Reciprocal Interaction Between Pericytes and Macrophage in Poststroke Tissue Repair and Functional Recovery
Reciprocal Interaction Between Pericytes and Macrophage in Poststroke Tissue Repair and Functional Recovery
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DOI：
10.1161/strokeaha.120.029827
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发表时间：
2020-10-01
期刊：
影响因子：
8.3
通讯作者：
Kitazono, Takanari
中科院分区：
文献类型：
--
作者：
Shibahara, Tomoya;Ago, Tetsuro;Kitazono, Takanari
背景和目的：卒中后组织修复是功能恢复的重要过程，包括巨噬细胞介导的髓鞘碎片清除和梗死区域内周细胞介导的纤维化反应。在此，我们研究了周细胞和巨噬细胞在卒中后修复和功能恢复过程中的相互作用。研究方法：我们在野生型和周细胞缺陷型PDGFR β（血小板衍生生长因子受体β）杂合敲除（Pdgfrb（+/-））小鼠中进行了永久性大脑中动脉闭塞，并比较了两组之间的组织学变化和神经功能。我们还研究了从培养的周细胞或骨髓来源的巨噬细胞中收获的条件培养基对其他细胞类型功能的影响。结果如下：永久性大脑中动脉闭塞后，PDGFR β阳性周细胞和F4/80阳性巨噬细胞的定位在时间和空间上非常相似。在Pdgfrb（+/-）小鼠中，梗塞内巨噬细胞的积聚显著减弱。梗死周细胞表达CCL 2（C-C基序配体2）和CSF 1（集落刺激因子1），这两种蛋白在Pdgfrb（+/-）小鼠中均显著降低。培养的周细胞表达Ccl 2和Csf 1，这两种蛋白在PDGF-BB作用下显著增加，而在PDGFR β抑制剂作用下被抑制。周细胞条件培养液能显著促进骨髓源性巨噬细胞的迁移和增殖。中风后髓鞘碎片的清除在Pdgfrb（+/-）小鼠中显著减弱。周细胞条件培养基促进骨髓源性巨噬细胞的吞噬活性，也增强STAT 3（信号转导和转录激活因子3）磷酸化和清道夫受体Msr 1和Lrp 1的表达。巨噬细胞处理髓鞘碎片产生营养因子，增强周细胞中的PDGFR β信号传导，导致ECM（细胞外基质）蛋白的产生和少突细胞发生。Pdgfrb（+/-）小鼠的功能恢复显著减弱，与组织修复的程度平行。结论：周细胞和巨噬细胞之间的相互作用对于卒中后组织修复和功能恢复是重要的。
Background and Purpose: Poststroke tissue repair, comprised of macrophage-mediated clearance of myelin debris and pericyte-mediated fibrotic response within the infarct area, is an important process for functional recovery. Herein, we investigated the reciprocal interaction between pericytes and macrophages during poststroke repair and functional recovery. Methods: We performed a permanent middle cerebral artery occlusion in both wild-type and pericyte-deficient PDGFR beta (platelet-derived growth factor receptor beta) heterozygous knockout (Pdgfrb(+/-)) mice and compared histological changes and neurological functions between the 2 groups. We also examined the effects of conditioned medium harvested from cultured pericytes, or bone marrow-derived macrophages, on the functions of other cell types. Results: Localization of PDGFR beta-positive pericytes and F4/80-positive macrophages was temporally and spatially very similar following permanent middle cerebral artery occlusion. Intrainfarct accumulation of macrophages was significantly attenuated inPdgfrb(+/-)mice. Intrainfarct pericytes expressed CCL2 (C-C motif ligand 2) and CSF1 (colony stimulating factor 1), both of which were significantly lower inPdgfrb(+/-)mice. Cultured pericytes expressedCcl2andCsf1, both of which were significantly increased by PDGF-BB and suppressed by a PDGFR beta inhibitor. Pericyte conditioned medium significantly enhanced migration and proliferation of bone marrow-derived macrophages. Poststroke clearance of myelin debris was significantly attenuated inPdgfrb(+/-)mice. Pericyte conditioned medium promoted phagocytic activity in bone marrow-derived macrophages, also enhancing both STAT3 (signal transducer and activator of transcription 3) phosphorylation and expression of scavenger receptors,Msr1andLrp1. Macrophages processing myelin debris produced trophic factors, enhancing PDGFR beta signaling in pericytes leading to the production of ECM (extracellular matrix) proteins and oligodendrogenesis. Functional recovery was significantly attenuated inPdgfrb(+/-)mice, parallel with the extent of tissue repair. Conclusions: A reciprocal interaction between pericytes and macrophages is important for poststroke tissue repair and functional recovery.