Neural Stem Cells Relieve Some of the Impairments of Dementia in Mice


Lewy bodies are aggregations of misfolded proteins in nerve cells that can kill them off and cause dementia. When Lewy bodies form in neurons, they can cause “dementia with Lewy bodies” or DLB. After Alzheimer’s disease, DLB is the second-most common type of age-related dementia, and it afflicted the beloved comedian Robin Williams, who took his own life earlier this year.

Scientists at the Sue and Bill Gross Stem Cell Research Center and the Institute for Memory Impairments and Neurological Disorders at UC Irvine have examined the ability of transplanted neural stem cells to ameliorate the symptoms of DLB is an animal model system.

Particular strains of laboratory mice have been genetically engineered to form Lewy bodies in their brains and show some of the symptoms of DLB. Natalie Goldberg and her colleagues used neural stem cells to treat some of these mice in order to determine if these cells could decrease the pathological consequences of DLB.

Transplantation of neural stem cells into the brains of these DLB mice resulted in increases in cognitive and motor function. A battery of tests established this. For example, the Rotarod test places the mouse on a rod that is then rotated at a specific speed. Normal mice can move around the rod and keep from falling off, but mice with motor or balance problems will fall off the rod prematurely. Cognitive tests included Novel Object Recognition (NOR) and Novel Place Recognition (NPR) tests, which are low-stress tasks that quantify the proportion of time spent examining a novel object and provide data on memory. In these tests, the mice that received the neural stem cell transplantation did significantly better than their non-treated siblings.

Goldberg and his team then asked how these cells improved the cognitive and motor function of the DLB mice. It turns out that neutral stem cells secrete respectable amounts of brain-derived neurotrophic factor (BDNF). Goldberg suspected that this growth factor was a major contributor to the healing capabilities of neural stem cells. Therefore, Goldberg’s team engineered neural stem cells that could not make BDNF and injected those directly into the brains of DLB mice. These mutant neural stem cells were incapable of improving the cognitive or motor function of these mice.

To further test her hypothesis, Goldberg then engineered a virus that would infect neurons and overexpress BDNF and used that to treat her DLB mice. Interestingly, the BDNF-expressing virus did a pretty good job at restoring motor functions in these DLB mice, but did not restore the cognitive functions.

Thus, while the secretion of BDNF by neural stem cells is important for their restorative capacities, but it is only part of the means they use to heal affected brains. Goldberg and her coworkers showed that the transplanted neural stem cells did not improve the pathology of the brains, they did preserve neural pathways that use the neurotransmitters dopamine and glutamate.

The neural stem cells used in these experiments were mouse neural stem cells. Before work like this can advance to human clinical trials, human neural stem cells must be tested. Since other neurodegenerative diseases like Parkinson’s disease also result from Lewy body formation in specific cells, neural stem cell treatments might prove beneficial for patients with much diseases.

This work was published in Stem Cell Reports October 2015 DOI: 10.1016/j.stemcr.2015.09.008.

cKit+ cells Do Make Heart Muscle After All


In the heart lies a population of cells that contains a protein called cKit, and are, therefore, called cKit+ cells. cKit+ cells have been the subject of a good deal of attention by researchers, but unfortunately, these have become the focus of a good deal of controversy.

When cKit+ cells were first discovered, there was a good deal of excitement about them, since they seemed to be able to make heart muscle cells and replace damaged heart muscle cells in the heart of living creatures (Beltrami AP, et al., Cell. 2003 Sep 19;114(6):763-76). In 2012, the results of a Phase I clinical trial with cKit+ cells (SCIPIO) were published (Chugh AR et al., Circulation 2012 Sep 11;126(11 Suppl 1):S54-64). This trial seemed to show that patients who received their own cKit+ cells had significant increases in heart function after a heart attack. Follow-up work in pigs even appeared to confirm that infused cKit+ cells could differentiate into heart muscle and integrate into the walls of the heart (Bolli R et al., Circulation 2013 Jul 9;128(2):122-31). So the cells were able to regenerate heart muscle in mice, pigs, and humans. It is not an understatement to say that cKit+ cells were once thought to be the key to cardiac regeneration.

