Wellcome Trust Sanger Institute scientists and their collaborators at the University of Cambridge have created a new technique that simplifies the production of human brain and muscle cells allowing millions of functional cells to be generated in just a few days. The results published in Stem Cell Reports open the door to producing a diversity of new cell types that could not be made before.

Human pluripotent stem cells offer the ability to create any tissue, including those which are typically hard to access, such as brain cells.

In a human, it takes nine to twelve months for a single brain cell to develop fully. To create human brain cells, including grey matter (neurons) and white matter (oligodendrocytes) from an induced pluripotent stem cell, it can take between three and twenty weeks using current methods. However, these methods are complex and time-consuming, often producing a mixed population of cells.

The new platform technology, OPTi-OX, optimises the way of switching on genes in human stem cells. Scientists applied OPTi-OX to the production of millions of nearly identical cells in a matter of days. In addition to the neurons, oligodendrocytes, and muscle cells the scientists created in the study, OPTi-OX holds the possibility of generating any cell type at unprecedented purities, in this short timeframe.

To produce the neurons, oligodendrocytes, and muscle cells, scientists altered the DNA in the stem cells. By switching on carefully selected genes, the team “reprogrammed” the stem cells and created a large and nearly pure population of identical cells. The ability to produce as many cells as desired combined with the speed of the development gives an advantage over other methods. The new method opens the door to drug discovery, and potentially therapeutic applications in which large amounts of cells are needed.

An author of the study, Dr Ludovic Vallier from the Wellcome Trust Sanger Institute said: “What is really exciting is we only needed to change a few ingredients — transcription factors — to produce the exact cells we wanted in less than a week. We over-expressed factors that make stem cells directly convert into the desired cells, thereby bypassing development and shortening the process to just a few days.”

OPTi-OX has applications in various projects, including the possibility to generate new cell types which may be uncovered by the Human Cell Atlas. The ability to produce human cells so quickly means the new method will facilitate more research.

Joint first author, Daniel Ortmann from the University of Cambridge, said: “When we receive a wealth of new information on the discovery of new cells from large scale projects, like the Human Cell Atlas, it means we’ll be able to apply this method to produce any cell type in the body, but in a dish.”

Mark Kotter, lead author and Clinician from the University of Cambridge, said: “Neurons produced in this study are already being used to understand brain development and function. This method opens the doors to producing all sorts of hard-to-access cells and tissues so we can better our understanding of diseases and the response of these tissues to newly developed therapeutics.”

Reference: Matthias Pawlowski, Daniel Ortmann, Alessandro Bertero, Joana M. Tavares, Roger A. Pedersen, Ludovic Vallier, Mark R.N. Kotter. Inducible and Deterministic Forward Programming of Human Pluripotent Stem Cells into Neurons, Skeletal Myocytes, and Oligodendrocytes. Stem Cell Reports, 2017; DOI: 10.1016/j.stemcr.2017.02.016

More and more Americans are demanding food free of synthetic chemicals. But tests by the U.S. Department of Agriculture found that nearly 70 percent of samples of 48 types of conventionally grown produce were contaminated with pesticide residues.

The USDA found a total of 178 different pesticides and pesticide breakdown products on the thousands of produce samples it analyzed. The pesticides persisted on fruits and vegetables even when they were washed and, in some cases, peeled.

But there are stark differences in the number and amount of pesticides on various types of produce. The Environmental Working Group’s annual Shopper’s Guide to Pesticides in Produce lists the 12 fruits and vegetables with the most pesticide residues, and the 15, for which few, if any, residues were detected.

When buying organic produce is not an option, use the Shopper’s Guide to choose foods lower in pesticide residues. With the Shopper’s Guide, you can have the health benefits of a diet rich in fruits and vegetables while limiting your exposure to pesticides.

