Considering the Rejuvenation of Muscle Satellite Cells

Stem cell populations in the body are responsible for tissue maintenance, at the very least by keeping up a steady supply of new somatic cells to replace those that have reached their replication limits, but also via a range of other less well cataloged signaling processes. The latter category has become much more interesting to clinical researchers since the advent of the present generation of stem cell therapies, many of which produce benefits despite the fact that the transplanted stem cells don't actually contribute any meaningful number of daughter cells to the recipient. The boost to regeneration is all in the signals exchanged between cells, the levels of various proteins in the tissue environment.

Stem cell activity declines with advancing age, and the progressive failure tissue maintenance provides a strong contribution to the onset of dysfunction and age-related disease. At present this phenomenon is most closely studied in muscle tissue and the supporting population of stem cells known as satellite cells. This is where researchers have the most experience and greatest body of knowledge, and it is where most of the really interesting discoveries in stem cell aging have occurred in recent years. The picture building here may or may not also be the case in other tissues, but it is encouraging nonetheless. Insofar as muscle goes, the failure of stem cell activity consists of growing quiescence more than a depletion of numbers or some form of damage inherent to stem cells. This is a reaction to a changing balance of signals in the tissue environment, which in turn is a consequence of growing levels of the low-level cellular and tissue damage that is at root the cause of aging. Since signals are the proximate cause, changing the signals - and cell behavior - is well within the reach of present day biotechnology. The hardest part of this process is finding the relevant signals amid the vast complexity of an aging biochemistry.

So in recent years, researchers have focused on FGF-2, and GDF-11, and a range of other possible candidate signal molecules associated with various fundamental cell behaviors. The degree to which stem cell activity can be restored without immediate signs of harm due to damage is very encouraging, albeit surprising. The caution here has all along been the threat of cancer: the predominant hypothesis regarding the existence of stem cell decline with aging is that, like cellular senescence, it is the result of an evolved balance between cancer and regeneration - which are, after all, two sides of the same coin. Unrestrained growth versus controlled growth. So it has been something of a surprise to find that instructing old, damaged stem cells in old, damaged tissues to act as though young has not produced the immediate enormous risk of cancer that was expected. Still, researchers remain sensibly cautious, as they should given that these approaches to invigorate old cells don't directly address any of the underlying reasons why the cells became quiescent in the first place.

Here is a recent paper on the topic of muscle stem cell rejuvenation that looks at some of the targets and research topics that have been pushed a little way out of the limelight by GDF-11 and its ilk, some of which have interesting associations with cellular senescence in aging - itself a hot topic these days:

Forever young: rejuvenating muscle satellite cells

Extended lifespan raises the issue of handling age-related disorders, which profoundly affect the quality of life of an increasing number of people. At the physiological level, the most relevant feature of aging is the functional decline of tissue functions. In particular, in the elderly, muscle mass declines progressively by means of a process named sarcopenia, making skeletal muscle one of the more compromised tissues during aging. Beyond the protein breakdown associated with the loss of sarcomeric proteins, aged muscles display compromised regenerative capacity associated with altered environmental cues.

Muscle regeneration is achieved by the interplay between adult stem cells, named muscle satellite cells (MuSCs), and other cellular types (i.e. macrophages and muscle interstitial cells) that participate in the orchestration of regeneration. Muscle niche derived and systemic cues contribute to regulate muscle homeostasis and functionality. In order to ensure optimal performance, it is critical that several properties of MuSCs are finely regulated and coordinated. Amongst these properties are survival, self-renewal, fine-tuning between exit from quiescence and proliferative expansion, and eventually commitment toward myogenic differentiation. All these processes are altered in the elderly leading to compromised muscle functionality.

Beyond the notion provided by parabiosis experiments that circulating systemic factors are able to restore muscle regeneration in aged mice, recent evidence supports the hypothesis that MuSCs are intrinsically defective in aged muscles. These new findings open the possibility to target this stem cell compartment to counteract functional decline of muscle during aging.

