Age-Specific Changes of Mesenchymal Stem Cells Are Paralleled by Upregulation of CD106 Expression As a Response to an Inflammatory Environment

Abstract

Regeneration, tissue remodeling, and organ repair after injury, which rely on the regulated activity of tissue-borne stem cells, become increasingly compromised with advancing age. Mesenchymal stroma cells were isolated from bone of differently aged healthy donors. The rare population of mesenchymal stem cells (MSCs) contained in the primary cell isolates barely declined in number, yet the stem cells displayed diminished long-term proliferation potential relative to the donor age and the expression of vascular cell adhesion molecule-1 (VCAM-1; CD106) was elevated on primary MSCs. In CD106(bright) MSCs, the abundance of a panel of stemness transcription factors remained unchanged. Because the CD106 level could be further enhanced by proinflammatory cytokines, we considered the rate of VCAM-1 expression to be a good reflection of an endogenous inflammatory milieu to which the MSCs are exposed. Treatment of MSCs with increasing doses of interferon-γ exerted no immediate influence on their self-renewal capacity. However, it impacted on the differentiation potential toward the adipogenic or osteogenic lineage. Moderately elevated levels of inflammatory stimuli supported osteoblastogenesis whereas the same treatment reduced adipogenic differentiation in MSCs from young and intermediately aged donors. In MSCs from elderly donors, however, osteoblastogenesis was greatly diminished in an inflammatory environment whereas adipogenic differentiation remained unchanged. Conclusively, moderate levels of inflammatory stimuli are being interpreted by MSCs at a young age as instructive signals for osteoblastogenesis, whereas at old age, an inflammatory milieu may effectively suppress bone remodeling and repair by tissue-borne MSCs while uninterrupted adipogenic differentiation may lead to adipose upgrowth.

TNFα and IL-1β influence the differentiation and migration of murine MSCs independently of the NF-κB pathway

“…Pro-inflammatory cytokines such as TNFα have significant effects on human MSCs; they can modulate proteins linked to immunosuppressive and signaling pathways such as manganese superoxide dismutase (SOD2), ribose-phosphate pyrophosphokinase 1, septin-9, and signal transducer and activator of transcription 1 (STAT1) [25]; enhance migration [26]; and inhibit chondrogenesis and osteogenesis [27, 28]. There is a negative relationship between the magnitude of synovial inflammation and the chondrogenic and clonal capacities of MSCs isolated from rheumatoid synovium, further supporting the hypothesis that the inflammatory milieu alters MSC characteristics [29].…”

Interferon-γ alters the microRNA profile of umbilical cord-derived mesenchymal stem cells

“…In addition, IFN-γ affects numerous other biological characteristics of MSCs (10–12). However, the mechanisms underlying the effect of IFN-γ on MSCs remain to be fully elucidated.…”

“…These inhibitory effects were verified by in vivo experiments; however, the underlying mechanisms remain unclear. IFN-γ may also influence the apoptosis, phenotype and chemotactic factors of MSCs (11,12). …”

Systemic impact molds mesenchymal stromal/stem cell aging

“…Differential expression analyses of aberrations which actually take place before a cell slithers into the final state of senescence resulted in meaningful insightsand showed the increased production of ROS, or deviating Super-Oxide Dismutase (SOD) activity. Moreover, whole genome gene expression profiles and epigenetic signatures have been reported only recently [24][25][26][27][28][29][30][31]. Also deviations of the age-associated MSC differentiation capacity have been reported by many laboratories inasmuch osteogenic potential of MSC isolated from aged donors appeared to decline while the respective adipogenic differentiation performance remained unchanged, or worse, was found to be enhanced.…”