Reviewing Potential Strategies for the Rejuvenation of Stem Cell Populations

Every type of tissue is supported by its own dedicated stem cell population, delivering a supply of daughter somatic cells that replace losses and maintain tissue function. Unfortunately, stem cell function declines with age. This has numerous causes, all of which descend from the underlying accumulation of molecular damage outlined in the SENS research proposals for rejuvenation biotechnologies. Downstream of those causes, stem cells become less active due to some combination of internal damage, damage to their niche of supporting cells, and changes in the signaling environment. The latter two classes of issue appear more influential in the best studied stem cell populations, such as the satellite cells of muscle tissue.

Thus most research and development intended to restore stem cell function is presently focused on trying to override signaling or cell programming in order to force stem cells into greater activity, regardless of the present state of their environment. This may produce benefits to tissue function that are sizable enough to be worth the effort and cost of development, but one cannot just forever ignore the underlying damage of aging with impunity.

For one thing, not every aspect of aging can be fixed by throwing cells at the problem: there are protein aggregates and other forms of molecular waste that are not adequately cleared for reasons that have little to do with stem cells. There is mitochondrial dysfunction throughout cell populations. And so forth. Further, is most likely that stem cells falter in function in response to a damaged environment because this acts to limit cancer risk, though at the cost of a drawn out decline. Thus many of the strategies outlined in this open access paper may turn out to have increased incidence of cancer as a side-effect, even when they achieve meaningful gains in the near term.

However, we can balance that expectation against the animal studies of telomerase gene therapies to lengthen telomeres. In mice that approach both improves stem cell function and reduces cancer risk. In that case, it may be that improved function of the immune system in anti-cancer immunosurveillance offsets the raised risk due to forcing damaged cells into greater activity. That said, a great deal more work is required to understand where the line is drawn on cancer risk in the many approaches to improved stem cell function.

Rejuvenating Strategies of Tissue-specific Stem Cells for Healthy Aging

DNA damage accumulation is critical for age-dependent loss of tissue-specific stem cell function. This type of accumulation is dependent on the attenuation of the DNA repair and response pathway. For example, DNA damage markers, such as histone H2A phosphorylation and comet tails, have been quantified in hematopoietic stem cells (HSCs) and muscle stem cells (MuSCs) from young and old mice and indicated strand breaks significantly accrue in HSCs and MuSCs during aging. It is therefore reasonable to suggest that an increase in the activity of DNA repair pathways may slow down or prevent the accumulation of age-related defects in stem cells and thereby promote the healthy function of aged tissues.

A gradual decline of the telomere length that occurs through the loss of telomerase during aging has been observed in mouse and human tissues. In the mouse model, the loss of telomerase displays telomere shortening, stem cell depletion, and impaired tissue injury responses. However, with telomerase reactivation, telomerase reverse transcriptase (TERT)-deficient mice extend telomeres and reverse degenerative phenotypes. Protection of telomeres 1A (Pot1a), a component of the Shelterin complex that protects telomeres, is highly expressed in young HSCs, whereas it progressively declines with age. In aged mice, treatment with exogenous Pot1a protein could reverse the HSC activity and sustain their self-renewal.

Increased expression of several cell cycle inhibitors, such as p53/p21, p16Ink4α, p19Arf, and p57Kip2 can lead to an essentially irreversible arrest of cell division and promote stem cell senescence. In MuSCs, HSCs, and neural stem cells (NSCs), the expression of p16Ink4α accumulates with age, but p16Ink4α repression through various methods can improve the function of aged stem cells and prevent cellular senescence. For example, silencing of p16Ink4α expression in geriatric satellite cells restores their quiescence and regenerative potential. In a potentially insightful study, researchers showed that autophagy is critical to the prevention of stem cell senescence by repressing the expression of p16Ink4α, and treatment with pharmacological rapamycin to stimulate autophagy could rejuvenate the MuSCs.