The first trouble in paradise came from mouse experiments. While cKit+ cells could indeed improve the function of damaged hearts, the evidence for engraftment of the cells into the walls of the heart was wanting. Scientists in the laboratory of Jeff Molkentin Cincinnati Children’s Hospital Medical Center reported in a high-profile paper in the journal Nature that cKit+ cells can readily produce cardiac blood vessel cells, they rarely make heart muscle cells (cardiomyocytes). Because Molkentin and his team had carefully marked and traced the cells that they implanted into mice, the result was pretty devastating to the status of cKit+ cells. Molkentin’s results, however, conflicted with data from the laboratory of Bernardo Nadal-Ginard from King’s College London, who showed that heart regeneration in laboratory rodents depends on cKit+ cells and depleting cKit+ populations from the heart abolishes the ability of the heart to repair itself (Ellison GM, et al., Cell. 2013 Aug 15;154(4). Technical differences between the two papers, however, made comparisons between them difficult.

The next issues came with the SCIPIO publication itself. Two of the figures appeared to have some mistakes in them. Piero Anversa from Brigham and Women’s Hospital’s, the senior author of the SCIPIO study, admitted that there might be problems with the figures but insisted that the clinical data of the trial were sound. Other concerns about SCIPIO were expressed as well in print.  Add to that the fact that Anversa had to retract one of his earlier papers, and the whole edifice of SCIPIO and cKit+ cells seemed to totter.  These issues knocked cKit+ cells off their pedestal. At the very least, they put a hold on the SCIPIO trial until other questions had been resolved.

A new study by Joshua Hare and his group from the University of Miami Miller School of Medicine has stirred up the controversy pot once again. Hare and his team have published a paper in the journal PNAS in which they showed that cKit+ cells can readily form heart muscle cells in culture. However, apparently the cKit+ cells are finicky and only form heart muscle conditions if the conditions are just right. These results from Hare’s group might (and oh what a big might) explain why other groups have not been able to replicate the results of either Anversa or Nadal-Ginard. In Hare’s own words, “It’s not that the [cKit+] cells don’t have the capacity [to form heart muscle], but they’re entering the heart at a time that’s nonpermissive for them to become cardiac myocytes.”

In a nutshell, Hare and his team used mouse induced pluripotent stem cells (iPSCs) and differentiated them into heart muscle cells. They found that if you inhibited bone morphogenetic protein (BMP) signaling in these cells, an integral signaling event in the development of the heart; the iPSCs would express cKit and differentiate into heart muscle cells. The Hare group also used fate-mapping techniques to trace the developmental origin of cKit+ cells in the heart and they discovered that cKit+ cells are derived from the neural crest cells that delaminate from the closing neural tube during the formation of the central nervous system and migrate throughout the body to form a whole host of cell types and contribute to many different tissues.

Unlike Molkentin’s group, Hare and his crew did not observe an increased tendency for cKit+ cells to form heart blood vessel (endothelium) cells. Hare was somewhat unsure why this might be the case, but suggested that the different ways that the two teams labeled their cells for fate mapping purposes might be at least part of the issue.

Despite his success at showing that cKit+ cells can become heart muscle cells, Hare does not think that his work necessarily explains the results of the SCIPIO clinical trial, but he does think that his work might suggest how the regenerative capacities of cKit+ cells might be augmented.

Bernardo Nadal-Ginard found Hare’s work “convincing,” but added that “the paper claims the quandary and the dispute is over. But, unfortunately, it is not.” I think we can say “Amen” to that, since more work almost certainly needs to be done. Nadal-Ginard also brought up a very good point when he added that no one really knows the frequency with which cKit+ cells differentiate into heart muscle cells or other cells types or even the rate with which they replace dead or dying cells. Hare’s paper did not focus on quantitating such events, and since it did not examine the ability of cKit+ cells to repopulate a living heart, these are still questions that must be addressed.