This year the list of produce with the highest loads of pesticide residues includes, in order starting with the highest contamination:

1. Strawberries
2. Spinach
3. Nectarines
4. Apples
5. Peaches
6. Celery
7. Grapes
8. Pears
9. Cherries
10. Tomatoes
11. Sweet bell peppers
12. Potatoes

Each of these foods tested positive for a number of different pesticide residues and contained higher concentrations of pesticides than other produce. More than 98 percent of samples of strawberries, spinach, peaches, nectarines, cherries and apples tested positive for residue of at least one pesticide. A single sample of strawberries showed 20 different pesticides. Spinach samples had, on average, twice as much pesticide residue by weight than any other crop.

The Environmental Working Group’s list of produce least likely to contain pesticide residues included:

1. Sweet Corn
2. Avocados
3. Pineapples
4. Cabbage
5. Onions
6. Frozen sweet peas
7. Papayas
8. Asparagus
9. Mangoes
10. Eggplant
11. Honeydew melon
12. Kiwis
13. Cantaloupe
14. Cauliflower
15. Grapefruit

Relatively few pesticides were detected on these foods, and tests found low total concentrations of pesticide residues on them. Avocados and sweet corn were the cleanest with only 1 percent of the samples showing any detectable pesticides. More than 80 percent of pineapples, papayas, asparagus, onions and cabbage had no pesticide residues. No single fruit sample from the cleanest list tested positive for more than four types of pesticides. Multiple pesticide residues are extremely rare on these vegetables. Only 5 percent of had two or more pesticides.

Most processed foods typically contain one or more ingredient derived from genetically engineered crops, such as corn syrup and corn oil made from predominantly GMO starchy field corn. Yet GMO food is not often found in the produce section of American supermarkets. A small percentage of zucchini, yellow squash and sweet corn is genetically modified. Most Hawaiian papaya is GMO. Other varieties of GMO foods are currently being tested. The USDA may approve them in the future.

Because federal law does not require labeling of genetically engineered produce, people who want to avoid GMO crops can purchase organically grown sweet corn, papaya, zucchini and yellow squash. For processed foods, look for items that are certified organic.

People who eat organic produce eat fewer pesticides. A 2015 study by Cynthia Curl of the University of Washington found that people who report they “often or always” buy organic produce had significantly less organophosphate insecticides in their urine samples. This was true even though they reported eating 70 percent more servings of fruits and vegetables per day than adults reporting they “rarely or never” purchase organic produce. Several long-term observational studies have indicated that organophosphate insecticides may impair children’s brain development.

In 2012, the American Academy of Pediatrics issued an important report that said children have “unique susceptibilities to [pesticide residues’] potential toxicity.” The pediatricians’ organization cited research that linked pesticide exposures in early life to “pediatric cancers, decreased cognitive function, and behavioral problems.” It advised its members to urge parents to consult “reliable resources that provide information on the relative pesticide content of various fruits and vegetables.”

Aging in humans (and animals) can be seen as either an inevitable process of wear and tear or as an inherent biological program by which the lifespan of each species is more or less predetermined. Recent research has shown that DNA methylation, an epigenetic modification which alters how DNA is read and expressed without altering the underlying sequence, can show age related changes. A sub-set of these modifications are so accurate that chronological age in humans can be predicted +/- 3.6 years from any tissue or fluid in the body (Horvath S. 2013). This is by far the best biomarker of age available and is referred to as the epigenetic clock. Interestingly, analysis of DNA methylation can also provide information on biological age, which is a measure of how well your body functions compared to your chronological age. For instance, people who are centenarians have a slower clock.

But, how does this epigenetic clock work? And is it possible to change the ticking rate? Researchers at the Babraham Institute and the European Bioinformatics Institute have now identified a mouse epigenetic aging clock. This work, published today in Genome Biology, shows that changes in DNA methylation at 329 sites in the genome are predictive of age in the mouse with an accuracy of +/- 3.3 weeks. Considering that humans live to approximately 85 years and mice to 3 years, the accuracy of the mouse and human clocks (better than 5%) are surprisingly similar.

Using the mouse model, researchers also showed that lifestyle interventions known to shorten lifespan sped up the clock. For example, removing the ovaries in female mice accelerates the clock, something that is also observed in early menopause in women. And interestingly a high fat diet which we know is detrimental to human health also accelerates the ageing clock. Remarkably, researchers were able to detect changes to the epigenetic clock as early as 9 weeks of age, bearing in mind that the lifespan of a mouse can easily be more than 3 years, this represents a massive reduction in both time and cost which the researchers believe will accelerate future ageing discoveries.

