Human progenitor cells from bone marrow or adipose tissue produce VEGF, HGF, and IGF-I in response to TNF by a p38 MAPK-dependent mechanism
Human progenitor cells from bone marrow or adipose tissue produce VEGF, HGF, and IGF-I in response to TNF by a p38 MAPK-dependent mechanism
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DOI：
10.1152/ajpregu.00280.2006
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发表时间：
2006-10-01
影响因子：
2.8
通讯作者：
Meldrum, Daniel R.
中科院分区：
文献类型：
--
作者：
Wang, Meijing;Crisostomo, Paul R.;Meldrum, Daniel R.
越来越多的证据表明，祖细胞可能通过抗凋亡机制减少破坏性炎症和减少组织损失。然而，它们的特征仍然很差，并且关于它们可能积极影响伤口愈合，组织重塑或组织再生的机制仍然存在许多问题。据推测，多种生长因子起作用，但伤口环境的哪些成分刺激祖细胞产生生长因子，通过什么机制？我们假设肿瘤坏死因子- α (tnf - α)通过p38丝裂原活化蛋白激酶（MAPK）依赖机制刺激祖细胞分泌血管内皮生长因子（VEGF）、肝细胞生长因子（HGF）和胰岛素样生长因子I （IGF-I）。将人间充质干细胞（hMSCs）和人脂肪祖细胞（hAPCs）分为对照、p38 MAPK抑制剂（p38MKI）、TNF和TNF + p38MKI四组。孵育24小时后，收集上清液进行VEGF、HGF和IGF-I的ELISA检测。收集细胞进行p38 MAPK活化的Western blot分析。在TNF的刺激下，hMSCs和hAPCs中VEGF、HGF和IGF-I的分泌显著增加，并与p38 MAPK激活增加相关。p38 MAPK抑制剂降低了tnf刺激的hMSCs和hAPCs中VEGF、HGF和IGF-I的产生。然而，单独使用p38 MAPK抑制剂对生长因子的产生没有影响。这些数据表明，祖细胞是VEGF、HGF和IGF-I的有效来源。TNF是一种重要的组织细胞因子，通过p38 mapk依赖机制强烈刺激hMSCs和hAPCs产生生长因子。
Accumulating evidence suggests that progenitor cells may decrease destructive inflammation and reduce tissue loss by antiapoptotic mechanisms. However, they remain poorly characterized, and many questions remain regarding the mechanisms by which they may positively affect wound healing, tissue remodeling, or tissue regeneration. It has been speculated that various growth factors are responsible, but what components of the wound milieu stimulate progenitor cell production of growth factors and by what mechanisms? We hypothesized that tumor necrosis factor-alpha (TNF-alpha) stimulated progenitor cell secretion of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and insulin-like growth factor I (IGF-I) by a p38 mitogen-activated protein kinase (MAPK)-dependent mechanism. Human mesenchymal stem cells (hMSCs) and human adipose progenitor cells (hAPCs) were divided into four groups: control, p38 MAPK inhibitor (p38MKI), TNF, and TNF + p38MKI. After 24 h of incubation, supernatants were harvested for ELISA of VEGF, HGF, and IGF-I. Cells were collected for Western blot analysis of p38 MAPK activation. Secretion of VEGF, HGF, and IGF-I in hMSCs and hAPCs was significantly increased by stimulation with TNF and was associated with increased activation of p38 MAPK. The p38 MAPK inhibitor decreased production of TNFstimulated VEGF, HGF, and IGF-I in hMSCs and hAPCs. However, p38 MAPK inhibitor alone had no effect on production of growth factors. These data demonstrate that progenitor cells are potent sources of VEGF, HGF, and IGF-I. TNF, a prominent tissue cytokine, strongly stimulated production of growth factors by hMSCs and hAPCs via a p38 MAPK-dependent mechanism.