Cornell University’s Michael Kotlikoff also made an excellent point by noting that Hare’s team did not show that cKit+ cells have the same ability to regenerate a living heart in laboratory animals as they do in culture. In an article in The Scientist by Kerry Grens, Kotlikoff said, “They never show the myogenic potential of those cells and don’t show them giving rise to cardiomyogensis” in vivo. Kotlikoff continued: “The expression of [cKit], per se, is not sufficient to identify cells as precursors and the further presumption that signaling processes observed in in vitro differentiation experiments limit such cells from undergoing myogenesis in the adult heart, the stage at which clinical regenerative efforts are focused, is not supported by data,” he added.

Hare almost certainly is either planning or is presently carrying out such experiments with laboratory mice. Presently, however, Hare has founded a company called Vestion, whose goal is to establish off-the-shelf regenerative heart therapies. According the Kerry Grens, Hare is also a part of two planned clinical trials that will administer cKit+ cells to patients with heart failure.

Piero Anversa, who remains a big fan of cKit+ cells despite their knocks, spoke approvingly of Hare’s paper and added, “To say human trials should be stopped because the experiment didn’t work in the mouse is a bit aggressive. The answer is going to be in the trial. If the trial goes well we win, if the trial doesn’t go well, we lose.”

Thyroid Organoids Made from Stem Cells Treat Thyroid-Deficient Mice


Darrell Kotton and his research team from Beth Deaconess Medical Center, in collaboration with researchers from the Boston University School of Medicine have devised a workable protocol for differentiating Human pluripotent stem cells into functional thyroid gland cells.

Every year, many people are diagnosed with an underactive thyroid and many others lose their thyroid as a result of thyroid cancer. Designing treatments that can help replace lost thyroid tissue would certainly be a welcome thing for these patients.

By working with mouse embryonic stem cells, Kotton and his colleagues showed that two growth factors, BMP4 and FGF2, and induce foregut endodermal cells to differentiate into thyroid cells. This simple signaling pathway not only efficiently generates thyroid tissue from endoderm, but this pathway turns out to be commonly used in species as diverse as frogs, mice and humans.

The BMP4/FGF2-treated foregut cells differentiated into small thyroid organics that Kotton and his team were able to transplant into thyroid-deficient mice. These transplantations restored normal thyroid function to these mice.

fx1 (6)

While mice cells are a fine model system for human diseases, they are not exactly the same. Can this procedure work with human cells? To answer that question, Kotton and his coworkers used human induced pluripotent stem cells (iPSCs) and subjected them to the same BMP4/FGF2 protocol after they had first differentiated the cells into endoderm. In addition, Kotton and his team made thyroid cells from iPSCs derived from cells taken from patients with a specific type of hypothyroidism (interactive thyroid). These patients lack a gene called NKX2-1, and suffer from congenital hypothyroidism.

The thyroid is responsible for your basal metabolic rate. Hypothyroidism or an interactive thyroid can cause patients to gain weight, feel tired constantly, have trouble concentrating, and have a slow heart rate. Hypothyroidism is usually treated with synthetic thyroid hormones that are taken orally. However, restoring a patient’s own thyroid tissue or even replacing defective thyroid tissue with repaired thyroid tissue would be a huge boon to thyroid patients.

This work has discovered the regulatory mechanisms that drive the establishment of the thyroid. It also provides a significant step toward cell-based regenerative therapy for hypothyroidism and the replacement of the thyroid after thyroid cancer treatments.

These results were published in the journal Cell Stem Cell, October 2015 DOI:10.1016/j.stem.2015.09.004.