Many studies point that altered epigenetic marks of aging stem cells not only alter the transcriptional programs that dictate the function of the stem cells but also alter the potential differentiation towards distinct effector lineages. Recently, aberrant global and site-specific induction of active chromatin marks such as Hoxa9, has been investigated in aged satellite cells, while the inhibition or deletion of Hoxa9 can improve MuSC function and muscle regeneration in aged mice. Another example of successful rejuvenation comes from a study in which aged HSCs express a lower level of the chromatin organizer Satb1 than their young counterparts, while overexpression of Satb1 can improve their ability to generate lymphoid progeny via epigenetic reprogramming.

Signals can directly influence all aspects of stem cell functions including quiescence, proliferation, and differentiation. Signaling pathways involving p38-MAPK, janus kinase (JAK) / signal transducers and activators of transcription (STAT), Notch, and mechanistic target of rapamycin kinase (mTOR) contribute to the modulation of tissue stem cell functions, and their changes with age could affect tissue maintenance and repair systems. Hence, the proper modulation of these pathways is related to the reverse senescence of adult stem cells, which present the enhanced regenerative capacity of the tissues. For example, following overactivation of the p38α/β MAPK pathway, aged satellite cells are over-activated, and then increasingly generate their committed progenitors, while reducing self-renewal. However, pharmacological inhibition of p38α/β MAPK in aged satellite cells is able to restore the engraftment potential and improve their self-renewal ability by restoring asymmetric division.

It is known that tissue-specific stem cells are located in niches. The niche components can be considered somatic and stromal cells, immune cells, extracellular matrix (ECM), innervating neuronal fibers, and the vasculature. Although the niche structure varies among the different adult stem cell types, the stem cell niche provides essential cues to influence cell fate decisions. The aging of niche cells and age-dependent alterations in the components of stem cell niche are able to cause a loss of stem cell function. Fibroblast growth factor-2 (FGF-2), for example, is upregulated in the aged satellite cell microenvironment, whereas inhibition of FGF signaling can rescue the self-renewal capacity of old MuSCs. In addition, the cell surface receptor β1-integrin and the ECM protein fibronectin are dysregulated in aged MuSCs, and reconstitution of these components is able to restore the muscle regenerative capacity.

In addition to stem cell niche, aging also causes changes in circulating signals that directly or indirectly impact functions of tissue stem cells. These signals include soluble molecules secreted by any tissue in the body, which can be hormones, growth factors, and other signaling molecules or immune-derived signals secreted by infiltrating immune cells. Wnt ligand level is higher in old mouse serum and canonical Wnt signaling directly antagonizes Notch signaling in satellite cells. But Wnt inhibitors effectively restored the satellite cell function in aging, and a similar result is obtained in aged mesenchymal stem cells. The level of TGF-β is significantly increased in old human and mouse serum, which causes the damage and senescence of satellite cells. However, blockage of TGF-β signaling can reverse the activity of satellite stem cells, improving the myogenesis of aged mice.

Senescent cells accumulate with aging in several tissues of humans and animals, which is a common feature of age-related pathologies. Not only differentiated cells but also tissue-specific stem cells become senescence during aging. Moreover, the complex senescence-associated secretory phenotype (SASP) is highly expressed with accumulated senescent cells, which can alter the microenvironment and contribute to age-related pathologies. For example, the tissue regenerative capacity is impaired by the limited stem cell function because of their senescent state. And this decreased regenerative capacity is also regulated by the SASP that is secreted by senescent cells. Thus, the selective clearance of senescent cells and SASP suppression will be a promising therapy for age-related diseases. This concept has been successfully tested in physiologically aged mouse models.

As stem cells are the longest-living cells within an organism, stem cell aging is highly relevant as a driver of organismal aging, health, and longevity. In this review, we demonstrate that by targeting aging mechanisms, the aging associated phenotypes and functions of tissue-specific stem cells can be reversed. These restorative interventions hold promise for the possibilities of regenerative medicine and the treatment of many age-related diseases and dysfunctions.

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