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CD271 promotes STZ-induced diabetic wound healing and regulates epidermal stem cell survival in the presence of the pTrkA receptor

  • Min Zhang
  • Rui Zhang
  • Xiaohong Li
  • Yongqian Cao
  • Kaifeng Huang
  • Jun Ding
  • Mengyao Liu
  • Zhang Feng
  • Siyuan Yin
  • Jiaxu Ma
  • Huayu Zhang
  • Yibing WangEmail author
Regular Article
  • 16 Downloads

Abstract

Diabetes mellitus (DM) often causes delayed wound healing in patients, which can lead to limb loss, disability, and even death. Many conventional therapeutic strategies have been proposed, but there is still no effective therapy for DM wounds. This study aimed to explore the effects of CD271 and phosphorylated tyrosine kinase receptor A (pTrkA) on the migration and proliferation abilities of epidermal stem cells (eSCs) and on the activation of DM wound healing. We investigated the interventional effects of CD271-overexpressing eSC (CD271 eSC) treatment and pTrkA inhibition (through k252a treatment) on delayed wound healing using mice with streptozotocin-induced DM. The migration and proliferation abilities of control eSCs, CD271 eSCs, and k252a-treated CD271 eSCs were observed under high-glucose conditions. Decreases in CD271 and increases in pTrkA were observed in DM mouse skin compared with control mouse skin; in addition, the rate of wound closure in DM mice was promoted by CD271 eSC treatment but delayed by pTrkA inhibition. Furthermore, the CD271 eSC migration and proliferation were greater than of control eSCs. Compared with that of CD271 eSCs, the number of CD271+k252a eSCs decreased significantly under high-glucose conditions. In parallel, the expression levels of the pERK, pAkt, and pJNK pathways increased in CD271 eSCs and decreased in CD271+k252a eSCs under high glucose. Our findings demonstrate that CD271 and pTrkA affect DM wound closure by promoting the eSC migration and proliferation. This mechanism involving the pERK, pAkt, and pJNK pathways might be a new therapeutic target for the treatment of delayed wound re-epithelialization in DM.

Keywords

CD271 Diabetes mellitus Epidermal stem cells Skin wound healing pTrkA 

Abbreviations

DM

Diabetes mellitus

Egfr

Epidermal growth receptor

eSCs

Epidermal stem cells

GAPDH

Glyceraldehydes-3-phosphate dehydrogenase

High-Glu

High glucose

PI

Propidium iodide

STZ

Streptozotocin

Notes

Author contributions

Yibing Wang designed the experiments; Xiaohong Li, Min Zhang, and Mengyao Liu performed the experiments; Rui Zhang, Zhang Feng, Jiaxu Ma, Huayu Zhang, Kaifeng Huang, and Mengyao Liu contributed reagents, materials, analysis tools, added, and repeated the animal experiments; Mengyao Liu also edited the manuscript. Yongqian Cao and Siyuan Yin analyzed the data; Jun Ding, Xiaohong Li, Mengyao Liu, and Min Zhang wrote and reviewed the paper.

Funding information

Science and Technology Development Program of Shandong Province (No. 2016GSF201080), and National Natural Science Foundation of China (No. 81772092 and 81571911) supported this study.

Compliance with ethical standards

Conflict of interests

The authors declare that there are no conflicts of interests.

According to the National Institutes of Health (NIH) Guide, all surgeries and experiments were performed under the pentobarbital sodium anesthesia, and followed the rules of the Committee on the Ethics of Shandong University.

Supplementary material

441_2019_3125_Fig9_ESM.png (430 kb)
Supplementary figure 1:

HE staining and immunohistochemical staining in normal control mouse skin and DM-control mouse skin. (a, b) HE staining showed that the epidermal layer was thinner in DM-control mice than in normal-control mice.Bar=120 μm. (a’, b’) Immunohistochemical staining revealed that CD271 was expressed at lower levels in DM-control mouse epidermal skin than in normal-control mouse epidermal skin. Bar=120 μm. (PNG 430 kb)

441_2019_3125_MOESM1_ESM.tif (1.1 mb)
High resolution image (TIF 1154 kb)
441_2019_3125_Fig10_ESM.png (2.1 mb)
Supplementary figure 2:

Schematic of the effects of injected eSCs on the wound healing model. (PNG 2178 kb)

441_2019_3125_MOESM2_ESM.tif (654 kb)
High resolution image (TIF 653 kb)
441_2019_3125_Fig11_ESM.png (419 kb)
Supplementary figure 3:

Expression levels of CD271 in control eSCs, CD271 (CD271-overexpressing) eSCs, and CD271+k252a eSCs cultured with High-Glu-containing KSFM. a WB analysis of the protein expression of CD271. b The expression levels were calculated relative to those of the internal control GAPDH (ANOVA, *p<0.05, n=3). (PNG 418 kb)

441_2019_3125_MOESM3_ESM.tif (910 kb)
High resolution image (TIF 909 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Min Zhang
    • 1
  • Rui Zhang
    • 2
  • Xiaohong Li
    • 3
  • Yongqian Cao
    • 4
  • Kaifeng Huang
    • 5
  • Jun Ding
    • 6
  • Mengyao Liu
    • 7
  • Zhang Feng
    • 4
  • Siyuan Yin
    • 4
  • Jiaxu Ma
    • 4
  • Huayu Zhang
    • 4
  • Yibing Wang
    • 1
    Email author
  1. 1.Department of Plastic and Reconstructive SurgeryThe First Affiliated Hospital of Shandong First Medical UniversityJinanChina
  2. 2.Department of Pathology, Basic Medical Science SchoolShandong Medical CollegeJinanChina
  3. 3.Health Management CenterShandong Provincial Hospital affiliated to Shandong UniversityJinanChina
  4. 4.Department of Burns and Plastic SurgeryShandong Provincial Hospital affiliated to Shandong UniversityJinanChina
  5. 5.Department of Endocrinology and MetabolismShangrao People’s HospitalShangraoChina
  6. 6.Department of Mechanical EngineeringUniversity of Maryland Baltimore CountyBaltimoreUSA
  7. 7.Department of Molecular Cell BiologyUniversity of CaliforniaBerkeleyUSA

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