Rios Carmen, D'Ippolito Gianluca, Curtis Kevin M, Delcroix Gaëtan J-R, Gomez Lourdes A, El Hokayem Jimmy, Rieger Megan, Parrondo Ricardo, de Las Pozas Alicia, Perez-Stable Carlos, Howard Guy A, Schiller Paul C
1 Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine , Miami, Florida.
2 GRECC and Research Service, Veterans Affairs Medical Center , Miami, Florida.
Stem Cells Dev. 2016 Jun 1;25(11):848-60. doi: 10.1089/scd.2015.0362. Epub 2016 May 9.
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 and participate in their repair. Maintaining throughout adult life such cell subpopulations should help prevent or delay the onset of age-related degenerative conditions. Low oxygen tension, the physiological environment in progenitor cell-rich regions of the bone marrow microarchitecture, stimulates the self-renewal of marrow-isolated adult multilineage inducible (MIAMI) cells and expression of Sox2, Nanog, Oct4a nuclear accumulation, Notch intracellular domain, notch target genes, neuronal transcriptional repressor element 1 (RE1)-silencing transcription factor (REST), and hypoxia-inducible factor-1 alpha (HIF-1α), and additionally, by decreasing the expression of (i) the proapoptotic proteins, apoptosis-inducing factor (AIF) and Bak, and (ii) senescence-associated p53 expression and β-galactosidase activity. Furthermore, low oxygen increases canonical Wnt pathway signaling coreceptor Lrp5 expression, and PI3K/Akt pathway activation. Lrp5 inhibition decreases self-renewal marker Sox2 mRNA, Oct4a nuclear accumulation, and cell numbers. Wortmannin-mediated PI3K/Akt pathway inhibition leads to increased osteoblastic differentiation at both low and high oxygen tension. We demonstrate that low oxygen stimulates a complex signaling network involving PI3K/Akt, Notch, and canonical Wnt pathways, which mediate the observed increase in nuclear Oct4a and REST, with simultaneous decrease in p53, AIF, and Bak. Collectively, these pathway activations contribute to increased self-renewal with concomitant decreased differentiation, cell cycle arrest, apoptosis, and/or senescence in MIAMI cells. Importantly, the PI3K/Akt pathway plays a central mechanistic role in the oxygen tension-regulated self-renewal versus osteoblastic differentiation of progenitor cells.
人类骨髓多能间充质基质细胞（hMSC）数量随衰老而减少。hMSC亚群可分化为存在于骨骼、脉管系统、软骨、肠道及其他组织中的细胞，并参与这些组织的修复。在成年期维持此类细胞亚群应有助于预防或延缓与年龄相关的退行性疾病的发生。低氧张力是骨髓微结构中富含祖细胞区域的生理环境，可刺激骨髓分离的成年多谱系诱导（MIAMI）细胞的自我更新以及Sox2、Nanog、Oct4a核积累、Notch细胞内结构域、Notch靶基因、神经元转录抑制元件1（RE1）-沉默转录因子（REST）和缺氧诱导因子-1α（HIF-1α）的表达，此外，还可通过降低（i）促凋亡蛋白凋亡诱导因子（AIF）和Bak以及（ii）衰老相关p53表达和β-半乳糖苷酶活性来实现。此外，低氧可增加经典Wnt通路信号共受体Lrp5的表达以及PI3K/Akt通路的激活。Lrp5抑制会降低自我更新标志物Sox2 mRNA、Oct4a核积累和细胞数量。渥曼青霉素介导的PI3K/Akt通路抑制在低氧和高氧张力下均导致成骨细胞分化增加。我们证明，低氧刺激了一个涉及PI3K/Akt、Notch和经典Wnt通路的复杂信号网络，该网络介导了观察到的核Oct4a和REST增加，同时p53、AIF和Bak减少。总的来说，这些通路激活有助于MIAMI细胞自我更新增加，同时分化、细胞周期停滞、凋亡和/或衰老减少。重要的是，PI3K/Akt通路在氧张力调节祖细胞的自我更新与成骨细胞分化中起着核心机制作用。
