Open AccessCornea‐Derived Mesenchymal Stromal Cells Therapeutically Modulate Macrophage Immunophenotype and Angiogenic Function
Author(s) -
Eslani Medi,
Putra Ilham,
Shen Xiang,
Hamouie Judy,
Tadepalli Asha,
Anwar Khandaker N.,
Kink John A.,
Ghassemi Samaneh,
Agnihotri Gaurav,
Reshetylo Sofiya,
Mashaghi Alireza,
Dana Reza,
Hematti Peiman,
Djalilian Ali R.
Publication year - 2018
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.2781
Subject(s) - biology , mesenchymal stem cell , immunophenotyping , stromal cell , macrophage , cornea , microbiology and biotechnology , function (biology) , immunology , cancer research , in vitro , flow cytometry , neuroscience , genetics
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 CD14 hi CD16 hi CD163 hi CD206 hi 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 cocultured (“educated”) by cMSCs express significantly higher levels of anti‐angiogenic and anti‐inflammatory factors compared with control macrophages. In vivo, injured corneas treated with cMSC‐educated macrophages demonstrate significantly less neovascularization compared with corneas treated with control macrophages. Knocking down the expression of pigment epithelial derived factor (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 vascular endothelial growth factor‐A in the cocultured macrophages. Similarly, cMSCs isolated from PEDF knockout mice are less effective compared with 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. S tem C ells 2018;36:775–784