Tom Stubbs, PhD Student in the Reik group at the Babraham Institute and lead author of the paper, said: “The identification of a human epigenetic ageing clock has been a major breakthrough in the ageing field. However, with this finding came a number of questions about its conservation, its mechanism and its function. Our discovery of a mouse epigenetic ageing clock is exciting because it suggests that this epigenetic clock may be a fundamental and conserved feature of mammalian ageing. Importantly, we have shown that we can detect changes to the ticking rate in response to changes, such as diet, therefore in the future we will be able to determine the mechanism and function of this epigenetic clock and use it to improve human health.”

Dr. Marc Jan Bonder, postdoctoral researcher at the European Bioinformatics Institute, adds: “Dissecting the mechanism of this mouse epigenetic ageing clock will yield valuable insights into the aging process and how it can be manipulated in a human setting to improve health span.”

With further study, scientists will be able to understand the inner mechanistic workings of such a clock (for example using knowledge about enzymes that regulate DNA methylation in the genome) and change its ticking rate in the mouse model. This will reveal whether the clock is causally involved in aging, or whether it is a read-out of other underlying physiological processes. These studies will also suggest approaches to wind the aging clock back in order to rejuvenate tissues or even a whole organism.

Professor Wolf Reik, Head of the Epigenetics Programme at the Babraham Institute, said: “It is fascinating to imagine how such a clock could be built from molecular components we know a lot about (the DNA methylation machinery). We can then make subtle changes in these components and see if our mice live shorter, or more interestingly, longer.” Such studies may provide deeper mechanistic insights into the ageing process and whether lifespan in a species is in some way programmed.”

Reference: Thomas M. Stubbs, Marc Jan Bonder, Anne-Katrien Stark, Felix Krueger, Ferdinand von Meyenn, Oliver Stegle, Wolf Reik. Multi-tissue DNA methylation age predictor in mouse. Genome Biology, 2017; 18 (1) DOI: 10.1186/s13059-017-1203-5

When a person is severely burned it is a serious skin injury. Typically the treatment involves grafting a layer of skin from a healthy part of the body to the injured area. Once the grafted skin heals which can take some time there is usually very unsightly scarring which the person has to live with the rest of their life. If the scarring is on the face the disfigurement can cause major emotional problems. Also grafted skin often lacks flexibility which leads to pain, stiffness and other problems.

What if there was a way to isolate stem cells from healthy skin, process them and spray them on the burned or injured area. The stem cells would generate fresh new skin within days and without scarring or other problems associated with grafting. This might seem like one of those articles about a stem cell technology that is in the research and development stage with the prospect that it will be available for actual human treatment in 10 or 15 years, however it has already been successfully used to treat human burn patients in Europe. An actual example is shown in the before and after image. This treatment can also be used for cosmetic purposes such as replacing scar tissue with healthy new skin.

The CellMist? Solution is a new invention that involves a liquid suspension containing a patient?s own regenerative skin stem cells. A small sample (as little as a square inch) of the patient?s skin is quickly processed to liberate the stem cells from surrounding tissue. The resulting product is referred to as the ?CellMist? Solution? containing the patient?s stem cells. The CellMist? Solution is placed in a device called the SkinGun? for spray application onto the patient?s wound.

The SkinGun? sprays the cells onto wound sites to begin healing. Unlike conventional aerosol and pump systems, this next-generation fluid sprayer does not expose fragile cells to strong forces that can tear them apart. Instead the SkinGun? gently delivers the CellMist? Solution directly to the wound site using a positive-pressure air stream.

RenovaCare, a developer of novel medical grade liquid spray devices and patented CellMist? and SkinGun? technologies*, announced favorable outcomes from laboratory studies conducted by Berlin-Brandenburg Center for Regenerative Therapies (BCRT), a translational research center at Charit? Universit?tsmedizin Berlin, one of the world?s largest university hospitals.

