Back in 2007 scientists announced that they had created embryonic like stem cells from adult human skin cells. IPS cells (induced pluripotent stem cells) have been very valuable in research, however converting them into any type of cell that could be used for actual stem cell therapy is extremely complicated and far from becoming safe or available. Embryonic stem cells exist to create an entire organism not to repair an adult. A new breakthrough allows researchers to take differentiated cells from potentially any part of the body and reverse age them without going all the way back to an embryonic like state. In a study of mice these have already been used successfully for cell replacement therapy. This may be the breakthrough needed to rebuild damaged, diseased or old organs with a few injections back to a young and healthy condition in the not too distant future.

A modified version of iPS methodology, the new approach is called interrupted reprogramming and it allows for a highly controlled, potentially safer, and more cost-effective strategy for generating progenitor-like cells from adult cells. As demonstrated November 30 in the journal Stem Cell Reports, researchers in Canada converted adult mouse respiratory tract cells called Club cells into large, pure populations of induced progenitor-like (iPL) cells, which retained a residual memory of their parental cell lineage and therefore specifically generated mature Club cells. Moreover, these cells showed potential as a cell replacement therapy in mice with cystic fibrosis.

“A major block in the critical path of regenerative medicine is the lack of suitable cells to restore function or repair damage,” says co-senior author Tom Waddell, a thoracic surgeon at the University of Toronto. “Our approach starts with purifying the cell type we want and then manipulating it to give those cell types characteristics of progenitor cells, which can grow rapidly but produce only a few cell types. As such, it is much more direct, more rapid, and the batches of cells are more purified.”

In recent years, induced pluripotent stem (iPS) cells have generated a great deal of interest as a potentially unlimited source of various cell types for transplantation. This method involves genetically reprogramming skin cells taken from adult donors to an embryonic stem-cell-like state, growing these immature cells to large numbers, and then converting them into specialized cell types found in different parts of the body. A major advantage of this approach is the ability to generate patient-specific iPS cells for transplantation, thereby minimizing the risk of harmful immune reactions.

Despite significant progress, these protocols remain limited by low yield and purity of the desired mature cell types, as well as the potential of immature cells to form tumors. Moreover, there is no standardized approach applicable to all cell types, and the development of personalized therapies based on patient-derived pluripotent cells remains very expensive and time consuming. “We have pursued cell therapy for lung diseases for many years,” Waddell says. “One key issue is how to get the right type of cells and lots of them. To avoid rejection, we need to use cells from the actual patient.”

To address these issues, Waddell and co-senior study author Andras Nagy of Mount Sinai Hospital developed an interrupted reprogramming strategy, which is a modified version of the iPS methodology. The researchers started to genetically reprogram adult Club cells isolated from mice, transiently expressing the four iPS reprogramming factors, but interrupted the process early, prior to reaching the pluripotent state, to generate progenitor-like cells, which are more committed to a specific lineage and show more controlled proliferation than pluripotent cells.

“The reprogramming process had previously been considered as an all-or-none process,” Waddell says. “We were surprised to the extent that it can be fine-tuned by the timing and dosing of the drug used to activate the reprogramming factors. That is interesting as it gives lots of opportunities for control, but it does mean we have lots of work to do to get it right.”

The researchers showed that the resulting Club-iPL cells could give rise to not only Club cells, but also to other respiratory tract cells such as mucus-secreting goblet cells and ciliated epithelial cells that produce the CFTR protein, which is mutated in patients with cystic fibrosis. When the Club-iPL cells were administered to CFTR-deficient mice, the cells incorporated into tissue lining the respiratory tract and partially restored levels of CFTR in the lungs without inducing tumor formation. This technology can theoretically be applied to almost any cell type that can be isolated and purified, and isolation of highly purified populations of adult cells from most organs is already possible with existing techniques.

“To create specialized cell types for use in cell therapy requires only that we insert the genes (or use non-transgenic approaches) and then test the drug dose and timing required for each cell type and each patient, so it should be relatively scalable at low cost compared to other approaches using each patient’s own cells,” Waddell says. “It should be very easy for other labs to use a similar approach.”

