PMID- 33691762
OWN - NLM
STAT- MEDLINE
DCOM- 20210708
LR  - 20220727
IS  - 1757-6512 (Electronic)
IS  - 1757-6512 (Linking)
VI  - 12
IP  - 1
DP  - 2021 Mar 10
TI  - mTOR inhibitor INK128 promotes wound healing by regulating MDSCs.
PG  - 170
LID - 10.1186/s13287-021-02206-y [doi]
LID - 170
AB  - 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.
FAU - Li, Yi
AU  - Li Y
AD  - Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, The 
      Affiliated Hospital of Nanjing University Medical School, Nanjing, 210093, 
      People's Republic of China.
AD  - The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, 
      Medical School, Nanjing University, Nanjing, 210093, People's Republic of China.
FAU - Xu, Yujun
AU  - Xu Y
AD  - The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, 
      Medical School, Nanjing University, Nanjing, 210093, People's Republic of China.
FAU - Liu, Xinghan
AU  - Liu X
AD  - The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, 
      Medical School, Nanjing University, Nanjing, 210093, People's Republic of China.
FAU - Yan, Xin
AU  - Yan X
AD  - Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, The 
      Affiliated Hospital of Nanjing University Medical School, Nanjing, 210093, 
      People's Republic of China.
FAU - Lin, Yue
AU  - Lin Y
AD  - Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, The 
      Affiliated Hospital of Nanjing University Medical School, Nanjing, 210093, 
      People's Republic of China.
FAU - Tan, Qian
AU  - Tan Q
AD  - Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, The 
      Affiliated Hospital of Nanjing University Medical School, Nanjing, 210093, 
      People's Republic of China. smmutanqian@sina.com.
FAU - Hou, Yayi
AU  - Hou Y
AD  - The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, 
      Medical School, Nanjing University, Nanjing, 210093, People's Republic of China. 
      yayihou@nju.edu.cn.
AD  - Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 
      210093, People's Republic of China. yayihou@nju.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210310
PL  - England
TA  - Stem Cell Res Ther
JT  - Stem cell research & therapy
JID - 101527581
RN  - 0 (Benzoxazoles)
RN  - 0 (Pyrimidines)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - JGH0DF1U03 (sapanisertib)
SB  - IM
EIN - Stem Cell Res Ther. 2021 Sep 6;12(1):494. PMID: 34488864
MH  - Animals
MH  - Benzoxazoles
MH  - *Diabetes Mellitus, Experimental
MH  - Humans
MH  - Mice
MH  - *Myeloid-Derived Suppressor Cells
MH  - Pyrimidines
MH  - TOR Serine-Threonine Kinases/genetics
MH  - Wound Healing
PMC - PMC7944919
OTO - NOTNLM
OT  - Immunology
OT  - Macrophages
OT  - Myeloid-derived suppressor cells
OT  - Wound healing
COIS- The authors declare that they have no competing interests.
EDAT- 2021/03/12 06:00
MHDA- 2021/07/09 06:00
PMCR- 2021/03/10
CRDT- 2021/03/11 05:52
PHST- 2020/08/06 00:00 [received]
PHST- 2021/02/02 00:00 [accepted]
PHST- 2021/03/11 05:52 [entrez]
PHST- 2021/03/12 06:00 [pubmed]
PHST- 2021/07/09 06:00 [medline]
PHST- 2021/03/10 00:00 [pmc-release]
AID - 10.1186/s13287-021-02206-y [pii]
AID - 2206 [pii]
AID - 10.1186/s13287-021-02206-y [doi]
PST - epublish
SO  - Stem Cell Res Ther. 2021 Mar 10;12(1):170. doi: 10.1186/s13287-021-02206-y.