Macrophages at the nexus of mesenchymal stromal cell potency: The emerging role of chemokine cooperativity.
Macrophages at the nexus of mesenchymal stromal cell potency: The emerging role of chemokine cooperativity.
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处于间充质基质细胞潜能核心的巨噬细胞：趋化因子协同作用的新兴角色
DOI：
10.1002/stem.3380
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Galipeau J
中科院分区：
文献类型：
--
作者：
Galipeau J
体内用脂质体氯膦酸盐对巨噬细胞进行药理耗竭，会使小鼠对间充质基质细胞（MSCs）的过继转移无反应，从而影响急性炎症病理的结果。这一实验观察结果表明，宿主巨噬细胞在介导MSCs作为一种细胞药物的有益抗炎特性方面是必需的。这一理论得到了以下观察结果的支持：MSCs的输注导致肺部驻留巨噬细胞迅速吞噬近一半滞留在肺部的MSCs，引发白细胞介素（IL）-10抑制性胞葬作用反应。此外，具有环氧化酶2（COX2）活性的未被吞噬的MSCs通过诱导组织巨噬细胞表达IL - 10来塑造免疫环境。更多的实验证据表明，MSCs产生的IL - 6、吲哚胺2,3 - 双加氧酶（IDO）和肿瘤坏死因子刺激基因6（TSG - 6）直接参与巨噬细胞的极化。沿着类似的功能汇聚路线，在与肺部驻留的血管周围巨噬细胞无相互作用的血管外空间植入表达趋化因子（CCL2）的MSCs，也会导致远离MSCs储存库的急性损伤组织内表达趋化因子受体2（CCR2）的巨噬细胞向IL - 10极化。有趣的是，MSCs衍生的CCL2本身不足以使巨噬细胞极化，它需要与MSCs产生的趋化因子（CXCL12）异二聚化，通过CCR2而非CXCR4触发巨噬细胞的IL - 10极化。这种趋化因子的协同作用为分析MSCs的效力开辟了新的途径，特别是考虑到暴露于炎症刺激的MSCs丰富的趋化因子分泌产物。总体而言，这些数据强调了MSCs和宿主巨噬细胞之间必要的功能对偶关系，这可能为MSCs的效力属性分析提供信息——包括趋化因子相互作用组——这可能与体内临床抗炎和再生反应直接相关。
间充质基质细胞（MSCs）和巨噬细胞对偶定理。MSCs通过含有异源复合趋化因子（和其他活性因子）的分泌产物或胞葬作用使巨噬细胞极化为具有白细胞介素（IL）-10抗炎和再生功能的细胞。巨噬细胞IL - 10激活的两种途径——依赖MSCs功能和不依赖MSCs功能——汇聚起来影响炎症组织损伤综合征的临床结果。
Pharmacological depletion of macrophages in vivo with liposomal clodronate renders mice unresponsive to adoptive transfer of mesenchymal stromal cells (MSCs) for affecting outcomes of acute inflammatory pathology. This experimental observation identifies host macrophages as necessary in mediating the salutary anti‐inflammatory properties of MSCs as a cellular pharmaceutical. This theory is supported by the observation that transfusion of MSCs leads to the prompt phagocytosis of nearly half of lung entrapped MSCs by lung resident macrophages, triggering an interleukin (IL)‐10 suppressive efferocytotic response. In addition, non‐phagocytosed MSCs with COX2 competency shape the immune milieu by inducing tissue macrophages to express IL‐10. Additional experimental evidence identifies MSC‐borne IL‐6, IDO and TSG‐6 as directly involved in macrophage polarization. Along similar lines of functional convergence, implantation of CCL2+ MSCs in the extravascular space where interaction with lung resident perivascular macrophages is not operative, also leads to IL‐10 polarization of CCR2+ macrophages within acute injured tissue far removed from MSC depot. Intriguingly, MSC‐derived CCL2 on its own is not sufficient to polarize macrophages and requires heterodimerization with MSC‐borne CXCL12 to trigger macrophage IL‐10 polarization via CCR2, but not CXCR4. Such chemokine cooperativity opens a new venue for analysis of MSC potency especially considering the rich chemokine secretome of MSC exposed to inflammatory stimulus. As an aggregate, these data highlight a necessary MSC and host macrophage functional dyad that may inform potency attribute analysis of MSCs—including the chemokine interactome—that may be directly linked to in vivo clinical anti‐inflammatory and regenerative response. The mesenchymal stromal cell (MSC) and macrophage dyad theorem. MSCs polarize macrophages to an interleukin (IL)‐10 anti‐inflammatory and regenerative functionality via secretome containing heteroplexed chemokines (and other active factors) or efferocytosis. Both macrophage IL‐10 licensing pathways—MSC function dependent and independent—converge to affect clinical outcomes in inflammatory tissue injury syndromes.
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