According to the authors, the approach could be used for a variety of regenerative medicine practices, including cell replacement therapy, disease modelling, and drug screening for human diseases. But there is still a long way to go before clinical translation. For their own part, the researchers plan to test this approach with other cell types, including human cells. They will also try to determine if there are safe ways to engraft these cells in human lungs. “The study is a proof of principle, the way this concept may ultimately be used in humans could be different, and it will be many years before this will be attempted in humans,” Waddell says.

Reference: Li Guo, Golnaz Karoubi, Pascal Duchesneau, Maria V. Shutova, Hoon-Ki Sung, Peter Tonge, Christine Bear, Ian Rogers, Andras Nagy, Thomas K. Waddell. Generation of Induced Progenitor-like Cells from Mature Epithelial Cells Using Interrupted Reprogramming. Stem Cell Reports, 2017; DOI: 10.1016/j.stemcr.2017.10.022

A researcher at the School of Medicine and his colleagues have succeeded in isolating mouse lung stem cells, growing them in large volumes and incorporating them into injured lung tissue in mice.

The work raises hopes for regenerative therapies that could heal currently intractable lung diseases.

A study describing the research was published online Nov. 6 in Nature Methods. Kyle Loh, PhD, an investigator at the Stanford Institute for Stem Cell Biology and Regenerative Medicine, and Bing Lim, MD, PhD, an investigator at the Genome Institute of Singapore, share senior authorship. The lead author is Massimo Nichane, PhD, currently a research scientist at the Stanford stem cell institute.

The lungs are among the most vital organs of the body. In conjunction with the cardiovascular system, they allow air to travel to every cell and get rid of the waste products of respiration, such as carbon dioxide. For many people with end-stage lung diseases, the only option is lung transplantation.

“Scientists have previously had little success in putting new lung cells into damaged lung to regenerate healthy tissue,” Loh said. “We decided to see if we could do that in an animal model.”

The researchers started by working to improve on current knowledge of lung stem cells. The lung is divided into two compartments, Loh said: the airway, which allows for passage of air in and out of the lung; and the alveoli, where gases pass in and out of the blood. Other researchers had previously isolated one stem cell for the airway and another stem cell for the alveoli. Loh and his colleagues searched for and found a single lung stem cell that could create cells in both the airway and the alveoli. These multipotent lung stem cells were typified by their display of a protein marker called Sox9.

Once they had isolated the stem cells, they were able to make them multiply dramatically. Each mouse lung stem cell that they start started with was able to grow into 100 billion billion lung stem cells over the course of six months. Previously, researchers had not had much success expanding any lung stem cell populations in the laboratory.

Finally, they injected the stem cells into mouse lungs that had been injured by a variety of toxins. “What we saw was that these multipotent stem cells repaired the injured tissue and were able to differentiate into the many different kinds of cells that make up the healthy lung,” said Nichane.

“Our newfound ability to grow these mouse multipotent lung stem cells in a petri dish in very large numbers, and the cells’ ability to regenerate both lung airway and alveolar tissue, constitutes a first step towards future lung regenerative therapies,” Loh said. “Future work will focus on whether analogous multipotent stem cells can be found and cultivated from humans, which may open the way to eventually replenishing damaged lung tissue in the clinic.”

Reference: Massimo Nichane et al. Isolation and 3D expansion of multipotent Sox9+ mouse lung progenitors, Nature Methods (2017). DOI: 10.1038/nmeth.4498

Engineered tissue containing human stem cells has allowed paraplegic rats to walk independently and regain sensory perception. The implanted rats also show some degree of healing in their spinal cords. The research, published in Frontiers in Neuroscience, demonstrates the great potential of stem cells undifferentiated cells that can develop into numerous different types of cells to treat spinal cord injury.

Spinal cord injuries often lead to paraplegia. Achieving substantial recovery following a complete spinal cord tear, or transection, is an as-yet unmet challenge.

Led by Dr. Shulamit Levenberg, of the Technion-Israel Institute of Technology, the researchers implanted human stem cells into rats with a complete spinal cord transection. The stem cells, which were derived from the membrane lining of the mouth, were induced to differentiate into support cells that secrete factors for neural growth and survival.

The work involved more than simply inserting stem cells at various intervals along the spinal cord. The research team also built a three-dimensional scaffold that provided an environment in which the stem cells could attach, grow and differentiate into support cells. This engineered tissue was also seeded with human thrombin and fibrinogen, which served to stabilize and support neurons in the rat’s spinal cord.

