PMID- 32248837
OWN - NLM
STAT- MEDLINE
DCOM- 20210618
LR  - 20220531
IS  - 1757-6512 (Electronic)
IS  - 1757-6512 (Linking)
VI  - 11
IP  - 1
DP  - 2020 Apr 5
TI  - HIF1alpha overexpression enhances diabetic wound closure in high glucose and low 
      oxygen conditions by promoting adipose-derived stem cell paracrine function and 
      survival.
PG  - 148
LID - 10.1186/s13287-020-01654-2 [doi]
LID - 148
AB  - BACKGROUND: Adipose-derived stem cell (ADSC) transplantation is a promising 
      strategy to promote wound healing because of the paracrine function of stem 
      cells. However, glucose-associated effects on stem cell paracrine function and 
      survival contribute to impaired wound closure in patients with diabetes, limiting 
      the efficacy of ADSC transplantation. Hypoxia-inducible factor (HIF)1alpha plays 
      important roles in wound healing, and in this study, we investigated the effects 
      of HIF1alpha overexpression on ADSCs in high glucose and low oxygen conditions. 
      METHODS: Adipose samples were obtained from BALB/C mice, and ADSCs were cultured 
      in vitro by digestion. Control and HIF1alpha-overexpressing ADSCs were induced by 
      transduction. The mRNA and protein levels of angiogenic growth factors in control 
      and HIF1alpha-overexpressing ADSCs under high glucose and low oxygen conditions were 
      analyzed by quantitative reverse transcription-polymerase chain reaction and 
      western blotting. The effects of ADSC HIF1alpha overexpression on the proliferation 
      and migration of mouse aortic endothelial cells (MAECs) under high glucose were 
      evaluated using an in vitro coculture model. Intracellular reactive oxygen 
      species (ROS) and 8-hydroxydeoxyguanosine (8-OHdG) levels in ADSCs were observed 
      using 2,7-dichlorodihydrofluorescein diacetate staining and enzyme-linked 
      immunosorbent assays, respectively. Apoptosis and cell cycle analysis assays were 
      performed by flow cytometry. An in vivo full-thickness skin defect mouse model 
      was used to evaluate the effects of transplanted ADSCs on diabetic wound closure. 
      RESULTS: In vitro, HIF1alpha overexpression in ADSCs significantly increased the 
      expression of vascular endothelial growth factor A, fibroblast growth factor 2, 
      and C-X-C motif chemokine ligand 12, which were inhibited by high glucose. HIF1alpha 
      overexpression in ADSCs alleviated high glucose-induced defects in MAEC 
      proliferation and migration and significantly suppressed ADSC ROS and 8-OHdG 
      levels, thereby decreasing apoptosis and enhancing survival. In vivo, HIF1alpha 
      overexpression in ADSCs prior to transplantation significantly enhanced 
      angiogenic growth factor expression, promoting wound closure in diabetic mice. 
      CONCLUSIONS: HIF1alpha overexpression in ADSCs efficiently alleviates high 
      glucose-induced paracrine dysfunction, decreases oxidative stress and subsequent 
      DNA damage, improves viability, and enhances the therapeutic effects of ADSCs on 
      diabetic wound healing.
FAU - Xu, Jin
AU  - Xu J
AD  - Department of Surgery, Shengjing Hospital of China Medical University, No. 36 
      Sanhao Street, Heping District, Shenyang, 110004, China.
FAU - Liu, Xiaoyu
AU  - Liu X
AD  - Department of Obstetrics and Gynecology, Reproductive Medicine Center, Shengjing 
      Hospital of China Medical University, No. 36 Sanhao Street, Heping District, 
      Shenyang, 110004, China.
FAU - Zhao, Feng
AU  - Zhao F
AD  - Department of Stem Cells and Regenerative Medicine, Shenyang Key Laboratory for 
      Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, Ministry of 
      Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, 
      China Medical University, No. 77 Puhe Street, Shenbei New District, Shenyang, 
      110122, China.
FAU - Zhang, Ying
AU  - Zhang Y
AD  - Department of Pathology, Shengjing Hospital of China Medical University, No. 36 
      Sanhao Street, Heping District, Shenyang, 110004, China.
FAU - Wang, Zhe
AU  - Wang Z
AD  - Department of Pathology, Shengjing Hospital of China Medical University, No. 36 
      Sanhao Street, Heping District, Shenyang, 110004, China. wangz@sj-hospital.org.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200405
PL  - England
TA  - Stem Cell Res Ther
JT  - Stem cell research & therapy
JID - 101527581
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - IY9XDZ35W2 (Glucose)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Adipose Tissue
MH  - Animals
MH  - *Diabetes Mellitus, Experimental/genetics/therapy
MH  - Endothelial Cells
MH  - Glucose
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Oxygen
MH  - Stem Cells
MH  - *Vascular Endothelial Growth Factor A/genetics
PMC - PMC7132964
OTO - NOTNLM
OT  - Adipose-derived stem cells
OT  - High glucose
OT  - Hypoxia-inducible factor 1alpha
OT  - Mice
OT  - Reactive oxygen species
OT  - Stem cell transplantation
OT  - Wound healing
COIS- The authors declare that they have no competing interests.
EDAT- 2020/04/07 06:00
MHDA- 2021/06/22 06:00
PMCR- 2020/04/05
CRDT- 2020/04/07 06:00
PHST- 2019/09/14 00:00 [received]
PHST- 2020/03/17 00:00 [accepted]
PHST- 2020/03/11 00:00 [revised]
PHST- 2020/04/07 06:00 [entrez]
PHST- 2020/04/07 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2020/04/05 00:00 [pmc-release]
AID - 10.1186/s13287-020-01654-2 [pii]
AID - 1654 [pii]
AID - 10.1186/s13287-020-01654-2 [doi]
PST - epublish
SO  - Stem Cell Res Ther. 2020 Apr 5;11(1):148. doi: 10.1186/s13287-020-01654-2.