Chromatin Changes in the Aging of Stem Cells

Chromatin is the name given to the packed structure of nuclear DNA and surrounding molecules, tightly coiled in the center of the cell. Chromatin structure and the molecules responsible for regulating that structure are a part of the complex epigenetic systems that determine the pace of protein production, and thus cell behavior. Chromatin changes in characteristic ways with age, a situation that is far from fully mapped and understood, but is particularly important in stem cell aging. Stem cell populations become less active with age, most likely an evolved response to rising levels of tissue damage that acts to limit the incidence of cancer. The cost of that protection is a slow decline into organ failure, disease, and death. Safely restoring youthful function in the scores of different stem cell populations throughout the body is an important goal for the future of medicine.

In most tissues, adult stem cells occupy a rare but powerful functional compartment, capable of differentiating into multiple tissue-specific lineages. Some stem cell types can remain quiescent until environmental signals prompt them to divide whereas other types continuously divide to repopulate lost or injured tissue. This process is critical and is harnessed during injury and disease to enhance tissue repair. Stem cells in adult tissues show dramatic reductions in regenerative capacity with age. Stem cells undergo replicative aging (due to repeat proliferative cycles), chronological aging (due to chronic changes during prolonged quiescent state) and even show senescence or exhaustion phenotypes. Prolonged quiescence can accumulate DNA damage and cause chronological aging due to additive insults and error-prone damage repair mechanisms.

In response to replication signals, stem cells are activated to divide. Two major aspects of stem cell division are self-renewal and differentiation. Studies across multiple organisms and stem cell types have revealed distinct effects of aging on self-renewal capacity and differentiation potential depending on stem cell type. This is manifested in either loss or gain of stem cell numbers, delay in activation kinetics, altered fate, lineage bias and/or compromised function of differentiated cells with age. Ultimately, these changes in aged stem cells eventually lead to physiological disorders and age-dependent pathologies in the organism.

Evidence suggests a reconfiguration of the chromatin state to a global increase in DNA hypermethylation, an imbalanced heterochromatin, a loss of active enhancers, even a disruption of chromosome territories. The consequences of these epigenomic changes are reflected in functional outcomes such as altered self-renewal patterns and/or senescence phenotypes that impact stem cell number. Additionally, there is dramatic change in stem cell potential, lineage bias, delayed activation kinetics and ultimately higher frequencies of disease phenotypes such as cancer.

While "drift" patterns are not necessarily programmed, it may be possible to delay their accumulation or even reverse the changes by late-life epigenetic drug interventions or cellular epigenome reprogramming strategies that "wipe out and start over". Complete reprogramming of aged hematopoietic stem cells (HSCs) into induced pluripotent stem cells - by overexpression of OCT4, SOX2, KLF4, and MYC (OSKM) - followed by blastocyst complementation, re-differentiation into HSCs, and serial transplantation showed remarkable repopulation capacity invariant with young cells. Since the genetic material of the stem cells was unchanged, this type of rejuvenation was attributed to an epigenetic resetting although the exact mechanisms remain to be identified. Partial reprogramming by short-term cyclic expression of OSKM also had positive outcomes in aged mice. There is also evidence from other studies that partial reprogramming can turn back the DNA methylation clock further supporting the notion that reprogramming directly affects the epigenome. However, whether similar changes occur in stem cells remains to be investigated.

Link: https://doi.org/10.1016/j.tma.2020.08.002

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