There’s no place like home — particularly if you’re a muscle stem cell.
Snuggled comfortably along the length of our muscle fibers, these stem cells rest quietly, biding their time until the muscle needs to be repaired after injury. Although it’s possible to maintain muscle stem cells in a laboratory dish, they’re not really happy there. Within a short time they begin to divide and lose their ability to function as stem cells.
Now researchers at the Stanford University School of Medicine have come up with a way to create a home away from home for the stem cells in the form of artificial muscle fibers. They’ve also identified the particular “soup” of molecules and nutrients necessary to keep the cells in their most potent, regenerative state.
“Normally these stem cells like to cuddle right up against their native muscle fibers,” said Thomas Rando, MD, PhD, professor of neurology. “When we disrupt that interaction, the cells are activated and begin to divide and become less stemlike. But now we’ve designed an artificial substrate that, to the cells, looks, smells and feels like a real muscle fiber. When we also bathe these fibers in the appropriate factors, we find that the stem cells maintain high-potency and regenerative capacity.”
Dr. Rando participated in a webinar hosted by the journal ‘Current Opinion in Cell Biology’, and sponsored by Beckman Coulter. A recording is available on demand at the link to the left.
Many adult stem cells reside in the quiescent state, or the G0 state of the cell cycle, for prolonged periods of time. This state, one reversible cell cycle withdrawal, has long been viewed as a dormant state with minimal basal activity. However, increasingly there is evidence that suggests that quiescent cells have specific transcriptional, post-transcriptional and metabolic programs that serve at least two functions. The first is to actively maintain the quiescent state, indicating that this is not simply a state of dormancy but in fact under active regulation. The second is to prime the cells for activation, a process that is characterized by the upregulation of multiple cellular processes necessary for cells to enter the cell cycle and begin the process of differentiation.
Skeletal muscle stem cells, or satellite cells, have proven to be extremely valuable in the study of stem cell quiescence because they persist in the quiescent state for weeks, months, and at least in long-lived mammals, perhaps years. In addition, they can be readily identified in situ, they can be rapidly purified by FACS at very high yield and very high purity, and the states of quiescence, activation and “re-quiescence” (i.e. the process by which a proliferating cell returns to quiescence in the process of stem cell self-renewal) can be modeled and studied in vitro. We have focused our studies of stem cell quiescence on this population, and we have discovered unexpected levels of regulation of quiescence and activation. These include the maintenance of the quiescent state by quiescence-specific miRNAs and by active signaling via the Notch pathway. Recent epigenetic profiling using ChIP-seq analysis has revealed evidence of dynamic regulation of chromatin in quiescent stem cells and intriguing epigenetic changes that occur during chronological stem cell aging. Finally, recent results from our laboratory have revealed an unexpected ability of quiescent stem cells to respond to systemic signals and poise themselves in a “pre-activation” state, which we call the “alert state”, and which suggests that in addition to the traditional cell cycle there is also a “quiescence cycle” that allows stem cells to cycle between the quiescent state and the alert state while remaining in G0. Deciphering the molecular mechanisms regulating the quiescent state of adult stem cells will offer new insights into how tissue regeneration is accomplished and how it is dys regulated in pathological conditions and in ageing.
Dr. Rando and his co-principal investigator, Tony Wyss-Coray, PhD, were awarded one of 10 Transformative Research by the NIH. These awards, open to both individuals and teams of investigators, were created to support research projects that have the potential to create or overturn fundamental paradigms.
“Thomas Rando, MD, PhD, professor of neurology, and Tony Wyss-Coray, PhD, professor of neurology and a senior research career scientist at the Veterans Affairs Palo Alto Health Care System, have received a $4.26 million award to explore the basis for physical activity’s robust positive effect on cognitive function.
Aging is associated with a progressive decline in cognitive ability, the consequences of which can be enormous for individuals and society. Muscle is increasingly understood to be a secretory tissue with effects on bone structure, metabolism and blood vessel formation.
