem Cell Transplant For Rheumatoid Arthritis

A local woman is poised to become only the fifth person ever to receive a stem cell transplant for rheumatoid arthritis.

Cheryl Wright, 46, formerly of Ocala but now a resident of Dunnellon, has suffered the pain of rheumatoid arthritis for years. Her symptoms began when she was 16 and she was diagnosed at age 22.

According to the National Institute of Arthritis and Musculoskeletal and Skin Disease, “Rheumatoid arthritis (RA) is an inflammatory disease that causes pain, swelling, stiffness and loss of function in the joints. It occurs when the immune system, which normally defends the body from invading organisms, turns its attack against the membrane lining the joints.”

Wright’s condition is severe progressive rheumatoid arthritis, with a lot of joint damage, which has not responded to any FDA approved medicines. She was a candidate for bilateral elbow replacements and both of her hands were severely deformed.

“I went through a year of intensive hand therapy (very painful), and had custom splints made to help with my hand and wrist deformities, that I wore while I slept each night,” she said.

She has a local RA doctor and also consulted with two physicians at the Mayo Clinic in Jacksonville to seek relief from her pain.

As her condition worsened, she lost a lot of time away from her job as a phlebotomist.

“I fought hard to keep working, despite my increasing limitations, but without enough medications I would progress to a full cripple within a year,” she said. “I had it in my head that if I could just get a new immune system, this nightmare would go away and I could have my life back. I am in need of a stem cell transplant.”

Wright began six months of research “from how the biologics work to reading medical journals and publications,” she said.

The name Dr. Richard Burt kept popping up and she soon learned he is the pioneering doctor of stem cell transplants.

According to http://www.nm.org, Burt is the Chief of the Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, in Chicago. He pioneered the use of hematopoietic stem cells to treat autoimmune diseases.

“Not only had I found the one doctor in the USA who did this, but found the best doctor in the world,” Wright said.

Wright contacted Burt’s office, then flew to Chicago last year, where she also consulted with an allergist and rheumatologist at Northwestern.

“It was decided that I needed a stem cell transplant to erase my existing immune system to give me a new one,” Wright said.

Families are checked first for donor potential, but, typically, 70 percent are not a match. The doctors then can widen the search, as was the case with Wright after her brother proved to not be a suitable donor. She was recently notified that Burt has two perfectly matched cord blood units reserved for her. She expects to have the transplant in July. Beforehand, she will have three to five chemotherapy treatments to kill her autoimmune system.

Wright said Burt has done four stem cell transplants for RA and that all of those patients are all doing well, including Annie Ballantine, 32, of Chicago, who was diagnosed with RA at 18 months. She was Burt’s fourth stem cell transplant, on Dec. 9, 2013, and also found him by doing personal research.

“Having a stem cell transplant was my last hope for a life with some normalcy, and the same is true for Cheryl. For me, the transplant has been life-changing,” Ballantine said.

“The improvement in my symptoms was almost instantaneous. I started chemotherapy to prepare for the transplant, and just two days later I had absolutely no pain in my joints.” Ballantine said. “Before the transplant, she said, I couldn’t open a Ziplock bag or button a cardigan. Now, 18 months post-transplant, I am doing push-ups every morning.”

“I am so excited for Cheryl and all of the possibilities that are in her future that is free from pain and suffering from rheumatoid arthritis,” Ballantine added.

Wright said after she receives new stem cells, “the new cells won’t know I’m sick. They will grow and divide into new healthy disease free cells.”

The transplant is dangerous and costly. Wright’s insurance approved $150,000 for the transplant, baring complications, but there will be about $50,000 in out-of-pocket costs as she will have to return to Chicago six months post-transplant, one year post-transplant, and once a year for five more years. In the meantime, Burt is setting her up with a follow-up physician at UF Health Shands Hospital in Gainesville.

“I believe this transplant will be a success, just as the ones before me. I have overcome so many obstacles and have beaten the odds that I know this is exactly where I need to be to get better,” Wright said. “I have absolutely no doubts and while there is a chance I could die during the process, death does not scare me, living the rest of my life crippled in a constant state of pain terrifies me. What I’m trying to do is bring awareness and hope for a cure.”

Source : http://goo.gl/uNW7fy