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Updated: Nov 14, 2025
Murine Excisional Wound Healing Model and Histological Morphometric Wound Analysis
Published on: August 21, 2020
mTOR inhibitor INK128 promotes wound healing by regulating MDSCs
Yi Li1,2, Yujun Xu2, Xinghan Liu2
1Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210093, People's Republic of China.
Background:
Skin wounds in diabetic patients hardly recover. Accumulating evidence has shown that mammalian target of rapamycin (mTOR) pathway and myeloid-derived suppressor cells (MDSCs) are involved in inflammatory-related response. INK128 is a novel mTOR kinase inhibitor in clinical development. However, the exact roles of MDSCs and INK128 in healing wound of diabetic patients are unclear.
Methods:
Mice models of normal, diabetic, and diabetic+INK128 were constructed. Bone marrow (BM)-derived macrophages and RAW264.7 cell line co-cultured with MDSCs, which were induced at different conditions. Flow cytometry, western blot, quantitative real-time PCR, and immunohistochemical analysis were performed.
Results:
Diabetic mice (DM) had a slower recovery rate, thinner epidermis and dermis, and less blood vessels than those of normal mice. MDSCs were abnormally accumulated in DM, mTOR was activated in MDSCs of DM, and the cells were treated with high glucose. Moreover, mTOR signaling inhibitor INK128 could promote wound healing through reducing the MDSCs. MDSC function was disordered in DM and high-glucose environments, while INK128 could help retrieve their function. Furthermore, high glucose and other factors in DM could promote M-MDSC differentiation to M1 pro-inflammatory macrophage cells, thus inhibiting wound healing. The differentiation, which was dependent on mTOR signaling, could be reversed by INK128.
Conclusion:
INK128 is potential to be developed as a clinical strategy to promote wound healing of diabetic patients.
Insights
The mTOR inhibitor INK128 promotes diabetic wound healing by reducing myeloid-derived suppressor cells (MDSCs). This novel approach may offer a clinical strategy for improving recovery in diabetic patients with chronic wounds.
Area of Science:
- Wound healing research
- Immunology
- Pharmacology
Background:
- Diabetic patients exhibit impaired skin wound healing.
- Mammalian target of rapamycin (mTOR) pathway and myeloid-derived suppressor cells (MDSCs) are implicated in inflammatory responses.
- The roles of MDSCs and the mTOR inhibitor INK128 in diabetic wound healing remain unclear.
Purpose of the Study:
- To investigate the roles of MDSCs and INK128 in diabetic wound healing.
- To determine if INK128 can modulate MDSCs and improve wound recovery in diabetic models.
Main Methods:
- Constructed mouse models: normal, diabetic, and diabetic treated with INK128.
- Co-cultured bone marrow-derived macrophages and RAW264.7 cells with MDSCs.
- Utilized flow cytometry, western blot, qPCR, and immunohistochemistry for analysis.
Main Results:
- Diabetic mice showed delayed wound healing, thinner skin, and reduced vascularization.
- Abnormal accumulation and activated mTOR signaling in MDSCs were observed in diabetic mice.
- INK128 treatment promoted wound healing by reducing MDSCs and restoring their function.
- INK128 reversed high glucose-induced differentiation of MDSCs to pro-inflammatory M1 macrophages.
Conclusions:
- INK128 demonstrates potential as a clinical strategy to enhance wound healing in diabetic patients.
- Targeting MDSCs via mTOR inhibition offers a promising therapeutic avenue.