Using innovative experimental models and tools, the Rando and Wyss-Coray teams will test the idea that factors produced in exercised muscle are secreted into the circulation, where they gain access to the brain and induce cognitive benefits. In particular, the researchers will investigate the mechanisms by which the profile of factors secreted by muscle tissue changes during exercise.
Further, they will identify the neural cells whose behavior is modified by those secreted factors and that mediate the effects those factors induce during exercise, as well as afterward. The results of these endeavors may drastically alter current thinking about exercise’s beneficial effects on the brain cells’ function and regeneration, remodeling of neuronal circuitry, and cognition itself.
How sleeping muscle stem cells might be awakened to fight aging, with Thomas Rando (9:42) (Cell Reports).
Plus, sample a selection of the hottest new papers from Cell Press (19:30).
BY BRUCE GOLDMAN
A chemical code scrawled on histones — the protein husks that coat DNA in every animal or plant cell — determines which genes in that cell are turned on and which are turned off. Now, Stanford University School of Medicine researchers have taken a new step in the deciphering of that histone code.
In a study published June 27 in Cell Reports, a team led by Thomas Rando, MD, PhD, professor of neurology and neurological sciences and chief of the Veterans Affairs Palo Alto Health Care System’s neurology service, has identified characteristic differences in “histone signatures” between stem cells from the muscles of young mice and old mice. The team also distinguished histone-signature differences between quiescent and active stem cells in the muscles of young mice.
The 30 members of the Telethon Scientific Committee met on June 20-21 to give their final assessment of 160 projects that have passed all previous stages of the 2013 selection process.
Thomas Rando, M.D., Ph.D., professor of neurology and neurological sciences at Stanford University School of Medicine and director of Stanford’s Glenn Laboratories for the Biology of Aging, has focused his entire career researching muscular dystrophy.
The main areas of interest of the Rando Laboratory are muscle stem cell biology, muscle stem cell aging, muscular dystrophies, tissue engineering and basic muscle cell biology. Dr. Rando’s research focuses on the restorative and repair mechanism of stem cells. The lab has a long-standing interest in understanding the mechanisms of cell injury and cell death in muscular dystrophies and the development of novel therapeutics. The long term goal is to develop stem cell therapies for Duchenne muscular dystrophy.
BY BRUCE GOLDMAN
Stanford University School of Medicine scientists have created a mouse model of muscular dystrophy in which degenerating muscle tissue gives off visible light.
The observed luminescence occurs only in damaged muscle tissue and in direct proportion to cumulative damage sustained in that tissue, permitting precise monitoring of the disease’s progress in the mice, the researchers say.
While this technique cannot be used in humans, it paves the way to quicker, cheaper and more accurate assessment of the efficacy of therapeutic drugs. The new mouse strain is already being employed to test stem cell and gene therapy approaches for muscular dystrophies, as well as drug candidates now in clinical trials, said Thomas Rando, MD, PhD, professor of neurology and neurological sciences and director of Stanford’s Glenn Laboratories for the Biology of Aging.
NIH Director’s Wednesday Afternoon Lecture Series: The Annual Florence Mahoney Lecture
Aging is a process that is generally viewed as unidirectional, relentless, and inevitable. However, in addition to the existence of non-aging species, or at least species with negligible senescence, data from a wide range of living organisms suggests that environmental influences can markedly slow and even halt the aging process. Furthermore, recent experimental evidence suggests that aspects of the molecular and functional characteristics of aged cells and tissues even in mammals can be restored to a more youthful state. Analyses of age-related changes in cells have revealed clear epigenetic changes, and the reversibility of some of those processes, in essence leading to cell and tissue rejuvenation, suggest epigenetic mechanisms.
Current studies focus on understanding the nature and regulation of those epigenetic mechanisms and the extent to which the aging clock can be rewound or reset by defined environmental influences while leaving other cellular characteristics, such as their state of differentiation, intact.
Regenerative Medicine Today welcomes Thomas Rando, MD, PhD.
Dr. Rando discusses his research in muscle stem cell biology as well as his role in the upcoming Regenerative Rehabilitation Symposium in Pittsburgh.