Research has provided evidence that constitutive activation of the p38 MAPK in aged MuSCs leads to a decline in their self-renewal and regenerative capacity. Partial pharmacological inhibition of p38 is sufficient to restore the ability of MuSCs to participate efficiently in muscle regeneration and to maintain the stem cell pool. Interestingly, an alteration of the FGF-2/FGFR1 axis was identified as a feature of aged MuSC dysfunction. Earlier authors suggest that increased activity of FGFR1 results in the disruption of MuSC quiescence in aged muscles, but recent work supports the hypothesis that FGF-2 increase in the aged niche is a compensatory response to the loss of function of FGFR1 activity observed in aged MuSCs.

Other recent work has demonstrated that geriatric MuSCs fail to support muscle regeneration and display defective activation. Serial transplantation experiments supported the conclusion that this defect is a cell intrinsic feature of geriatric MuSCs. The authors identify the master regulator of senescence p16INK4a as a key determinant responsible for a quiescence-senescence switch (a process named geroconversion) operating in geriatric MuSCs in coincidence with their impaired regenerative potential. Indeed, genetic inactivation of p16INK4a locus was sufficient to recover the cells from the senescence-associated cell cycle arrest and restore their self-renewal capacity, leading to the reconstitution of the stem cell pool after muscle damage. The novelty of this study relies on the finding that geriatric stem cells are associated with the progressive accumulation of DNA damage and senescence-associated markers that in turn contribute to the loss of reversible quiescence mediated by p16INK4a.

These studies demonstrate that in addition to the regenerative environment that profoundly affects the niche and stem cell function, there is another level of tissue homeostasis regulation that is intrinsic to adult stem cells. The cell autonomous functionality declines in the elderly due to de-regulated p38 signaling and accumulation of DNA damage and senescence-associated features. This evidence suggests new avenues to reverse the dysfunctional status of MuSCs from aged tissues. For instance, constitutive FGFR1 signaling can restore MuSCs asymmetric division and self-renewal, and pharmacological blockade of p38 signaling can promote MuSCs self-renewal and engraftment by silencing p16INK4a, thus reversing geroconversion and allowing MuSCs to support muscle regeneration.

Comments

Signals in the blood can and do return dormant Stem cells to action. Irina Conboy has demonstrated rejuvenation in her studies (funded in part by SENS) showing that signalling can be used to rejuvenate.

Rando, Conboy, Katcher, Wyss-Corey, Villeda, Wagers and others have all shown that factors could be a potent rejuvenation approach. The problem is as suggest identifying the factors needed, however industrial scale assays is something we are very good at and so working that out is not as daunting task as some might think.

Gene therapy can also produce practically any required protein so even identifying a number of the key players from blood factors would almost certainly boost lifespan as it has in other animals.

CRISPR would also allow multiple genes to be targeted at once so a package of changes could be made once the important ones are found. We already know a number of them already.

We have the tools to begin experimenting with this and its about time we started instead of letting the old guard dictate and sit on the fence. Medical tourism will see this happen soon anyway as people dare to try.

Posted by: Steve H at May 12th, 2015 3:57 AM

There is also little evidence that returning dormant Stem cells to activity would cause Cancer, in fact a recent study I read demonstrated that groups of Stem cells rejuvenated in-vivo did not promote cancer at all. I will try to link the paper when I find it again.

Its a similar situation to Telomerase, the fear of Cancer has held back experimenting with it but its either we try it and try or sit on the fence and do nothing and die anyway. Unfortunately there comes a time in when we have to test any new therapies, they are risky just the same as any drug trial is, but at some point it comes down to trying something or doing nothing.

Posted by: Steve H at May 12th, 2015 4:22 AM

"So it has been something of a surprise to find that instructing old, damaged stem cells in old, damaged tissues to act as though young has not produced the immediate enormous risk of cancer that was expected"

They have also taken aged Stem Cells and reprogrammed them to a younger state in-vivo and the daughter cells produced in fact showed no DNA damage. Shows that certain types of DNA damage is certainly reversible via signalling.

Signalling cannot repair all damage but it can potentially do a large amount. The easiest way is use youthful Plasma which contains all the signals and infuse this into someone for long enough to reset the Stem Cell niche, this would restore function considerably. Rodent livers regrew in under five weeks so changes would likely be fairly rapid.

There are also ways to emulate plasma and methods to assay the factors available so IMO signalling is not a dead end and could be used in combination with other SENS approaches.

Posted by: Steve H at May 12th, 2015 4:34 AM

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