Rats treated with the engineered tissue containing stem cells showed higher motor and sensory recovery compared to control rats. Three weeks after introduction of the stem cells, 42% of the implanted paraplegic rats showed a markedly improved ability to support weight on their hind limbs and walk. 75% of the treated rats also responded to gross stimuli to the hind limbs and tail.

In contrast, control paraplegic rats that did not receive stem cells showed no improved mobility or sensory responses.

In addition, the lesions in the spinal cords of the treated rats subsided to some extent. This indicates that their spinal cords were healing.

While the results are promising, the technique did not work for all implanted rats. An important area for further research will be to determine why stem cell implantation worked in some cases but not others. As the research team notes, “This warrants further investigation to shed light on the mechanisms underlying the observed recovery, to enable improved efficacy and to define the intervention optimal for treatment of spinal cord injury.”

Although the study in itself does not solve the challenge of providing medical treatments for spinal cord injury in humans, it nevertheless points the way to that solution. As Dr. Levenberg puts it: “Although there is still some way to go before it can be applied in humans, this research gives hope.”

Reference: Javier Ganz, Erez Shor, Shaowei Guo, Anton Sheinin, Ina Arie, Izhak Michaelevski, Sandu Pitaru, Daniel Offen, Shulamit Levenberg. Implantation of 3D Constructs Embedded with Oral Mucosa-Derived Cells Induces Functional Recovery in Rats with Complete Spinal Cord Transection. Frontiers in Neuroscience, 2017; 11 DOI: 10.3389/fnins.2017.00589

Easy strength training exercises which require no equipment such as wall push ups or ordinary push ups could add years to your life according to a new study of over 80,000 adults led by the University of Sydney.

The largest study to compare the mortality outcomes of different types of exercise found people who did strength-based exercise had a 23 percent reduction in risk of premature death by any means, and a 31 percent reduction in cancer-related death.

Lead author Associate Professor Emmanuel Stamatakis from the School of Public Health and the Charles Perkins Centre said while strength training has been given some attention for functional benefits as we age, little research has looked at its impact on mortality.

“The study shows exercise that promotes muscular strength may be just as important for health as aerobic activities like jogging or cycling,” said Associate Professor Stamatakis.

“And assuming our findings reflect cause and effect relationships, it may be even more vital when it comes to reducing risk of death from cancer.”

The World Health Organization’s Physical Activity Guidelines for adults recommend 150 minutes of aerobic activity, plus two days of muscle strengthening activities each week.

Associate Professor Stamatakis said governments and public health authorities have neglected to promote strength-based guidelines in the community, and as such misrepresented how active we are as a nation.

He cites the example of The Australian National Nutrition and Physical Activity Survey which, based on aerobic activity alone, reports inactivity at 53 percent. However, when the World Health Organization’s (WHO) strength-based guidelines are also taken into account, 85 percent of Australians fail to meet recommendations.

“Unfortunately, less than 19 percent of Australian adults do the recommended amount of strength-based exercise,” said Associate Professor Stamatakis.

“Our message to date has just been to get moving but this study prompts a rethink about, when appropriate, expanding the kinds of exercise we are encouraging for long-term health and wellbeing.”

The analysis also showed exercises performed using one’s own body weight without specific equipment were just as effective as gym-based training.

“When people think of strength training they instantly think of doing weights in a gym, but that doesn’t have to be the case.

“Many people are intimidated by gyms, the costs or the culture they promote, so it’s great to know that anyone can do classic exercises like triceps dips, sit-ups, push-ups or lunges in their own home or local park and potentially reap the same health benefits.”

The research, published in the American Journal of Epidemiology today, is based on a pooled population sample of over 80,306 adults with data drawn from the Health Survey for England and Scottish Health Survey, linked with the NHS Central Mortality Register.

The study was observational, however adjustments were made to reduce the influence of other factors such as age, sex, health status, lifestyle behaviours and education level. All participants with established cardiovascular disease or cancer at baseline and those who passed away in the first two years of follow up were excluded from the study to reduce the possibility of skewing results due to those with pre-existing conditions participating in less exercise.