Sleep Deprivation Decreases Stem Cell Activity


We have all been there: You are at your computer, working hard and then a yawn hits you. Alternatively, you are on the phone late at night and you start to nod. We all have our late nights burning the midnight oil, but we need our shut-eye.

Now it turns out that sleep deprivation might wreak havoc with your stem cells. New research in mice might (let me emphasize, might) have profound implications for patients undergoing bone marrow stem cell transplants.

This research was led by Dr. Asya Rolls, who formerly worked as a postdoctoral research fellow at Stanford University, but is now an assistant professor at the Israel Institute of Technology.

With regards to the clinical implications of this work, Dr. Rolls said, “Considering how little attention we typically pay to sleep in the hospital setting, this finding is troubling. We go to all this trouble to find a matching donor, but this research suggests that if the donor is not well-rested it can impact the outcome of the transplantation. However, it’s heartening to think that this is not an insurmountable obstacle; a short period of recovery sleep before transplant can restore the donor’s cells’ ability to function normally.”

Rolls and her colleagues used laboratory mice for this study and broke them into two different groups. One group of mice was physically handled by members of the research team for four hours in order prevent them from going to sleep. The other group of mice were not handled and slept soundly in their cages. Then Rolls and her collaborators isolated bone marrow stem cells from the sleepless and well-rested mice. These bone marrow stem cells were then used to them to help reconstitute the bone marrow of twelve different mice that had been given radiation treatments that wiped out their bone marrow stem cells. It is important to note that these donor mice had bone marrow stem cells that glowed when put under a fluorescent light.

The irradiated mice were then examined eight and 16 weeks after they had received the bone marrow stem cell transplants. By taking blood samples, Roll and others measured the production of blood cells by the transplanted bone marrow stem cells. Mind you, the irradiated mice also received some of their own bone marrow stem cells in combination with the bone marrow stem cells from the donor mice. This was to help determine the percentage of blood cells made by the stem cells from the donor mice. Surveys of the blood cells of the irradiated mice showed that donated stem cells from the mouse donors that had a good night’s sleep gave rise to about 26 percent of the examined blood cells. However, bone marrow stem cells from sleepless donor mice only produced approximately 12 percent of the surveyed blood cells.

Next, the Stanford team investigated the ability of the transplanted stem cells to find their way to the bone marrow of the recipient mice, twelve hours after transplantation. When the bone marrow of the donor mice was subjected to fluorescent light, the 3.3 percent of the bone marrow stem cells were from the well-rested donor mice. However, the same experiment in those recipient mice that had received mice had received bone marrow stem cells from the sleep-deprived mice showed that only 1.7 percent of the stem cells in the bone came from the donor mice. Thus the bone marrow stem cells from those mice that had a good night’s sleep were twice as likely to find their way to the bone marrow of the recipient.

When hematopoietic stem cells from the donor mice were tested in culture, stem cells from the sleepless mice showed a weak response to chemical cues found in bone marrow that activate migration to the bone marrow. Conversely, hematopoietic stem cells from the well-rested mice responded much more robustly to these same chemical cues and migrated appropriately.

Think of it; not sleeping for only four hours can decrease the activity of transplanted bone marrow stem cells by up to half. Remember that bone marrow stem cells contain the coveted hematopoietic stem cell population that produces all the blood cells coursing through our bloodstream. When transplanted into recipient animals (or patients), these stem cells must actively find their way to the bone marrow, take up residence there, and begin to produce all the blood cells necessary for the life and health of the recipient. Therefore even a small reduction in the health or activity of hematopoietic stem cells could drastically affect the success of the bone marrow transplant procedure.

Are the effects of sleeplessness permanent? Not at all, at least in mice. Rolls and her team showed that the decrease in bone marrow stem cell activity could be reversed by allowing the sleep-deprived mice to sleep. In fact, in the hands of Rolls and her co-workers, even letting mice get only two hours of recovery sleep effectively restored the activity of their bone marrow stem cells to properly reconstitute the bone marrow of a recipient in a bone marrow transplant procedure.

