Chronic inflammation and angiogenic signaling axis impairs differentiation of dental-pulp stem cells.
Chronic inflammation and angiogenic signaling axis impairs differentiation of dental-pulp stem cells.
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DOI：
10.1371/journal.pone.0113419
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Alapati S
中科院分区：
文献类型：
--
作者：
Boyle M;Chun C;Strojny C;Narayanan R;Bartholomew A;Sundivakkam P;Alapati S
牙髓组织经常遭受炎症损伤。炎症损伤后释放的隔离生长因子或血管生成信号蛋白在修复性牙本质的形成中发挥着关键作用。虽然有限或适度的血管生成可能有助于牙髓维护，但诱导显着水平的血管生成可能非常有害。迄今为止，一些研究已经在体外探讨了促炎刺激对牙髓干细胞（DPSC）存活和分化的影响。然而，参与 DPSC 存活和分化的炎症和血管生成信号传导的共同机制仍然未知。我们的研究观察到，短期暴露于 TNF-α（6 小时和 12 小时 [hrs]）会诱导细胞凋亡，并上调 VEGF 表达和 NF-κB 信号传导。然而，长期（慢性）暴露于 TNF-α 会导致增殖增加，同时端粒长度缩短。有趣的是，用 Nemo 结合域 (NBD) 肽（一种细胞渗透性 NF-κB 抑制剂）预处理的 DPSC 显着改善了 TNF-α 和/或 VEGF 诱导的增殖和端粒长度的缩短。 NBD 肽预处理显着改善了 TNF-α 诱导的分化必需蛋白的下调，例如骨形态发生蛋白 (BMP)-1 和 2、BMP 受体亚型-1 和 2、转化生长因子 (TGF)、骨激活素和骨钙素。此外，抑制 NF-κB 信号传导可显着增加矿化潜力，而长期暴露于 TNF-α 会消除这一过程。因此，我们的研究表明，慢性炎症通过人 DPSC 中的 NF-κB 信号传导介导端粒缩短。由此产生的染色体不稳定导致 DPSC 增殖增加，同时在体外负调节 DPSC 的分化。
Dental-pulp tissue is often exposed to inflammatory injury. Sequested growth factors or angiogenic signaling proteins that are released following inflammatory injury play a pivotal role in the formation of reparative dentin. While limited or moderate angiogenesis may be helpful for dental pulp maintenance, the induction of significant level of angiogenesis is probably highly detrimental. Hitherto, several studies have addressed the effects of proinflammatory stimuli on the survival and differentiation of dental-pulp stem cells (DPSC), in vitro. However, the mechanisms communal to the inflammatory and angiogenic signaling involved in DPSC survival and differentiation remain unknown. Our studies observed that short-term exposure to TNF-α (6 and 12 hours [hrs]) induced apoptosis with an upregulation of VEGF expression and NF-κB signaling. However, long-term (chronic) exposure (14 days) to TNF-α resulted in an increased proliferation with a concomitant shortening of the telomere length. Interestingly, DPSC pretreated with Nemo binding domain (NBD) peptide (a cell permeable NF-κB inhibitor) significantly ameliorated TNF-α- and/or VEGF-induced proliferation and the shortening of telomere length. NBD peptide pretreatment significantly improved TNF-α-induced downregulation of proteins essential for differentiation, such as bone morphogenic proteins (BMP)-1 & 2, BMP receptor isoforms-1&2, trasnforming growth factor (TGF), osteoactivin and osteocalcin. Additionally, inhibition of NF-κB signaling markedly increased the mineralization potential, a process abrogated by chronic exposure to TNF-α. Thus, our studies demonstrated that chronic inflammation mediates telomere shortening via NF-κB signaling in human DPSC. Resultant chromosomal instability leads to an emergence of increased proliferation of DPSC, while negatively regulating the differentiation of DPSC, in vitro.
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DOI：
10.1080/10623320600972101
发表时间：
2006-09-01
影响因子：
--
作者：
Arfuso, Frank
通讯作者：
Arfuso, Frank
影响因子：
3.9
作者：
Feng, Xingmei;Feng, Guijuan;Gu, Zhifeng
通讯作者：
Gu, Zhifeng
影响因子：
4.1
作者：
Papagerakis, P;Berdal, A;Macdougall, M
通讯作者：
Macdougall, M
影响因子：
5.2
作者：
Challen, GA;Little, MH
通讯作者：
Little, MH
影响因子：
4.4
作者：
Martin, M;Katz, J;Michalek, SM
通讯作者：
Michalek, SM