Key findings:

?Participation in any strength-promoting exercise was associated with a 23 percent reduction in all-cause mortality and a 31 percent reduction in cancer mortality

?Own bodyweight exercises that can be performed in any setting without equipment yielded comparable results to gym-based activities

?Adherence to WHO’s strength-promoting exercise guideline alone was associated with reduced risk of cancer-related death, but adherence to the WHO’s aerobic physical activity guideline alone was not

?Adherence to WHO’s strength-promoting exercise and aerobic guidelines combined was associated with a greater risk reduction in mortality than aerobic physical activity alone

?There was no evidence of an association between strength-promoting exercise and cardiovascular disease mortality.

Reference: Emmanuel Stamatakis, I-Min Lee, Jason Bennie, Jonathan Freeston, Mark Hamer, Gary O’Donovan, Ding Ding, Adrian Bauman, Yorgi Mavros. Does strength promoting exercise confer unique health benefits? A pooled analysis of eleven population cohorts with all-cause, cancer, and cardiovascular mortality endpoints. American Journal of Epidemiology, 2017; DOI: 10.1093/aje/kwx345

As scientists work to unlock the mysteries of why some 80-year-olds play tennis every week while others must live in nursing homes, researchers with the University of Miami?s Interdisciplinary Stem Cell Institute report they have found the beginnings of what may be the first therapeutic treatment for frailty, a common condition of aging that can lead to falls and other adverse effects. An early stage clinical trial conducted in Miami found that elderly patients breathed easier and walked longer distances after receiving a single infusion of stem cells from young and healthy donors.

Scientists have been making significant headway recently, studying a variety of anti-aging targets from discovering a protein that can restore hair and improve fitness in old mice to revealing how fecal transplants increase the lifespan of some fish. But the arena of stem cell transplantation has offered some of the most exciting anti-aging research outcomes.

Mesenchymal stem cells (MSCs) are a particular type of adult stem cell generating a great deal of interest in the world of science. MSCs are currently being trialed as treatment for no less than a dozen different types of conditions.

The results of two human clinical trials into a stem cell therapy that can reverse symptoms of age-associated frailty have been published, and the indications are that this landmark treatment is both safe and strikingly effective in tackling key factors in aging.

This new MSC treatment is targeted at reducing the effects of frailty on senior citizens. This is the first anti-aging stem cell treatment directed specifically at the problem of age-associated frailty to move close to a final FDA approval stage.

The treatment derives human mesenchymal stem cells from adult donor bone marrow and in these clinical trials involves a single infusion in patients with an average age of 76. Both Phase 1 and Phase 2 human trials have demonstrated the treatment to have no adverse health effects.

Although the two human trials were ostensibly designed to just demonstrate safety they do offer remarkable results in efficacy as well, paving the way for larger, Phase 3 clinical trials.

In the first trial 15 frail patients received a single MSC infusion collected from bone marrow donors aged between 20 and 45 years old. Six months later all patients demonstrated improved fitness outcomes, tumor necrosis factor levels and overall quality of life.

The second trial was a randomized, double blind study with placebo group. Again no adverse affects were reported and physical improvements were noted by the researchers as “remarkable”.

“There are always caveats associated with interpreting efficacy in small numbers of subjects, yet it is remarkable that a single treatment seems to have generated improvement in key features of frailty that are sustained for many months,” writes David G. Le Couter and colleagues in a guest editorial in The Journals of Gerontology praising the research.

The next stage for the research is to move into an expanded Phase 2b clinical trial involving 120 subjects across 10 locations. After that a final, large randomized Phase 3 clinical trial will be the only thing holding the treatment back from final public approval by the FDA.

“With the aging of the population, stem cells hold great promise to treat aging-related disability and frailty, improving physical capacity and quality of life,” says one of the scientists working on the project Joshua M. Hare, Director of the Interdisciplinary Stem Cell Institute at the University of Miami Miller School of Medicine.

“There is no FDA approved treatment for aging frailty and an enormous unmet need that will only increase with the changing demographics.”

The results of the Phase 1 and Phase 2 clinical trials were recently published in The Journals of Gerontology.

