Genipin guides and sustains the polarization of macrophages to the pro-regenerative M2 subtype via activation of the pSTAT6-PPAR-gamma pathway.
Genipin guides and sustains the polarization of macrophages to the pro-regenerative M2 subtype via activation of the pSTAT6-PPAR-gamma pathway.
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京尼平通过激活pSTAT6 - PPAR - γ通路，引导并维持巨噬细胞向促再生的M2亚型极化。
DOI：
10.1016/j.actbio.2021.06.043
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发表时间：
2021-09-01
影响因子：
9.7
通讯作者：
Akkus O
中科院分区：
文献类型：
--
作者：
Isali I;McClellan P;Shankar E;Gupta S;Jain M;Anderson JM;Hijaz A;Akkus O
M2巨噬细胞与伤口愈合过程中间质胶原和其他细胞外基质蛋白的沉积以及对生物材料的炎症反应有关。开发先进的生物材料以促进M2亚型可能是改善组织加固手术结果的有效方法。在这项研究中，京尼平，一种天然衍生的交联剂，对M0 → M2-极化的影响进行了研究。京尼平通过将细胞接种在由试剂交联的对齐的胶原蛋白生物纺织品上间接引入，或者通过直接添加到培养基中以可溶形式引入。还研究了细胞伸长对由胶原蛋白生物织物诱导的巨噬细胞极化的影响，作为巨噬细胞极化的潜在诱导剂。M0和M2巨噬细胞在对齐的胶原线表面上表现出显著的伸长，而M1亚型的细胞保持圆形表型。M0 → M2极化，如通过胰蛋白酶和Ym-1产生所反映的，仅当胶原线被京尼平交联时在胶原线上观察到，这暗示京尼平是与细胞骨架延伸相比更有效的再生表型诱导剂。将京尼平直接添加到培养基中还驱动了促再生表型的出现，如通过标记物（脱氢酶和Ym-1）和通过pSTAT 6-PPAR-gamma途径的激活所测量的。本研究表明京尼平交联胶原生物纺织品可用作生物材料植入后促进再生反应的递送平台。免疫应答是组织修复和再生速率以及结果的关键决定因素之一。已知M2巨噬细胞亚型通过产生促再生因子来解决炎症反应并支持组织修复。因此，促进M2亚型的生物材料可以是增强组织再生的可行策略。在这项研究中，我们研究京尼平交联的电化学排列胶原蛋白生物纺织品的能力，以诱导促再生极化的M0巨噬细胞。结果表明，京尼平，而不是基质诱导的细胞伸长，是负责M0 → M2极化在没有其他生物诱导因子和维持M2极化状态的巨噬细胞。此外，我们发现京尼平通过激活pSTAT 6-PPAR-gamma途径使M2巨噬细胞表型极化。
M2 macrophages are associated with deposition of interstitial collagen and other extracellular matrix proteins during the course wound healing and also inflammatory response to biomaterials. Developing advanced biomaterials to promote the M2 subtype may be an effective way to improve tissue reinforcement surgery outcomes. In this study, the effect of genipin, a naturally derived crosslinking agent, on M0 → M2-polarization was investigated. Genipin was introduced either indirectly by seeding cells on aligned collagen biotextiles that are crosslinked by the agent or in soluble form by direct addition to the culture medium. Cellular elongation effects on macrophage polarization induced by the collagen biotextile were also investigated as a potential inducer of macrophage polarization. M0 and M2 macrophages demonstrated significant elongation on the surface of aligned collagen threads, while cells of the M1 subtype-maintained a round phenotype. M0 → M2 polarization, as reflected by arginase and Ym-1 production, was observed on collagen threads only when the threads were crosslinked by genipin, implicating genipin as a more potent inducer of the regenerative phenotype compared to cytoskeletal elongation. The addition of genipin to the culture medium directly also drove the emergence of pro-regenerative phenotype as measured by the markers (arginase and Ym-1) and through the activation of the pSTAT6-PPAR-gamma pathway. This study indicates that genipin-crosslinked collagen biotextiles can be used as a delivery platform to promote regenerative response after biomaterial implantation. The immune response is one of the key determinants of tissue repair and regeneration rate, and outcome. The M2 macrophage subtype is known to resolve the inflammatory response and support tissue repair by producing pro-regenerative factors. Therefore, a biomaterial that promotes M2 sub-type can be a viable strategy to enhance tissue regeneration. In this study, we investigated genipin-crosslinked electrochemically aligned collagen biotextiles for their capacity to induce pro-regenerative polarization of M0 macrophages. The results demonstrated that genipin, rather than matrix-induced cellular elongation, was responsible for M0 → M2 polarization in the absence of other bioinductive factors and maintaining the M2 polarized status of macrophages. Furthermore, we identified that genipin polarizes the M2 macrophage phenotype via activation of the pSTAT6-PPAR-gamma pathway.
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影响因子：
9.3
作者：
Krasnow, Stephanie M.;Knoll, J. Gabriel;Marks, Daniel L.
通讯作者：
Marks, Daniel L.
影响因子：
3.9
作者：
Graney, Pamela L.;Roohani-Esfahani, Seyed-Iman;Spiller, Kara L.
通讯作者：
Spiller, Kara L.
影响因子：
7.3
作者：
Iula L;Keitelman IA;Sabbione F;Fuentes F;Guzman M;Galletti JG;Gerber PP;Ostrowski M;Geffner JR;Jancic CC;Trevani AS
通讯作者：
Trevani AS
影响因子：
3.5
作者：
BINDER, SW;SAID, JW;PINKUS, GS
通讯作者：
PINKUS, GS
影响因子：
4.1
作者：
Koci, Zuzana;Sridharan, Rukmani;O'Brien, Fergal J.
通讯作者：
O'Brien, Fergal J.