The goal was to work towards the use of CellMist? and SkinGun? technologies to quickly isolate a patient?s own stem cells and gently spray them onto burns and wounds for rapid self-healing. The results of a new study provide pre-clinical support for first isolating keratinocytes from skin samples, and subsequently achieving even and gentle spray application without harming these powerful yet delicate cells.

Charit? scientists presented their findings from in vitro studies at the EPUAP Focus Meeting 2016 in Berlin, Germany. Data demonstrated that human skin stem cells sprayed with the company?s patented SkinGun? device maintained 97.3% viability. Cell viability is essential to regenerating skin for burns, wounds, and cosmetic applications. Cell growth was comparable to pipetting, the industry?s widely accepted ?gold-standard? for the deposition of cells.

The results show that the described method consistently allows isolating keratinocytes with characteristics suitable for therapeutic applications. This indicates that use of the SkinGun? for spray application of keratinocytes may allow for even distribution of cells with no impairment of cell viability or cell growth when evaluated in vitro, in contrast to those evaluations with conventionally seeded cells, according to study authors, Dr. Christa Johnen, Nadja Strahl, and Dr. Katrin Zeilinger.

Among specific aims of the study, was evaluation of several factors important to the regeneration of human skin, including cell yield, viability, metabolic activity, and cell growth. Positive results were reported from experiments related to each of these investigations. After spraying skin stem cells using the RenovaCare SkinGun?, investigators recorded favorable metabolic activity from measurements of glucose consumption and lactate release. Cell morphology was evaluated by microscopic observation, and cell integrity was determined by LDH release.

The study was funded by RenovaCare, Inc. Tissue samples for skin cell isolation were obtained from surgical treatments with approval of the Charit? ethical committee.

*RenovaCare products are currently in development. They are not available for sale in the United States. There is no assurance that the company?s planned or filed submissions to the U.S. Food and Drug Administration, if any, will be accepted or cleared by the FDA.

RenovaCare, Inc. is developing first-of-their-kind autologous (self-donated) stem cell therapies for the regeneration of human organs, and novel medical grade liquid sprayer devices.

In addition to its liquid spray devices for wound irrigation, the company?s pipeline products under development target the body?s largest organ, the skin. The RenovaCare CellMist? System will use the patented SkinGun? to spray a liquid suspension of a patient?s stem cells ? the CellMist? Solution ? onto wounds. RenovaCare is developing its CellMist? System as a promising new alternative for patients suffering from burns, chronic and acute wounds, and scars. In the U.S. alone, this $45 billion market is greater than the spending on high-blood pressure management, cholesterol treatments, and back pain therapeutics.

A video of a patient who was treated for severe burns can be viewed at https://renovacareinc.com/2016/07/burn-recovery-video-state-trooper/

Life Code supplements are formulated to improve the quality of life and increase lifespan. An important study has just been released showing that one of the many ingredients (Astaxathin) in our nutraceutical supplement EpiMax upregulates the FOX03 longevity gene. We use a natural Astaxathin derived from algae which includes other lipid soluble anti-oxidants and synergistic co-factors.

The University of Hawaii John A. Burns School of Medicine (“JABSOM”) and Cardax, Inc., a Honolulu based life sciences company, jointly announced the results of the animal study evaluating the effectiveness of Astaxathin and demonstrating that it holds promise in anti-aging therapy.

“All of us have the FOXO3 gene, which protects against aging in humans,” said Dr. Bradley Willcox, MD, Professor and Director of Research at the Department of Geriatric Medicine, JABSOM, and Principal Investigator of the National Institutes of Health-funded Kuakini Hawaii Lifespan and Healthspan Studies. “But about one in three persons carry a version of the FOXO3 gene that is associated with longevity. By activating the FOXO3 gene common in all humans, we can make it act like the “longevity” version. Through this research, we have shown that Astaxanthin “activates” the FOXO3 gene,” said Willcox.

“This preliminary study was the first of its kind to test the potential of Astaxanthin to activate the FOXO3 gene in mammals,” said Dr. Richard Allsopp, PhD, Associate Professor, and researcher with the JABSOM Institute of Biogenesis Research.

