Mapping Macrophage Polarization and Origin during the Progression of the Foreign Body Response to a Poly(ethylene glycol) Hydrogel Implant.
Mapping Macrophage Polarization and Origin during the Progression of the Foreign Body Response to a Poly(ethylene glycol) Hydrogel Implant.
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DOI：
10.1002/adhm.202102209
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发表时间：
2022-05
影响因子：
10
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聚（乙二醇）（PEG）水凝胶有望用于体内应用，但会诱导异物反应（FBR）。虽然巨噬细胞是FBR的关键，但仍存在许多问题。本研究调查了植入物相关单核细胞转录组的时间变化（即，新来的）和巨噬细胞。与对照单核细胞相比，促炎途径在植入物相关单核细胞中上调，但在第14天消退。植入物相关巨噬细胞最初是促炎性的，但到第14天转变为替代性活化的促纤维化状态，与纤维囊出现一致。接下来，这项研究使用野生型，缺乏招募巨噬细胞的CCR 2 −/−小鼠和能够消融所有巨噬细胞的MaFIA小鼠评估了负责纤维包裹的巨噬细胞的起源。鉴定募集的和组织驻留的巨噬细胞的亚群。纤维包裹在CCR 2 −/−小鼠中进行，与野生型小鼠相似。然而，MaFIA小鼠的研究表明，巨噬细胞是纤维囊形成所必需的。这些发现表明巨噬细胞来源影响FBR进展，并提供了组织驻留巨噬细胞而不是募集的巨噬细胞可能驱动FBR至PEG水凝胶中的纤维化的证据。本研究表明，植入物相关单核细胞和巨噬细胞在FBR中具有时间上不同的转录组，并且与巨噬细胞相关的促纤维化途径可能在组织驻留巨噬细胞中富集。在对PEG水凝胶植入物的异物反应期间，植入物相关单核细胞和巨噬细胞表现出时间上不同的转录组。这项研究的结果表明，组织驻留的巨噬细胞而不是招募的巨噬细胞是FBR中纤维包裹的驱动因素。
Poly(ethylene glycol) (PEG) hydrogels hold promise for in vivo applications but induce a foreign body response (FBR). While macrophages are key in the FBR, many questions remain. This study investigates temporal changes in the transcriptome of implant-associated monocytes (i.e., newly arrived) and macrophages. Pro-inflammatory pathways are up-regulated in implant-associated monocytes compared to control monocytes but subsided by day 14. Implant-associated macrophages are initially pro-inflammatory but shift to an alternatively activated pro-fibrotic state by day 14, coinciding with the fibrous capsule emergence. Next, this study assesses the origin of macrophages responsible for fibrous encapsulation using wildtype, CCR2−/− mice that lack recruited macrophages, and MaFIA mice that enable ablation of all macrophages. Subpopulations of recruited and tissue-resident macrophages are identified. Fibrous encapsulation proceeds in CCR2−/− mice similar to wildtype mice. However, studies in MaFIA mice indicate that macrophages are necessary for fibrous capsule formation. These findings suggest that macrophage origin impacts the FBR progression and provides evidence that tissue-resident macrophages and not the recruited macrophages may drive fibrosis in the FBR to PEG hydrogels. This study demonstrates that implant-associated monocytes and macrophages have temporally distinct transcriptomes in the FBR and that pro-fibrotic pathways associated with macrophages may be enriched in tissue-resident macrophages. Implant-associated monocytes and macrophages exhibit temporally distinct transcriptomes during the foreign body response to PEG hydrogel implants. Findings from this study implicate tissue-resident macrophages and not recruited macrophages as the driver of fibrous encapsulation in the FBR.