Age‐related changes in mesenchymal stem cells derived from rhesus macaque bone marrow

Abstract

Summary The regeneration potential of mesenchymal stem cells (MSCs) diminishes with advanced age and this diminished potential is associated with changes in cellular functions. This study compared MSCs isolated from the bone marrow of rhesus monkeys (rBMSCs) in three age groups: young (< 5 years), middle (8–10 years), and old (> 12 years). The effects of aging on stem cell properties and indicators of stem cell fitness such as proliferation, differentiation, circadian rhythms, stress response proteins, miRNA expression, and global histone modifications in rBMSCs were analyzed. rBMSCs demonstrated decreased capacities for proliferation and differentiation as a function of age. The production of heat shock protein 70 (HSP70) and heat shock factor 1 (HSF1) were also reduced with increasing age. The level of a core circadian protein, Rev-erb α, was significantly increased in rBMSCs from old animals. Furthermore, analysis of miRNA expression profiles revealed an up-regulation of mir-766 and mir-558 and a down-regulation of mir-let-7f, mir-125b, mir-222, mir-199-3p, mir-23a, and mir-221 in old rBMSCs compare to young rBMSCs. However, there were no significant age-related changes in the global histone modification profiles of the four histone core proteins: H2A, H2B, H3, and H4 on rBMSCs. These changes represent novel insights into the aging process and could have implications regarding the potential for autologous stem cells therapy in older patients.

Overexpression of the Circadian Clock Gene Rev-erbα Affects Murine Bone Mesenchymal Stem Cell Proliferation and Osteogenesis

“…Recently, studies showed that Rev-erba expression was increased, while Bmal1 expression was decreased in older BMSCs in vitro without the induction of circadian rhythm by dexamethasone exposure or serum shock [20,[29][30][31]. As a unit, the clock genes may regulate the aging process of cells in some way.…”

“…Compared with Rora, Rev-erba has a pivotal role in metabolism and was speculated to be the molecular junction for communicating clock gene signals to the metabolism [18,19]. Moreover, Yu et al found that the expression of Rev-erba in Rhesus macaques declines with age [20].…”

Temporal- and Strain-Specific Host MicroRNA Molecular Signatures Associated with Swine-Origin H1N1 and Avian-Origin H7N7 Influenza A Virus Infection

“…2D). The direct targets of miR-766 have not been identified, but its predicted targets are involved in pathways associated with cell survival after chemotherapy and aging (27,64). The deregulation of these miRNAs, along with others, indicate that the downregulation of cell cycle-related pathways is an important feature of infA infection.…”

Circadian Rhythms in Stem Cell Biology and Function

“…When MSCs are cultured in vitro, 24-h oscillations in gene expression of core clock genes such as Bmal1 , Cry1 , Per2/3 , Rev-erbα/β , and Dbp are found, indicating that the peripheral circadian clock is present in these cells, independent of the presence of the central clock (Wu et al 2008 ). Differences in expression between MSCs of old and young animals are observed (Yu et al 2011 ). These rhythms seem to play an important role in physiology and pathophysiology.…”