Cornea-Derived Mesenchymal Stromal Cells Therapeutically Modulate Macrophage Immunophenotype and Angiogenic Function.
Cornea-Derived Mesenchymal Stromal Cells Therapeutically Modulate Macrophage Immunophenotype and Angiogenic Function.
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DOI：
10.1002/stem.2781
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发表时间：
2018-05
期刊：
影响因子：
--
通讯作者：
Djalilian AR
中科院分区：
文献类型：
--
作者：
Eslani M;Putra I;Shen X;Hamouie J;Tadepalli A;Anwar KN;Kink JA;Ghassemi S;Agnihotri G;Reshetylo S;Mashaghi A;Dana R;Hematti P;Djalilian AR
巨噬细胞是炎症性角膜新生血管的重要驱动力，因此是免疫调节治疗的潜在靶点。我们推测，角膜间充质基质细胞(CMSCs)的治疗应用可能改变巨噬细胞的功能。我们发现cMSCs可以调节巨噬细胞的表型和血管生成功能。在体外，cMSCs诱导巨噬细胞凋亡，同时优先促进一种独特的CD14hiCD16hiCD163hiCD206hi免疫表型，根据体外血管生成实验，这种免疫表型显著降低了血管生成效应。在体内，将cMSCs应用于小鼠角膜损伤后，可减少巨噬细胞的浸润，增加巨噬细胞CD206的表达。与对照巨噬细胞相比，cMSCs共培养(“培养”)的巨噬细胞表达显著更高水平的抗血管生成和抗炎因子。在体内，与对照巨噬细胞治疗的角膜相比，接受cMSC教育的巨噬细胞治疗的受损角膜显示明显较少的新生血管。下调PEDF在cMSCs中的表达可显著取消其对巨噬细胞的调控作用，表现为共培养的巨噬细胞凋亡率降低，sFlt-1/PEDF表达降低，VEGF-A表达增加。同样，从PEDF基因敲除小鼠分离的cMSCs在应用于野生型角膜损伤后抑制巨噬细胞渗透方面不如野生型cMSCs有效。总之，这些结果表明cMSCs在治疗上抑制了巨噬细胞的血管生成能力，并强调了cMSC分泌的PEDF在调节巨噬细胞表型和功能中的作用。在严重的角膜损伤或炎症情况下，趋化因子和细胞因子招募炎症细胞，进而通过血管内皮生长因子-A诱导角膜血管生成。角膜MSCs的细胞治疗可以通过诱导巨噬细胞的凋亡和促进分泌高水平sFlt-1、PEDF和TSG-6的独特的巨噬细胞免疫表型(cMSC教育的巨噬细胞-cMEMq)来部分地通过PEDF来调节这种炎症。
Macrophages are crucial drivers of inflammatory corneal neovascularization and thus are potential targets for immunomodulatory therapies. We hypothesized that therapeutic use of cornea derived mesenchymal stromal cells (cMSCs) may alter the function of macrophages. We found that cMSCs can modulate the phenotype and angiogenic function of macrophages. In vitro, cMSCs induce apoptosis of macrophages while preferentially promoting a distinct CD14hiCD16hiCD163hiCD206hi immunophenotype that has significantly reduced angiogenic effects based on in vitro angiogenesis assays. In vivo, application of cMSCs to murine corneas after injury leads to reduced macrophage infiltration and higher expression of CD206 in macrophages. Macrophages co-cultured (“educated”) by cMSCs express significantly higher levels of anti-angiogenic and anti-inflammatory factors compared to control macrophages. In vivo, injured corneas treated with cMSC-educated macrophages demonstrate significantly less neovascularization compared to corneas treated with control macrophages. Knocking down the expression of PEDF in cMSCs significantly abrogates its modulating effects on macrophages, as shown by the reduced rate of apoptosis, decreased expression of sFLT-1/PEDF, and increased expression of VEGF-A in the co-cultured macrophages. Similarly, cMSCs isolated from PEDF knockout mice are less effective compared to wild type cMSCs at inhibiting macrophage infiltration when applied to wild type corneas after injury. Overall, these results demonstrate that cMSCs therapeutically suppress the angiogenic capacity of macrophages and highlight the role of cMSC secreted PEDF in the modulation of macrophage phenotype and function. In the setting of severe corneal injury or inflammation, chemokines and cytokines recruit inflammatory cells which in turn induce corneal angiogenesis via VEGF-A. Cell therapy with corneal derived MSCs could modulate this inflammation in part via PEDF by inducing apoptosis of macrophages and promoting a distinct macrophage immunophenotype (cMSC-educated macrophages - cMEMq) that secrete high levels of sFLT-1, PEDF, and TSG-6.
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影响因子：
5.9
作者：
Espagnolle N;Balguerie A;Arnaud E;Sensebé L;Varin A
通讯作者：
Varin A
影响因子：
4.8
作者：
Cai, J;Jiang, WG;Boulton, M
通讯作者：
Boulton, M
DOI：
10.1152/ajprenal.00138.2003
发表时间：
2004-02-01
影响因子：
4.2
作者：
Kanellis, J;Bick, R;Sheikh-Hamad, D
通讯作者：
Sheikh-Hamad, D
DOI：
10.1073/pnas.0506112103
发表时间：
2006-07-25
影响因子：
11.1
作者：
Cursiefen, Claus;Chen, Lu;Dana, Reza
通讯作者：
Dana, Reza
影响因子：
4.4
作者：
Hayashi, Takahiko;Yamagami, Satoru;Mizuki, Nobuhisa
通讯作者：
Mizuki, Nobuhisa