“Everyone has these stem cells, and they continuously replenish our blood and immune system,” said Rolls. “We still don’t know how sleep deprivation affects us all, not just bone marrow donors. The fact that recovery sleep is so helpful only emphasizes how important it is to pay attention to sleep.”

Bone marrow transplants are used to treat patients with blood cancers, immune system disorders or others types of conditions. Each year, many thousands of bone marrow transplant procedures are performed. Therefore refining the bone marrow stem cell transplant procedure is essential to helping patients who need such a procedure.

This study was published in Nature Communications, with Asya Rolls as the lead author, who did her work in the laboratory of Irving Weissman, the director of the Stanford Institute of Stem Cell Biology and Regenerative Medicine.

New Gene Therapy Effectively Treats All Muscles in Dogs With Muscular Dystrophy


The X-linked genetic disease, muscular dystrophy, affects the structure and function of skeletal muscles. Muscular dystrophy patients harbor mutations in a gene that encodes a protein known as dystrophin. Dystrophin attaches the internal skeleton of skeletal muscle cells to the cell membrane. In turn, proteins in the skeletal muscle membrane attach to the intracellular matrix that acts as the foundational material upon which muscle cells (and other cells) sit. Therefore, the dystrophin protein serves to attach skeletal muscle cells to the extracellular matrix. The loss of dystrophin causes muscles to separate from the cell matrix and detach from each other. The lack of attachment of muscles to each other causes them to degenerate and die.

Dystrophin

The death of skeletal muscles in muscular dystrophy patients leads to the replacement of what was once skeletal muscle with scar tissue, fatty tissue, or even bone. Because muscular dystrophy is caused by mutations in an X-linked gene, the majority of muscular dystrophy patients are boys. The losses of muscle structure, function, and mass cause patients to lose their ability to walk and eventually breath (since the diaphragm is a skeletal muscle) as they age. Thus muscular dystrophy tends to put patients in wheelchairs and condemn them to respirators.

The most common form of muscular dystrophy is called Duchenne Muscular Dystrophy or DMD. Close to 250,000 people in the United States suffer from muscular dystrophy. Treatment options are very limited and usually palliative. However, a research team from the University of Missouri has successfully treated dogs that suffer from DMD. They are optimistic that human clinical trials can be planned in the next few years.

This is a remarkable finding, especially, when you consider that the dystrophin gene is extremely large. In fact, the dystrophin gene is the largest gene in the human genome. This makes gene therapy treatments for DMD problematic.

Dongsheng Duan, who serves as the lead scientist in this study, and is the Margaret Proctor Mulligan Professor in Medical Research at the MU School of Medicine “This is the most common muscle disease in boys, and there is currently no effective therapy. This discovery took our research team more than 10 years, but we believe we are on the cusp of having a treatment for the disease.

Duan continued: “Due to its size, it is impossible to deliver the entire gene with a gene therapy vector, which is the vehicle that carries the therapeutic gene to the correct site in the body,” Duan said. “Through previous research, we were able to develop a miniature version of this gene called a microgene. This minimized dystrophin protected all muscles in the body of diseased mice.”

Duan and his colleagues worked for almost ten years to develop a viable strategy that can safely transfer the micro-dystrophin gene to every muscle in a the body of dogs that have a canine form of DMD. Dogs are an excellent model system for human medicine, since dogs are about the same size as a human boy. Successful treatment of DMA dogs can provide the foundation for human clinical trials.

In this new study, Duan and his team demonstrated that by using a common virus to deliver the micro-dystrophin gene to all the muscles in the body of a diseased dog. Duan and others injected DMA dogs with this genetically engineered virus when they were two-three months old. For dogs, this is about the time when they begin to show some of the DMD-associated signs and symptoms. Now, these dogs are six-seven months old and they are experiencing normal development and muscular activity.