In the study, mice were fed either normal food or food containing a low or high dose of the Astaxanthin compound CDX-085 which is a synthetically manufactured Astaxanthin. The animals that were fed the higher amount of the Astaxanthin compound experienced a significant increase in the activation of the FOXO3 gene in their heart tissue. Because only a limited amount of naturally produced Astaxathin is available a synthetic version has the advantage that unlimited quantities can be manufactured.

“We found a nearly 90% increase in the activation of the FOXO3 “Longevity Gene” in the mice fed the higher dose of the Astaxanthin compound CDX-085,” said Dr. Allsopp.

Astaxanthin is a naturally occurring compound found in seafood such as shrimp, lobster, and salmon, and is typically sourced from algae, krill, or synthesis. Multiple animal studies have demonstrated that Astaxanthin provides heart, liver, blood and other benefits.

Astaxanthin is the active ingredient in CDX-085, Cardax’s patented second generation compound. “This proprietary compound, like our first generation product ZanthoSyn, delivers Astaxanthin to the blood stream with superior absorption and purity, but in a more concentrated form, allowing higher doses per capsule and improved dosing convenience,” said Watumull. In animal study results published in peer-reviewed papers, CDX-085 statistically significantly lowered triglycerides by 72% as well as atherosclerosis and blood clots.

Researchers with the Kuakini Hawaii Lifespan Study, sponsored by the National Institutes of Health and Kuakini Medical Center, discovered that for those who have a certain gene (the FOXO3 “G” genotype) there is “extra protection” against the risk of death as you get older, compared to average persons. Using data from the Kuakini Hawaii Lifespan Study, a substudy of the 50-year Kuakini Honolulu Heart Program (Kuakini HHP), and the National Institute on Aging’s Health, Aging and Body Composition (Health ABC) study as a replication cohort, researchers found that people with this FOXO3 gene have an impressive 10% reduced risk of dying overall over a 17 year period. Data are based on a 17-year prospective cohort study of 3,584 older American men of Japanese ancestry from the Kuakini HHP cohort study and a 17-year prospective replication study of 1,595 white and 1,056 African-American elderly individuals from the Health ABC cohort.

UC San Francisco scientists identified a previously unknown pool of blood making stem cells in the lungs capable of restoring blood production when the stem cells of the bone marrow, previously thought to be the principal site of blood production, are depleted. Using video microscopy in the living mouse lung, the scientists have revealed that the lungs play this previously unrecognized role in blood production. As reported online March 22, 2017 in Nature, the researchers found that the lungs produced more than half of the platelets blood components required for the clotting that stanches bleeding in the mouse circulation.

“This finding definitely suggests a more sophisticated view of the lungs that they’re not just for respiration but also a key partner in formation of crucial aspects of the blood,” said pulmonologist Mark R. Looney, MD, a professor of medicine and of laboratory medicine at UCSF and the new paper’s senior author. “What we’ve observed here in mice strongly suggests the lung may play a key role in blood formation in humans as well.”

The findings could have major implications for understanding human diseases in which patients suffer from low platelet counts, or thrombocytopenia, which afflicts millions of people and increases the risk of dangerous uncontrolled bleeding. The findings also raise questions about how blood stem cells residing in the lungs may affect the recipients of lung transplants.

Mouse lungs produce more than 10 million platelets per hour, live imaging studies show

The new study was made possible by a refinement of a technique known as two-photon intravital imaging recently developed by Looney and co-author Matthew F. Krummel, PhD, a UCSF professor of pathology. This imaging approach allowed the researchers to perform the extremely delicate task of visualizing the behavior of individual cells within the tiny blood vessels of a living mouse lung.

Looney and his team were using this technique to examine interactions between the immune system and circulating platelets in the lungs, using a mouse strain engineered so that platelets emit bright green fluorescence, when they noticed a surprisingly large population of platelet-producing cells called megakaryocytes in the lung vasculature. Though megakaryocytes had been observed in the lung before, they were generally thought to live and produce platelets primarily in the bone marrow.

