Low Oxygen Modulates Multiple Signaling Pathways, Increasing Self-Renewal, While Decreasing Differentiation, Senescence, and Apoptosis in Stromal MIAMI Cells.

摘要: Human bone marrow multipotent mesenchymal stromal cell (hMSC) number decreases with aging. Subpopulations of hMSCs can differentiate into cells found in bone, vasculature, cartilage, gut, and other tissues participate their repair. Maintaining throughout adult life such subpopulations should help prevent or delay the onset age-related degenerative conditions. Low oxygen tension, physiological environment progenitor cell-rich regions microarchitecture, stimulates self-renewal marrow-isolated multilineage inducible (MIAMI) expression Sox2, Nanog, Oct4a nuclear accumulation, Notch intracellular domain, notch target genes, neuronal transcriptional repressor element 1 (RE1)-silencing transcription factor (REST), hypoxia-inducible factor-1 alpha (HIF-1α), additionally, by decreasing (i) proapoptotic proteins, apoptosis-inducing (AIF) Bak, (ii) senescence-associated p53 β-galactosidase activity. Furthermore, low increases canonical Wnt pathway signaling coreceptor Lrp5 expression, PI3K/Akt activation. inhibition marker Sox2 mRNA, numbers. Wortmannin-mediated leads to increased osteoblastic differentiation at both high tension. We demonstrate that a complex network involving PI3K/Akt, Notch, pathways, which mediate observed increase REST, simultaneous decrease p53, AIF, Bak. Collectively, these activations contribute concomitant decreased differentiation, cycle arrest, apoptosis, and/or senescence MIAMI cells. Importantly, plays central mechanistic role tension-regulated versus