“The virus we are using is one of the most common viruses; it is also a virus that produces no symptoms in the human body, making this a safe way to spread the dystrophin gene throughout the body,” Duan said. “These dogs develop DMD naturally in a similar manner as humans. It’s important to treat DMD early before the disease does a lot of damage as this therapy has the greatest impact at the early stages in life.”

Bone Marrow Stem Cell Injections Restore Fertility In Mice Made Sterile by Chemotherapy


Every year, over 20,000 women of childbearing age are diagnosed with cancer. Cancer treatments often include chemotherapy regimens that damage other tissues and the ovaries and its eggs are particularly sensitive to such treatments. Consequently, many young, female, cancer survivors are infertile as a result of their cancer treatments, and suffer early menopause and ovarian failure.

Now an earth-shaking study by Egyptian and American scientists has shown that stem cell injections into the ovaries can rejuvenate them and restore the fertility of laboratory animals.

“This approach carries high promise to women with chemotherapy-induced and potentially other types of premature ovarian failure,” said Dr Sara Mohamed, lead researcher for this project.

Woman who must undergo chemotherapy are routinely advised to freeze their eggs before they undergo any cancer treatments. However this procedure is labor intensive and takes time, and in urgent cases, there is not enough time to preserve the patient’s eggs. This leaves the woman in the unsavory position of having to decide between her fertility or her life.

A procedure like the one used in this study might give female patients other options that do not force them to choose between the Scylla of their ability to have their own children and the Charybdis of their survival.

To date, this procedure has been successfully performed in laboratory mice. In this experiment, a clutch of eighteen laboratory mice were broke into three groups of six. One group of six female mice was treated with anticancer chemotherapeutic agents, followed by injections of bone marrow stem cells into their ovaries. The second group of six female mice also received chemotherapy, followed by injections of sterile saline into their ovaries. The third group, a control group, received injections of sterile saline into their ovaries without receiving prior treatments with chemotherapy.

One week after receiving their treatments, the stem cell-treated mice showed a significant increase in estrogen production. Since estrogen is a sex steroid hormone that is essential to ovulation, these results suggested that the menstrual cycles of the infertile mice was actually being reconstituted. Then a week later, mice in the stem cell-treated group showed regeneration of their ovarian tissue and increased numbers of ovarian follicles. Ovarian follicles produce the sex steroid hormones estrogen and progesterone and contain a single egg that matures during the follicular stage of the menstrual cycle and is potentially released during ovulation. These same mice, which had experienced ovarian failure as a result of chemotherapy, were able to mate with male mice, and eventually give birth to large litters of healthy mouse pups while those who had saline injections continued to suffer from reduced fertility of even infertility.

follicular-phase

These treatments worked so remarkably well, that the members of the researcher team who were involved with this project want to move to human trials as soon as possible.

Dr Sara Mohamed, of Mansoura Medical School in Egypt, who served as the lead researcher of this project, said she had come up with the idea after meeting a 22-year-old cancer patient who had a high risk of infertility from chemotherapy. Dr. Mohamed said: “It was a very emotional for me so I decided to pursue it and work on it to figure it out. It [is] a very common problem based on statistics of cancer female diagnosis every year. “

Dr. Mohamed continued: “We inject[ed] stem cells in[to] the ovaries of mice which had chemotherapy and were damaged and we got very good ovarian function restoration in form of follicle number, hormonal production, and finally getting pregnant and having new pups, which was our ultimate goal.  We are now working on translating that into clinical trials (for humans).  This approach carries high promise to women with chemotherapy-induced and potentially other types of premature ovarian failure.”

Imperial College gynecologist Stuart Lavery said: “This is very exciting piece of research that adds to our understanding of how cells differentiate to become egg stem cells.” Dr. Lavery served as a consultant on this research. I must add at this point as an aside that it is rather unlikely that the bone marrow stem cells are differentiating into eggs. Instead the bone marrow stem cells are probably augmenting the survival and health of existing eggs in the ovary.