BY KRISTA CONGER
A tiny piece of RNA plays a key role in determining when muscle stem cells from mice activate and start to divide, according to researchers at the Stanford University School of Medicine. The finding may help scientists learn how to prepare human muscle stem cells for use in therapies for conditions such as muscular dystrophy and aging by controlling their activation state.
It’s the first time that a small regulatory RNA, called a microRNA, has been implicated in the maintenance of the adult stem cell resting, or quiescent, state.
“Although on the surface the quiescent state seems to be relatively static, it’s quite actively maintained,” said Thomas Rando, MD, PhD, professor of neurology and neurological sciences. “We’ve found that changing the levels of just one specific microRNA in resting muscle stem cells, however, causes them to spring into action.”
Advances in the study of stem cells have fueled hopes that someday, via regenerative medicine, doctors could restore aging people’s hearts, livers, brains and other organs and tissues to a more youthful state. A key to reaching this goal — to be able to provide stem cells that will differentiate into other types of cells a patient needs — appears to lie in understanding “epigenetics,” which involves chemical marks stapled onto DNA and its surrounding protein husk by specialized enzyme complexes inside a cell’s nucleus. These markings produce long-lasting changes in genes’ activity levels within the cell — locking genes into an “on” or “off” position. Epigenetic processes enable cells to remain true to type (a neuron, for instance, never suddenly morphs into a fat cell) even though all our cells, regardless of type, share the same genetic code. But epigenetic processes also appear to play a critical role in reducing cells’ vitality as they age.
BY JONATHAN RABINOVITZ
A dozen state-of the-art buildings that will advance the medical school’s clinical, educational and research missions are beginning to rise, but Stanford isn’t leading the effort.
With a construction budget of more than $1 billion, the Veterans Affairs Palo Alto Health Care System, or VAPAHCS, has launched an ambitious building project on its flagship campus on Miranda Avenue in Palo Alto, leaving almost no spot of the 93-acre site untouched. The plan includes a new mental health center; the Department of Veterans Affairs’ largest rehabilitation center, which will combine polytrauma and blind rehabilitation; additional research space; and additional lodging facilities for veteran patients and family members.
The project is driven by an emphasis on patient-centric care and concerns about seismic safety. The project is also part of a broader shift by the VA and health care in general toward more outpatient services, concentrating the most advanced tertiary care services at flagship facilities, such as the Palo Alto site. VAPAHCS, in addition to revamping and expanding its outpatient facilities outside the Palo Alto campus, is taking steps to ensure that its main campus continues to offer the latest treatment modalities and meet new and pressing needs, such as those of the increasing numbers of veterans who have suffered multiple injuries, including traumatic brain injury. As part of that process, VAPAHCS is enhancing its 50-year affiliation with the School of Medicine, adding space for the education of Stanford doctors who treat veterans and the research by Stanford faculty on injuries and illness that affect veterans and others.
No one likes to develop arthritis and more wrinkles. However, it’s a fact of life that we all grow old, and always will…Or is it? Cutting-edge studies indicating that old cells and tissues can be “rejuvenated” prompt us to question the timeless theory that aging is unavoidable.
Dr. Rando was an invited speaker at the Aspen Ideas Festival, where he gave a talk titled ‘Can We Reverse Aging? Science and Mythology Behind Growing Old’.
BY RUTHANN RICHTER
The Glenn Foundation for Medical Research has awarded a $5 million grant to Stanford University to launch a new center on the biology of aging, focusing on the role of stem cells in the aging process.
At the new Paul F. Glenn Laboratories for the Biology of Aging at Stanford, researchers at the Stanford University School of Medicine will look at how stem cells change as an individual ages and how that contributes to the development of age-related diseases and disorders.
Thomas Rando and Anne Brunet provide a general overview on the process and potential prevention of aging. The topics they cover vary from symptoms of aging to unusual characteristics that seem to prolong longevity.
Stanford Mini Med School is a series arranged and directed by Stanford’s School of Medicine and presented by the Stanford Continuing Studies program.
