Myeloid-derived suppressor cells improve corneal graft survival through suppressing angiogenesis and lymphangiogenesis

Abstract

Myeloid‐derived suppressor cells (MDSC) are one of the major negative regulators of immune responses during many pathological conditions such as cancer and transplantation. Emerging evidence indicates that MDSC also contribute to tumor progression through their pro‐angiogenic activity in addition to immunosuppressive function. However, virtually nothing is known about the role of MDSC in the regulation of neovascularization after transplantation. Here we showed that antibody‐mediated depletion of MDSC in mice led to robust growth of blood and lymphatic neovessels and rapid allograft rejection after corneal penetrating keratoplasty. In contrast, adoptive transfer of ex vivo generated MDSC from cytokine‐treated bone marrow cells (evMDSC) suppressed neovascularization and prolonged corneal allograft survival in an inducible nitric oxide synthase (iNOS)‐dependent manner. Mechanistically, compared to naïve MDSC control, evMDSC have increased expression of an anti‐angiogenic factor thrombospondin 1 (Tsp‐1) and decreased expression of two critical pro‐angiogenic factors, vascular endothelial growth factor A (VEGF‐A), and VEGF‐C. These findings demonstrate MDSC as a critical anti‐angiogenic regulator during transplantation. Our study also indicates that evMDSC are a valuable candidate agent for development of novel cell therapy to improve allograft survival after transplantation.

Emerging Roles of Myeloid-Derived Suppressor Cells in Diabetes

“…Human umbilical cord mesenchymal stem cells (Huc-MSCs), which are widely used in NOD mice, can inhibit the differentiation of MDSC by secreting the soluble factors COX2/PGE2 and IFN-β and enhance their inhibitory ability on immune cells so as to achieve effective therapeutic effects against diabetes ( Qi et al, 2020 ). Based on the aforementioned findings, the metastasis of MDSC, f-MDSC, or the transfer of Huc-MSCs may possess the enhanced inhibitory ability on immunity and demonstrate the therapeutic effect on diabetic mice ( Yin et al, 2010 ; Xia et al, 2011 ; Torbica et al, 2019 ; Ren et al, 2021 ). MDSC-related stem cells also may be a promising treatment for diabetes.…”

Ex Vivo–Induced Bone Marrow-Derived Myeloid Suppressor Cells Prevent Corneal Allograft Rejection in Mice

“…The ex vivo – induced BM-MDSCs (1 × 10 6 cells) were suspended in 10 µL PBS and injected subconjunctivally into allograft recipients using a 33-gauge metal needle and 1-mL syringe (M. S. Surgical, Kalol, India) immediately after corneal transplantation according to previous studies. 19 , 25 , 26 The control mice received a PBS injection.…”

“… 18 In mice corneal transplantation, MDSCs prompted effective results. For example, Ren et al 19 reported that these cell improved graft survival through suppressing angiogenesis and lymphangiogenesis. Therefore the application of ex vivo – induced bone marrow MDSCs (BM-MDSCs) is promising for high-risk corneal transplantation in a local inflammatory environment as a potential approach for preventing graft rejection.…”

Treatment With Melatonin After Corneal Graft Attenuates Rejection

“…Photos were automatically taken to reconstruct the entire image of the cornea. ImageJ software was then used (NIH, Bethesda, Maryland, United States) to outline the innermost lymph nodes of the limbus to calculate the total area of the cornea, and the area of the newborn lymphatic vessels in each mouse were subsequently calculated ( Ren et al, 2020 ).…”