Human Periodontal Stem Cells Release Specialized Proresolving Mediators and Carry Immunomodulatory and Prohealing Properties Regulated by Lipoxins.
Human Periodontal Stem Cells Release Specialized Proresolving Mediators and Carry Immunomodulatory and Prohealing Properties Regulated by Lipoxins.
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DOI：
10.5966/sctm.2015-0163
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发表时间：
2016-01
影响因子：
6
通讯作者：
Romano M
中科院分区：
文献类型：
--
作者：
Cianci E;Recchiuti A;Trubiani O;Diomede F;Marchisio M;Miscia S;Colas RA;Dalli J;Serhan CN;Romano M
观察人牙周膜干细胞(HPDLSCs)对中性粒细胞(PMN)凋亡和抗菌功能的影响，以及脂氧素A4(LXA4)对其的影响。HPDLSCs通过细胞-细胞相互作用和旁分泌机制显著减少人PMN的凋亡并刺激其杀菌活性。HPDLSCs还能生物合成前列环脂介质和前列腺素。本研究还证实了LXA4-ALX/FPR2轴通过一种新的受体介导机制来调节人PDLSCs的再生功能。未解决的炎症和组织破坏是牙周炎的潜在机制，与中性粒细胞(PMN)功能失调有关。脂氧素A4(LXA4)是一种特殊的促分解脂质介质(SPM)，它可以抑制过度的炎症，促进分解，并防止白细胞介导的组织损伤。人牙周膜干细胞(HPDLSCs)在组织再生过程中扮演着重要角色，并可能有助于炎症的消退，因此，它们有望成为牙科再生领域的一种有前途的工具。在本研究中，我们研究了hPDLSCs对PMN凋亡和抗菌功能的作用，并确定了LXA4对hPDLSCs的影响。HPDLSCs通过细胞-细胞相互作用和旁分泌机制显著减少人PMN的凋亡并刺激其杀菌活性。脂类代谢脂组学分析表明，hPDLSCs可生物合成α，包括分解蛋白D_1、D_2、D_5和D_6；保护素D_1、木脂素和LXB_4；以及前列腺素D_2、E_2和F_2 SPM。LXA4通过激活hPDLSCs上表达的同源受体ALX/FPR2，显著增强hPDLSCs的增殖、迁移和伤口愈合能力。综上所述，这些结果表明hPDLSCs调节PMN的功能，并首次提供了干细胞产生SPM的证据，LXA4-ALX/FPR2轴通过一种新的受体介导的机制调节hPDLSCs的再生功能。这些发现揭示了来自牙周膜的干细胞未知的特征，支持了这样的观点，即这些细胞可能通过释放促进炎症和细菌杀灭的介质来发挥病理生理事件的主要调节作用。这项研究还表明，利用脂氧素A4调节牙周干细胞的重要功能是可能的，脂氧素A4是一种有效的内源性炎症停止信号。因此，这项研究揭示了一种未知的抗炎再生回路，可能被利用来利用常驻干细胞来对抗牙周疾病。此外，这些数据可能代表了一个更通用的模板来解释干细胞的免疫调节功能。
The actions of human periodontal ligament stem cells (hPDLSCs) on polymorphonuclear neutrophil (PMN) apoptosis and antimicrobial functions, and the impact of lipoxin A4 (LXA4) on hPDLSCs were investigated. hPDLSCs significantly reduced apoptosis and stimulated microbicidal activity of human PMNs, via both cell-cell interactions and paracrine mechanisms. hPDLSCs also were found to biosynthesize proresolving lipid mediators and prostaglandins. This study also demonstrated that the LXA4-ALX/FPR2 axis regulates regenerative functions of hPDLSCs by a novel receptor-mediated mechanism. Unresolved inflammation and tissue destruction are underlying mechanisms of periodontitis, which is linked to dysregulated polymorphonuclear neutrophil (PMN) functions. Lipoxin A4 (LXA4) is a specialized proresolving lipid mediator (SPM) that dampens excessive inflammation, promotes resolution, and protects from leukocyte-mediated tissue damage. Human periodontal ligament stem cells (hPDLSCs) represent key players during tissue regeneration and may contribute to resolution of inflammation; thus, they may represent a promising tool in regenerative dentistry. In the present study, we investigated the actions of hPDLSCs on PMN apoptosis and antimicrobial functions, and determined the impact of LXA4 on hPDLSCs. hPDLSCs significantly reduced apoptosis and stimulated microbicidal activity of human PMNs, via both cell-cell interactions and paracrine mechanisms. Lipid mediator metabololipidomics analysis demonstrated that hPDLSCs biosynthesize SPMs, including resolvin D1, D2, D5, and D6; protectin D1; maresins; and LXB4; as well as prostaglandins D2, E2, and F2α. LXA4 significantly enhanced proliferation, migration, and wound healing capacity of hPDLSCs through the activation of its cognate receptor ALX/FPR2, expressed on hPDLSCs. Together, these results demonstrate that hPDLSCs modulate PMN functions, and provide the first evidence that stem cells generate SPM and that the LXA4-ALX/FPR2 axis regulates regenerative functions of hPDLSCs by a novel receptor-mediated mechanism. These findings uncovered unappreciated features of stem cells from the periodontal ligament, supporting the notion that these cells may act as master regulators of pathophysiological events through the release of mediators that promote the resolution of inflammation and bacterial killing. The study also demonstrated that it is possible to modulate important functions of periodontal stem cells using lipoxin A4, a potent endogenous stop signal of inflammation. Thus, this study revealed an unappreciated anti-inflammatory proregenerative circuit that may be exploited to combat periodontal pathologies using resident stem cells. Moreover, the data may represent a more general template to explain the immunomodulatory functions of stem cells.