“When we discovered this massive population of megakaryocytes that appeared to be living in the lung, we realized we had to follow this up,” said Emma Lefran?ais, PhD, a postdoctoral researcher in Looney’s lab and co-first author on the new paper.

More detailed imaging sessions soon revealed megakaryocytes in the act of producing more than 10 million platelets per hour within the lung vasculature, suggesting that more than half of a mouse’s total platelet production occurs in the lung, not the bone marrow, as researchers had long presumed. Video microscopy experiments also revealed a wide variety of previously overlooked megakaryocyte progenitor cells and blood stem cells sitting quietly outside the lung vasculature estimated at 1 million per mouse lung.

Newly discovered blood stem cells in the lung can restore damaged bone marrow

The discovery of megakaryocytes and blood stem cells in the lung raised questions about how these cells move back and forth between the lung and bone marrow. To address these questions, the researchers conducted a clever set of lung transplant studies:

First, the team transplanted lungs from normal donor mice into recipient mice with fluorescent megakaryocytes, and found that fluorescent megakaryocytes from the recipient mice soon began turning up in the lung vasculature. This suggested that the platelet-producing megakaryocytes in the lung originate in the bone marrow.

“It’s fascinating that megakaryocytes travel all the way from the bone marrow to the lungs to produce platelets,” said Guadalupe Ortiz-Mu?oz, PhD, also a postdoctoral researcher in the Looney lab and the paper’s other co-first author. “It’s possible that the lung is an ideal bioreactor for platelet production because of the mechanical force of the blood, or perhaps because of some molecular signaling we don’t yet know about.”

In another experiment, the researchers transplanted lungs with fluorescent megakaryocyte progenitor cells into mutant mice with low platelet counts. The transplants produced a large burst of fluorescent platelets that quickly restored normal levels, an effect that persisted over several months of observation — much longer than the lifespan of individual megakaryocytes or platelets. To the researchers, this indicated that resident megakaryocyte progenitor cells in the transplanted lungs had become activated by the recipient mouse’s low platelet counts and had produced healthy new megakaryocyte cells to restore proper platelet production.

Finally, the researchers transplanted healthy lungs in which all cells were fluorescently tagged into mutant mice whose bone marrow lacked normal blood stem cells. Analysis of the bone marrow of recipient mice showed that fluorescent cells originating from the transplanted lungs soon traveled to the damaged bone marrow and contributed to the production not just of platelets, but of a wide variety of blood cells, including immune cells such as neutrophils, B cells and T cells. These experiments suggest that the lungs play host to a wide variety of blood progenitor cells and stem cells capable of restocking damaged bone marrow and restoring production of many components of the blood.

“To our knowledge this is the first description of blood progenitors resident in the lung, and it raises a lot of questions with clinical relevance for the millions of people who suffer from thrombocytopenia,” said Looney, who is also an attending physician on UCSF’s pulmonary consult service and intensive care units.

In particular, the study suggests that researchers who have proposed treating platelet diseases with platelets produced from engineered megakaryocytes should look to the lungs as a resource for platelet production, Looney said. The study also presents new avenues of research for stem cell biologists to explore how the bone marrow and lung collaborate to produce a healthy blood system through the mutual exchange of stem cells.

“These observations alter existing paradigms regarding blood cell formation and lung biology. The observation that blood stem cells and progenitors seem to travel back and forth freely between the lung and bone marrow lends support to a growing sense among researchers that stem cells may be much more active than previously appreciated, Looney said. “We’re seeing more and more that the stem cells that produce the blood don’t just live in one place but travel around through the blood stream. Perhaps ‘studying abroad’ in different organs is a normal part of stem cell education.”

Reference: 1.Emma Lefran?ais, Guadalupe Ortiz-Mu?oz, Axelle Caudrillier, Be?at Mallavia, Fengchun Liu, David M. Sayah, Emily E. Thornton, Mark B. Headley, Tovo David, Shaun R. Coughlin, Matthew F. Krummel, Andrew D. Leavitt, Emmanuelle Passegu?, Mark R. Looney. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature, 2017; DOI: 10.1038/nature21706

A molecular key to aging of the blood and immune system has been discovered in new research conducted at UC San Francisco, raising hope that it may be possible to find a way to slow or reverse many of the effects of aging.