Thomas Rando, MD, PhD, associate professor of neurology and neurological sciences, is one of two recipients of the 2008 Breakthroughs in Gerontology Award sponsored by the Glenn Foundation for Medical Research and the American Federation for Aging Research. The award provides $200,000 for a small number of pilot research programs that may be of relatively high risk but which offer significant promise of yielding transforming discoveries in the fundamental biology of aging. Rando will investigate how stem cells are able to divide throughout the life of an individual to give rise to new stem cells in tissue, such as new skin cells or cells in the blood, without acquiring mutations in their DNA and causing cancer. Read more
By Louis Bergeron
STANFORD, Calif. — Communication is critical. Garbled in, garbled out, so to (mis-)speak. Workers who get incomplete instructions produce an incomplete product, and that’s exactly what happens with the stem cells in our aging muscles, according to researchers from the Stanford University School of Medicine.
Their study found that, as we age, the lines of communication to the stem cells of our muscles deteriorate and, without the full instructions, it takes longer for injured muscles to heal. Even then, the repairs aren’t as good. But now that the researchers have uncovered the conduit that conveys the work orders to muscle stem cells, that knowledge could open the door to new therapies for injuries in a host of different tissues.
The findings, from the lab of Thomas Rando, MD, PhD, associate professor of neurology and neurological sciences, suggest stem cells are careful when they undergo cell division so that random mutations in their chromosomes are not passed on to the next generation of stem cells. The results support a much-debated hypothesis proposed in 1975 by Oxford University geneticist John Cairns, PhD. Although other groups have uncovered hints that Cairns was right, Rando’s findings are the most detailed to date.
The results are published in the April 17 issue of the Public Library of Science-Biology.
Rando said no other work he’s done has created as much excitement among his colleagues in the stem cell field. “The lesson from this is that when something seems strange, don’t ignore it. Sometimes what puzzles you turns out to be the most interesting,” he said.
STANFORD, Calif. — A new gene therapy technique that has shown promise in skin disease and hemophilia might one day be useful for treating muscular dystrophy, according to a new study by researchers at Stanford University School of Medicine.
In the study, published online in the Proceedings of the National Academy of Sciences the week of Jan. 2, the researchers used gene therapy to introduce a healthy copy of the gene dystrophin into mice with a condition that mimics muscular dystrophy. The dystrophin gene is mutated and as a result produces a defective protein in the roughly 20,000 people in the United States with the most common form of the disease.
BY LOUIS BERGERON
Three School of Medicine scientists, including one jointly appointed with the School of Engineering, are among a select group of 13 researchers nationwide being recognized for their innovative work by the National Institutes of Health. The winners of the NIH Director’s 2005 Pioneer Awards will each receive up to $500,000 annually for five years to help fund their research.
With three winners, Stanford has more awardees this year than any other institution. The NIH announced the winners on Sept. 29. “Although the Pioneer Award is relatively new, it has quickly become one of the most prestigious and important recognitions by the NIH,” said Philip Pizzo, MD, dean of the School of Medicine. “Having three Pioneer Award winners is simply remarkable.”
STANFORD – Any older person can attest that aging muscles don’t heal like young ones. But it turns out that’s not the muscle’s fault. A study in the Feb. 17 issue of Nature shows that it’s old blood that keeps the muscles down.
The study, led by Thomas Rando, MD, PhD, associate professor of neurology and neurological sciences at the Stanford University School of Medicine, built on previous work showing that old muscles have the capacity to repair themselves but fail to do so. Rando and his group studied specialized cells called satellite cells, the muscle stem cells, that dot muscle tissue. These normally lie dormant but come to the rescue in response to damaged muscle-at least they do in young mice and humans.
STANFORD, Calif. – Any older athlete can attest that aging muscles don’t heal as fast as youthful ones. Now researchers at Stanford University School of Medicine have found a molecular link between older muscles and slow healing. This work could lead to ways of preventing atrophy from immobilization, space flight or simply due to aging.
“What you really want to do is maintain the youthfulness of the regeneration pathway,” said Thomas Rando, MD, PhD, associate professor of neurology and neurological sciences and an investigator at the Veterans Affairs Palo Alto Health Care System. The work will be published in the Nov. 28 issue of Science.