Dr. Lavery continued: “Clearly, there remains an enormous amount of work to see whether these results would be transferable into humans. But it does provide some realistic hope that post-chemotherapy patients who have been made menopausal could one day restore ovarian function and possibly fertility.”

Dr. Mohamed and her colleagues would like to initiate human trials using umbilical cord or even embryonic stem cells. They will need to convince regulatory agencies that the procedures they have designed are safe. For this reason, I find it unlikely in the extreme that the US Food and Drug Administration (FDA) would give approval for an embryonic stem cell-based trial in the ovaries, given the large numbers of regulatory and safety hurdles other recent embryonic stem cell-based trials have had to conquer. Also, it is worth noting that the FDA has not approved other proposed trials that sought to stimulate ovarian-based stem cells. For this reason, getting FDA approval for their trial might prove difficult. Also, one mouse experiment is not going to be enough to persuade the FDA to acquiesce to their proposals. Large experiments will need to be done and large animals studies would also be needed as well.

Women who opt to freeze their eggs can use in vitro fertilization (IVF) to have their own children. Alternatively, if the eggs are fertilized with her mate’s sperm, then the embryos can development to the blastocyst stage after which they are cryopreserved (frozen) before chemotherapy for later family-building purposes.

Such a strategy leads to some problems in countries with nationalized medicine: some provinces have decreased funding for IVF, since IVF is very expensive and the demand is below the cost to maintain such faculties. Likewise, at times, female cancer patients are denied the option of cryopreservation, again because of the costs and the lack of a nearby facility that has the space, means, or funding to keep her embryos on ice for a time. A new regenerative therapy might give such a female patient some solace with regards to her future fertility.

A consultant in Reproductive Medicine and Surgery at Hammersmith Hospital, London, Dr Geoffrey Trew, said of this research: “Fertility-wise, if this works it would be stupendous. Certainly it does appear promising and anything you can do to regenerate and ovary is a good thing. Theoretically if you are regenerating the ovary you should be getting better quality eggs. Clearly we’re not here yet, and it’s good that the researchers are not over-claiming their findings, but it’s a great proof of concept.”

Dr Edgar Mocanu, consultant gynecologist at Rotunda Hospital in Dublin and a board member of the International Federation of Fertility Societies, said: “This could open phenomenal opportunities for women. Millions of women around the world undergo cancer treatment and some of them will become infertile through ovarian failure. While cancer survival rates have increased dramatically, to date there is no effective method of preventing infertility after chemotherapy. It could also open new avenues for the treatment of menopause induced health issues.”

Dr Owen Davis president of the American Society for Reproductive Medicine: “If this experimental treatment can be translated to women who have lost ovarian function from chemotherapy, it will be a great advance. Restoring ovarian hormone production, follicle development and fertility to chemotherapy patients is a potential new application for bone marrow donation that could help many women.”

Anti-Aging Protein GDF11: Does it Work?


The protein is called GDF11 and some scientists claim that is can rejuvenate older laboratory animals and make them healthier. Sounds like science fiction, but could it be true?

Several decades ago, in the 1950s, some creative and enterprising scientists connected the circulatory systems of two inbred mice, one of which was old and the second of which was young. The blood from the young mouse seemed to rejuvenate the older mouse. That led to a question: “If blood from younger mouse rejuvenated the older mouse, what was it in the blood that did it?” Further work has landed on GDF11 as the rejuvenating protein, but the experimental path to this protein has been fraught with false starts, bumps, and wrong turns. New work by a team of Harvard University scientists hopes to set the record straight on GDF11.

Work by Harvard stem cell biologist Amy Wagers, cardiologist Richard Lee and the members of their laboratories and their collaborators have discovered that the blood concentrations of GDF11 drop in mice as they age. Such a finding is a correlation, which might be suggestive, but it falls short of proving that GDF11 is an anti-aging protein. However, Wagers and Lee and their colleagues also showed that when older mice are injected with GDF11, the protein partially reverses the thickening of the heart that comes with age. Wagers and her team also showed in two papers that were published in the journal Science that administration of GDF11 can rejuvenate the muscles and brains of older mice.

