期刊
ANNALS OF TRANSLATIONAL MEDICINE
卷 9, 期 20, 页码 -出版社
AME PUBL CO
DOI: 10.21037/atm-21-4978
关键词
Scar formation; adipose-derived mesenchymal stem cells (AMSCs); macrophages; procollagen-lysine 1; 2-oxoglutarate 5-dioxygenase 1 (PLOD1); miR-449
Inhibiting PLOD1 levels in AMSCs significantly reduces fibrosis in the injured region of mice, leading to altered macrophage polarization and decreased ROS levels and myofibroblast activation.
Background: The level of cutaneous scar formation is a critical parameter to determine the success of skin wound healing. Adipose-derived mesenchymal stem cells (AMSCs) have been applied to improve treatment of cutaneous injury with the purpose of reducing scar formation. Methods: The levels of procollagen-lysine 1,2-oxoglutarate 5-dioxygenase 1 (PLOD1) were assessed at scar sites. Then, PLOD1 in AMSCs was depleted by either expression of a PLOD1-specific short-hair interfering RNA (shPLOD1) or by expression of microRNA-449 (miR-449) that targets and suppresses protein translation of PLOD1 through 3 prime untranslated region (3'-UTR) interfering. For induction of skin injury, a blade cut of 1.5-cm long and 2-mm thick was made on the middle back of the mice. Transplantation of either AMSCs-shPLOD1 or AMSCs-miR-449 into the injured region of the mice was performed via tail vein injection. The fibrosis as well as underlying mechanisms were assessed. Results: The AMSCs expressed high levels of PLOD1, a potent stimulator of fibrosis. We knocked down PLOD1 in AMSCs by expression of either shPLOD1 or miR-449. Transplantation of either AMSCsshPLOD1 or AMSCs-miR-449 significantly reduced the fibrotic process in the injured region of the mice to a similar degree. Mechanistically, transplantation of either AMSCs-shPLOD1 or AMSCs-miR-449 shifted macrophage polarization from M2 to M1-like and reduced both reactive oxygen species (ROS) and activation of myofibroblasts from fibroblasts. Conclusions: Suppression of PLOD1 levels in AMSCs either directly by shPLOD1 or indirectly by miR449 may substantially improve the anti-fibrotic potential of AMSCs during wound healing, likely through altering macrophage polarization.
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