References

Phase 1 Trial: Samuel Golpanian Darcy L DiFede Aisha Khan Ivonne Hernandez Schulman Ana Marie Landin Bryon A Tompkins Alan W Heldman Roberto Miki Bradley J Goldstein Muzammil Mushtaq Silvina Levis-Dusseau John J Byrnes Maureen Lowery Makoto Natsumeda Cindy Delgado Russell Saltzman Mayra Vidro-Casiano Marietsy V Pujol Moisaniel Da Fonseca Anthony A Oliva, Jr Geoff Green Courtney Premer Audrey Medina Krystalenia Valasaki Victoria Florea Erica Anderson Jill El-Khorazaty Adam Mendizabal Pascal J Goldschmidt-Clermont Joshua M Hare; Allogeneic Human Mesenchymal Stem Cell Infusions for Aging Frailty; The Journals of Gerontology: Series A, Volume 72, Issue 11, 12 October 2017, Pages 1505?1512, https://doi.org/10.1093/gerona/glx056

Phase 2 Trial: Bryon A Tompkins, MD Darcy L DiFede, RN, BSN Aisha Khan, Msc, MBA Ana Marie Landin, PhD Ivonne Hernandez Schulman, MD Marietsy V Pujol, MBA Alan W Heldman, MD Roberto Miki, MD Pascal J Goldschmidt-Clermont, MD Bradley J Goldstein, MD Muzammil Mushtaq, MD Silvina Levis-Dusseau, MD John J Byrnes, MD Maureen Lowery, MD Makoto Natsumeda, MD Cindy Delgado, MA, CCRC Russell Saltzman, BS.Ed Mayra Vidro-Casiano, MPH Moisaniel Da Fonseca, AA Samuel Golpanian, MD Courtney Premer, PhD Audrey Medina, BSc Krystalenia Valasaki, MSc Victoria Florea, MD Erica Anderson, MA Jill El-Khorazaty, MS Adam Mendizabal, PhD Geoff Green, BA, MBA Anthony A Oliva, PhD Joshua M Hare, MD; Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial; The Journals of Gerontology: Series A, Volume 72, Issue 11, 12 October 2017, Pages 1513?1522, https://doi.org/10.1093/gerona/glx137

People who are overweight cut their life expectancy by two months for every extra kilogram (2.2 pounds) of weight they carry, research suggests.

A major study of the genes that underpin longevity has also found that education leads to a longer life, with almost a year added for each year spent studying beyond school.

Other key findings are that people who give up smoking, study for longer and are open to new experiences might expect to live longer.

Scientists at the University of Edinburgh analysed genetic information from more than 600,000 people alongside records of their parents’ lifespan.

Because people share half of their genetic information with each of their parents, the team were able to calculate the impact of various genes on life expectancy.

Lifestyle choices are influenced to a certain extent by our DNA/genes, for example, have been linked to increased alcohol consumption and addiction. The researchers were therefore able to work out which have the greatest influence on lifespan.

Their method was designed to rule out the chances that any observed associations could be caused by a separate, linked factor. This enabled them to pinpoint exactly which lifestyle factors cause people to live longer, or shorter, lives.

They found that cigarette smoking and traits associated with lung cancer had the greatest impact on shortening lifespan.

For example, smoking a packet of cigarettes per day over a lifetime knocks an average of seven years off life expectancy, they calculated. But smokers who give up can eventually expect to live as long as somebody who has never smoked.

Body fat and other factors linked to diabetes also have a negative influence on life expectancy.

The study also identified two new DNA differences that affect lifespan. The first is a gene that affects blood cholesterol levels and reduces lifespan by around eight months. The second is a gene linked to the immune system that adds around half a year to life expectancy.

The research, published in Nature Communications, was funded by the Medical Research Council.

Data was drawn from 25 separate population studies from Europe, Australia and North America, including the UK Biobank which is a major study into the role of genetics and lifestyle in health and disease.

Professor Jim Wilson, of the University of Edinburgh’s Usher Institute, said: “The power of big data and genetics allow us to compare the effect of different behaviours and diseases in terms of months and years of life lost or gained, and to distinguish between mere association and causal effect.”

Dr Peter Joshi, Chancellor’s Fellow at the University of Edinburgh’s Usher Institute, said: “Our study has estimated the causal effect of lifestyle choices. We found that, on average, smoking a pack a day reduces lifespan by seven years, whilst losing one kilogram of weight will increase your lifespan by two months.”

