Like a healthy balance between work and play can enhance our day-to-day lives, a new study suggests that stem cells require a healthy epigenetic balance between silent and active chromatin domains to support their ongoing normal functions. More specifically, researchers headed by the well-balanced quartet of Moshi Song, Weiqi Zhang, Jing Qu, and Guang-Hui Liu (University of the Chinese Academy of Sciences, Beijing, China) discovered that the nuclear accumulation of Apolipoprotein E (APOE) destabilizes heterochromatin to “tip” the epigenetic balance of human mesenchymal stem cells (MSCs) towards senescence, a cell state associated with tissue aging.
Notably, a subtype of APOE participates in Alzheimer’s disease and cardiovascular disease; furthermore, previous studies reporting APOE accumulation in stem cell-containing tissues such as the hippocampus, adipose, and blood during normal aging have suggested a vital role for this lipoprotein during normal aging. This all-too-familiar process occurs alongside the accumulation of senescent cells, stem cell exhaustion, organ dysfunction, and epigenetic alterations. Therefore, this tightrope-walking team sought to balance these earlier findings in their minds and encounter a novel link between increased APOE levels, MSC senescence, and epigenetic alterations.
Let’s hear more on this epigenetic balancing act from Zhao, Ji, Wu, and colleagues:
- Increases in APOE expression and nuclear accumulation occur in embryonic stem cell (ESC)-derived MSCs undergoing pathological (Hutchinson-Gilford progeria/Werner syndrome MSCs) or physiological replicative senescence
- Ectopic overexpression of APOE in MSCs accelerates senescence and reduces proliferation, suggesting that APOE deletion may promote a “geroprotective” state
- CRISPR–Cas9-mediated ablation of APOE in ESCs before differentiation to MSCs inhibits the onset of MSC senescence and enhances proliferation
- Short hairpin RNA-mediated APOE knockdown alleviates senescence stimulated by multiple different mechanisms in MSCs and rejuvenates human fibroblasts suffering from replicative/accelerated senescence
- At the mechanistic level, APOE induces targeted degradation of both heterochromatin- and nuclear lamina-associated proteins via the autophagy-lysosomal pathway
- Subsequent disorganization of the heterochromatinized epigenome and impairment of nuclear structure prompts the detachment of lamina-associated domains from the nuclear lamina, which increases transcription of repetitive genomic sequences and accelerates cellular senescence
- MSCs lacking APOE exhibit a more stable nuclear lamina and heterochromatin organization
Overall, this well-balanced study provides evidence that stem cell senescence triggered by APOE-mediated heterochromatin destabilization may represent a critical age-related mechanism that subsequently prompts the loss of tissue function. The authors also anticipate that therapeutically targeting APOE may represent a means to return some epigenetic balance to tissue-resident stem cells and slow/inhibit the aging process under physiological and/or pathological conditions.
For more on this epigenetic balancing act, see Nature Aging, March 2022.