The key is a link between the health of a rare population of adult stem cells that arise early in development and are responsible for replenishing all blood cell types throughout a lifetime, and a newly identified role for autophagy, an important cellular cleanup and recycling process that was the focus of the 2016 Nobel Prize in Physiology or Medicine.

In their new study, published online March 1 in Nature, the UCSF team discovered that in addition to its normal role in cellular waste-processing, autophagy also is needed for the orderly maintenance of blood-forming hematopoietic stem cells (HSCs), the adult stem cells that give rise to red blood cells, which carry oxygen, and to platelets, as well as the entire immune system.

The researchers found that autophagy keeps HSCs in check by allowing metabolically active HSCs to return to a resting, quiescent state akin to hibernation. This is the default state of adult HSCs, allowing their maintenance for a lifetime.

According to Emmanuelle Passegu?, PhD, the senior scientist for the study, “This is a previously unknown role for autophagy in stem cell biology.”

Failure to activate autophagy has profound impacts on the blood system, Passegu?’s team found, leading to the unbalanced production of certain types of blood cells. Defective autophagy also diminished the ability of HSCs to regenerate the entire blood system when they were transplanted into irradiated mice, a procedure similar to bone marrow transplantation.

The researchers determined that 70 percent of HSCs from old mice were not undergoing autophagy, and these cells exhibited the dysfunctional features common among old HSCs. However, the 30 percent of old HSCs that did undergo autophagy looked and acted like HSCs from younger mice.

Passegu? led the study while she was a professor of medicine with the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at UCSF. In January she became an Alumni Professor in the Department of Genetics & Development and the director of the Columbia Stem Cell Initiative at Columbia University Medical Center.

Scientists have identified many different tissue-specific stem cells, all of whose performance declines with age, Passegu? said. Finding out how this occurs has been an active area of research, and a focus of her laboratory group in recent years.

In a large series of experiments and analyses, many conducted by the study’s first author, Theodore Ho, a UCSF graduate student, the scientists compared characteristics of HSCs from old mice with those of HSCs from younger mice that had been genetically programmed so that they could not undergo autophagy. They found that loss of autophagy in young mice was sufficient to drive many of the defects that arise naturally in the blood of old mice, including changes in the cellular appearance of HSCs and a disruption in the normal proportions of the various types of blood cells, characteristics of old age.

Previous research had shown that autophagy causes the formation of “sacs” within cells that can engulf and enzymatically digest molecules and even major cellular structures, including mitochondria, the cell’s biochemical power plants. But in the new study, the researchers found that genetically programmed loss of autophagy resulted in the accumulation of activated mitochondria with increased oxidative metabolism that triggered chemical modifications of DNA in HSCs.

These “epigenetic” DNA modifications altered the activities of genes in a way that changed the developmental fate of HSCs. They triggered disproportionate production of certain blood cells and reduced the ability of HSCs to regenerate the entire blood system when transplanted. This result was similar to what the researchers observed in the majority of old HSCs that failed to activate autophagy.

In contrast, the minority of old HSCs that still exhibited significant levels of autophagy were able to keep their mitochondria and metabolism in check, and could re-establish a healthy blood system following transplantation, similar to HSCs from young mice.

However, in a hopeful sign for potential future therapies to rejuvenate blood stem cells, the researchers succeeded in restoring autophagy to old HSCs by treating them with pharmacological agents in a lab dish.

“This discovery might provide an interesting therapeutic angle to use in re-activating autophagy in all of the old HSCs, to slow the aging of the blood system and to improve engraftment during bone marrow or HSC transplantation,” Passegu? said. “It is our hope that the end point will be a way to really improve the fitness of stem cells and to use that capability to help the immune systems.”

Reference: Theodore T. Ho, Matthew R. Warr, Emmalee R. Adelman, Olivia M. Lansinger, Johanna Flach, Evgenia V. Verovskaya, Maria E. Figueroa & Emmanuelle Passegu?; Autophagy maintains the metabolism and function of young and old stem cells, Nature (2017). DOI: 10.1038/nature21388