Reference: Peter K. Joshi, Nicola Pirastu, […], James F. Wilson. Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity. Nature Communications, 2017; 8 (1) DOI: 10.1038/s41467-017-00934-5

Researchers at the Institute of Molecular Biology (IMB) in Mainz have made a breakthrough in understanding the origin of the aging process. They have identified that genes belonging to a process called autophagy, which is one of the cells most critical survival processes, promote health and fitness in young worms but drive the process of aging later in life. This research published in the journal Genes & Development gives some of the first clear evidence for how the aging process arises as a quirk of evolution. The researchers show that by promoting longevity through shutting down autophagy in old worms there is a strong improvement in neuronal and subsequent whole body health.

Getting old is something that happens to everyone and nearly every species on this planet, but the question is: should it? In a recent publication in the journal Genes & Development titled “Neuronal inhibition of the autophagy nucleation complex extends lifespan in post-reproductive C. elegans,” Dr. Holger Richly’s lab at IMB has found some of the first genetic evidence that may put this question to rest.

According to Jonathan Byrne, co-lead author of the paper: “These AP genes had not been found before because it is incredibly difficult to work with already old animals. We were the first to figure out how to do this on a large scale. From a relatively small screen, we found a surprisingly large number of genes that seem to operate in an antagonistic fashion.” Previous studies had found genes that encourage aging while still being essential for development, but the 30 genes the IMB researchers found represent some of the first found promoting aging specifically only in old worms. “Considering we tested only 0.05 percent of all the genes in a worm this suggests there could be many more of these genes out there to find,” stated Byrne.

According to Thomas Wilhelm, the other co-lead author of the paper. “What was most surprising was what processes those genes were involved in.” Not content to provide just the missing evidence for a 60-year-old puzzle, Wilhelm and his colleagues went on to describe what a subset of these genes do in C. elegans and how they might be driving the aging process. “This is where the results really get fascinating,” emphasized Dr. Holger Richly, the principal investigator of the study. “We found a series of genes involved in regulating autophagy, which accelerate the aging process.” These results are surprising indeed as the process of autophagy is a critical recycling process in the cell and is usually required to live a normal full lifetime. Autophagy is known to become slower with age and the authors of this paper show that it appears to completely deteriorate in older worms. They demonstrate that shutting down key genes in the initiation of the process allows the worms to live longer compared with leaving it running crippled. “This could force us to rethink our ideas about one of the most fundamental processes that exist in a cell,” Richly explained. “Autophagy is nearly always thought of as beneficial even if it is barely working. We instead show that there are severe negative consequences when it breaks down and then you are better off bypassing it all together. It is classic AP: in young worms, autophagy is working properly and is essential to reach maturity, but after reproduction it starts to malfunction causing the worms to age,” he continued.

In a final revelation, Richly and his team were able to track the source of the pro longevity signals to a specific tissue, namely the neurons. By inactivating autophagy in the neurons of old worms they were not only able to prolong the worms life but they increased the total health of the worms dramatically. “Imagine reaching the halfway point in your life and getting a drug that leaves you as fit and mobile as someone half your age and you even live longer. That is what it is like for the worms,” said Thomas Wilhelm. “We turn autophagy off only in one tissue and the whole animal gets a boost. The neurons are much healthier in the treated worms and we think this keeps the muscles and the rest of the body in good shape. The net result is a 50 percent extension of life.”

While the authors do not yet know the exact mechanism causing the neurons to stay healthier for longer, this finding could have wide implications. “It is possible that these autophagy genes could represent a good way to help preserve neuronal integrity in these cases,” elaborated Thomas Wilhelm. While any such treatment would be a long way off, assuming such findings could be recapitulated in humans it offers a tantalising hope for being able to prevent disease and get younger and healthier while doing so.

Reference: Thomas Wilhelm, Jonathan Byrne, Rebeca Medina, Ena Kolund?i?, Johannes Geisinger, Martina Hajduskova, Baris Tursun, Holger Richly. Neuronal inhibition of the autophagy nucleation complex extends life span in post-reproductive C. elegans. Genes & Development, 2017; 31 (15): 1561 DOI: 10.1101/gad.301648.117

One of regenerative medicine’s most compelling questions is why some organisms can regenerate major body parts such as hearts and limbs while others, such as humans, cannot. The answer may lie with the body’s innate immune system, according to a new study of heart regeneration in the axolotl, or Mexican salamander, an organism that takes the prize as nature’s champion of regeneration.

