2. Academic Validation
  3. Regenerative and protective effects of dMSC-sEVs on high-glucose-induced senescent fibroblasts by suppressing RAGE pathway and activating Smad pathway

Regenerative and protective effects of dMSC-sEVs on high-glucose-induced senescent fibroblasts by suppressing RAGE pathway and activating Smad pathway

  • Stem Cell Res Ther. 2020 Apr 29;11(1):166. doi: 10.1186/s13287-020-01681-z.
Xiaowei Bian 1 2 3 4,  Bingmin Li 2 3 4,  Jie Yang 2 3 4,  Kui Ma 2 3 4,  Mengli Sun 2 3 4,  Cuiping Zhang 5 6 7,  Xiaobing Fu 8 9 10
Affiliations

Affiliations

  • 1 Tianjin Medical University, No. 22, Qixiangtai Road, Heping District, Tianjin, 300070, People's Republic of China.
  • 2 Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College, Beijing, People's Republic of China.
  • 3 Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing, 100048, People's Republic of China.
  • 4 Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, People's Republic of China.
  • 5 Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College, Beijing, People's Republic of China. zcp666666@sohu.com.
  • 6 Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing, 100048, People's Republic of China. zcp666666@sohu.com.
  • 7 Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, People's Republic of China. zcp666666@sohu.com.
  • 8 Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College, Beijing, People's Republic of China. fuxiaobing@vip.sina.com.
  • 9 Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing, 100048, People's Republic of China. fuxiaobing@vip.sina.com.
  • 10 Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, People's Republic of China. fuxiaobing@vip.sina.com.
PMID: 32349787 DOI: 10.1186/s13287-020-01681-z
Abstract

Background: Fibroblasts are crucial for supporting normal wound healing. However, the functional state of these cells is impaired in diabetics because of a high-glucose (HG) microenvironment. Small extracellular vesicles (sEVs) have emerged as a promising tool for skin wound treatment. The aim of this study was to investigate the effects of sEVs derived from human decidua-derived mesenchymal stem cells (dMSC-sEVs) on HG-induced human dermal fibroblast (HDF) senescence and diabetic wound healing and explore the underlying mechanism.

Methods: We first created a HDF senescent model induced by HG in vitro. dMSC-conditioned medium (dMSC-CM) and dMSC-sEVs were collected and applied to treat the HG-induced HDFs. We then examined the proliferation, migration, differentiation, and senescence of these fibroblasts. At the same time, the expressions of RAGE, p21 Ras, SMAD2/3, and pSmad2/3 were also analyzed. Furthermore, pSmad2/3 inhibitor (SB431542) was used to block the expression of pSmad2/3 to determine whether dMSC-sEVs improved HDF senescence by activating Smad pathway. Finally, we assessed the effect of dMSC-sEVs on diabetic wound healing.

Results: The HG microenvironment impaired the proliferation, migration, and differentiation abilities of the HDFs and accelerated their senescence. dMSC-CM containing sEVs improved the proliferation and migration abilities of the HG-induced fibroblasts. dMSC-sEVs internalized by HG-induced HDFs not only significantly promoted HDF proliferation, migration, and differentiation, but also improved the senescent state. Furthermore, dMSC-sEVs inhibited the expression of RAGE and stimulated the activation of Smad signaling pathway in these cells. However, SB431542 (pSmad2/3 inhibitor) could partially alleviate the anti-senescent effects of dMSC-sEVs on HG-induced HDFs. Moreover, the local application of dMSC-sEVs accelerated collagen deposition and led to enhanced wound healing in diabetic mice. The detection of PCNA, CXCR4, α-SMA, and p21 showed that dMSC-sEVs could enhance HDF proliferation, migration, and differentiation abilities and improve HDF senescent state in vivo.

Conclusion: dMSC-sEVs have regenerative and protective effects on HG-induced senescent fibroblasts by suppressing RAGE pathway and activating Smad pathway, thereby accelerating diabetic wound healing. This indicates that dMSC-sEVs may be a promising candidate for diabetic wound treatment.

Keywords

Diabetic wounds; Fibroblasts; High-glucose; Senescence; Small extracellular vesicles.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z