A Niche New Way to Stay a Stem Cell

rando-150All quiescent on the fresh native myofiber, but…

Stem cells typically lose the capacity to differentiate when cultured in vitro. Their potency appears to depend on preserving the quiescent state, which has been difficult to accomplish with traditional culture methods. In the body, stem cells reside in specialized microenvironments, or niches, with unique chemical and physical properties. Quiescent stem cells isolated from their native environment and then plated become activated to divide and differentiate. A Stanford University research group led by Dr. Thomas A. Rando sought to create an enhanced culture system for studying the biology of quiescence.

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Helping stem cells sleep can boost their power to heal

rando-150We are often told that sleep is one of the most important elements of a healthy lifestyle, that it helps in the healing and repair of our heart and blood vessels – among other things.

It turns out that sleep, or something very similar, is equally important for stem cells, helping them retain their power or potency, which is a measure of their effectiveness and efficiency in generating the mature adult cells that are needed to repair damage. Now researchers from Stanford, with a little help from CIRM, have found a way to help stem cells get the necessary rest before kicking in to action. This could pave the way for a whole new approach to treating a variety of genetic disorders such as muscular dystrophy.

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Artificial muscle fibers help keep muscle stem cells potent in lab

rando-150There’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.”

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‘The Molecular Regulation of Stem Cell Quiescence’ Webinar

Click to play webinar

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.

Abstract:

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.

NIH Transformative Research Award: ‘A New Muscle-Brain Axis Underlying the Cognitive Benefits of Physical Activity’

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.

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