Wagers’ findings, however, received some push-back in May, 2015. According to Jocelyn Kaiser, writing at the Science web site, David Glass, who works at the Novartis Institutes for Biomedical Research in Cambridge, Massachusetts, and his colleagues have made use of an antibody that specifically binds to GDF11 to detect the protein and measure its concentration in the blood and tissues. Experiments with the anti-GDF11 antibody revealed that blood levels of GDF11 increase as rats and people get older. Also, in the hands of Glass and his team, injected GDF11 protein inhibited muscle regeneration in young mice. Furthermore, work from Steven Houser’s group at Temple University in Philadelphia, Pennsylvania, has shown that injections of GDF11 do not decrease the age-related thickening of the hearts of older mice. Now we have a genuine scientific controversy: so who’s right?

Wagers and Lee have concluded that the specific assay Novartis used to detect GDF11 and a related protein (GDF8 or myostatin) did not work properly. In their own experiments, the combined efforts of the Wagers and Lee teams showed that the main protein detected by the antibody test designed and used by the Glass group is immunoglobulin (antibodies). The levels of antibody proteins in the blood are known to rise in the blood as people get older. As a control, when the Wagers and Lee group used the Novartis-designed test to measure the proteins levels of laboratory mice that do not possess the gene that encodes antibodies, the blood of those mice tested negative. According to Jocelyn Kaiser, these data were published in a paper that appeared in the journal Circulation Research.

Wagers summarized the results of her and Lee’s laboratories, “They actually had very consistent findings to ours with respect to the blood levels of GDF11/8 with the antibody we all used.” However, according to Wagers, “their interpretation was confused by this case of mistaken identity.” To corroborate her point, Wagers cited a recently published study by scientists from the University of California, San Francisco, who found that GDF11/8 blood levels decline as people age, and are low in heart disease patients. These results support the hypothesis that GDF11 has antiaging activity.

The Harvard team’s paper also examined the results from the Houser laboratory. According to Wagers, Houser and his colleagues utilized commercially purchased GDF11, and this source of protein can vary in activity and levels. Wagers noted that it “wasn’t something that affected us early on, but we figured out it was an issue. The variability of commercially purchased GDF11 might explain why Houser and his colleagues were unable to see any results from injected GDF11. Houser and his team were quite careful to make sure that they injected the same dose of GDF11 as the Wagers and Lee. However, Wagers pointed out that if only a fraction of the protein was as active as the protein used by Wagers and Lee, then it is likely that Houser and his group actually used a lower effective dose than the Harvard group. Lee has also noted that he and his group have data that suggests that the GDF11 dose they used was actually higher than they initially thought.

Wagers and others also showed that daily injections of GDF11 can shrink heart muscle in both old and new mice, and, incredibly, the mice also lost weight. “We don’t have much insight into that right now, but we’re looking into it,” Wagers says. Wagers suspects that GDF11 only works within a particular therapeutic concentration, outside of which is will not work and above which it might cause side effects that are harmful.

What does the competition think? Houser thinks that Wager and Lee are probably correct that at least one of the assays used by the Novartis team to measure GDF11 detected immunoglobulin. However, both Houser David Glass have pointed out that the Novartis team used a different GDF11 detection assay whose accuracy was not challenged by the work in this new paper.

Houser remains sanguine about finding molecules that can delay aging.  “I’m going to be 65 in a couple months. I’d love to have something that improves my heart, brain, and muscle function,” said Houser. “I think the field is going to figure this out and this is another piece of the puzzle.”

The jury is still out when it comes to GDF11, but Wagers and Lee have made a positive contribution to a robust and thrillingly interesting scientific discussion.