The study, which was conducted by James Godwin, Ph.D., of the MDI Biological Laboratory in Bar Harbor, Maine, found that the formation of new heart muscle tissue in the adult axolotl after a heart attack is dependent on the presence of macrophages, a type of white blood cell. When macrophages were depleted, the salamanders formed permanent scar tissue that blocked regeneration.

The study has significant implications for human health. Since salamanders and humans share many of the same genes, it’s possible that the ability to regenerate is also built into our genetic code.

Godwin’s research demonstrates that scar formation plays a critical role in blocking the program for regeneration. “The scar shoots down the program for regeneration,” he said. “No macrophages means no cardiac regeneration.”

Godwin’s goal is to activate regeneration in humans through the use of drug therapies derived from macrophages that would promote scar-free healing directly, or those that would trigger the genetic programs controlling the formation of macrophages, which in turn could promote scar-free healing. His team is already looking at molecular targets for drug therapies to influence these genetic programs.

“If humans could get over the fibrosis hurdle in the same way that salamanders do, the system that blocks regeneration in humans could potentially be broken,” Godwin explained. “We don’t know yet if it’s only scarring that prevents regeneration or if other factors are involved. But if we’re really lucky, we might find that the suppression of scarring is sufficient in and of itself to unlock our endogenous ability to regenerate.”

The prevailing view in regenerative biology has been that the major obstacle to heart regeneration in mammals is insufficient proliferation of cardiomyocytes, or heart muscle cells. But Godwin found that cardiomyocyte proliferation is not the only driver of effective heart regeneration. His findings suggest that research efforts should pay more attention to the genetic signals controlling scarring.

The extraordinary incidence of disability and death from heart disease, which is the world’s biggest killer, is directly attributable to scarring. When a human experiences a heart attack, scar tissue forms at the site of the injury. While the scar limits further tissue damage in the short term, over time its stiffness interferes with the heart’s ability to pump, leading to disability and ultimately to terminal heart failure.

In addition to regenerating heart tissue following a heart attack, the ability to unlock dormant capabilities for regeneration through the suppression of scarring also has potential applications for the regeneration of tissues and organs lost to traumatic injury, surgery and other diseases, Godwin said.

Godwin’s findings are a validation of the MDI Biological Laboratory’s unique research approach, which is focused on studying regeneration in a diverse range of animal models with the goal of gaining insight into how to trigger dormant genetic pathways for regeneration in humans. In the past year and a half, laboratory scientists have discovered three drug candidates with the potential to activate regeneration in humans.

“Our focus on the study of animals with amazing capabilities for regenerating lost and damaged body parts has made us a global leader in the field of regenerative medicine,” said Kevin Strange, Ph.D., MDI Biological Laboratory president. “James Godwin’s discovery of the role of macrophages in heart regeneration demonstrates the value of this approach: we won’t be able to develop rational and effective therapies to enhance regeneration in humans until we first understand regeneration works in animals like salamanders.”

Godwin, who is an immunologist, originally chose to look at the function of the immune system in regeneration because its role as the equivalent of a first responder at the site of an injury means that it is responsible for preparing the ground for tissue repairs. The recent study was a follow-up to an earlier study which found that macrophages also play a critical role in limb regeneration.

The next step is to study the function of macrophages in salamanders and compare them with their human and mouse counterparts. Ultimately, Godwin would like to understand why macrophages produced by adult mice and humans don’t suppress scarring in the same way as in axolotls and then identify molecules and pathways that could be exploited for human therapies.

Godwin holds a dual appointment with The Jackson Laboratory, also located in Bar Harbor, which is focused on the mouse as a model animal. The dual appointment allows him to conduct experiments that compare genetic programming in the highly regenerative animals used as models at the MDI Biological Laboratory with genetic programming in neonatal and adult mice.

Reference: J. W. Godwin, R. Debuque, E. Salimova, N. A. Rosenthal. Heart regeneration in the salamander relies on macrophage-mediated control of fibroblast activation and the extracellular landscape. npj Regenerative Medicine, 2017; 2 (1) DOI: 10.1038/s41536-017-0027-y