Regenerative and protective effects of dMSC-sEVs on high-glucose-induced senescent fibroblasts by suppressing RAGE
Xiaowei Bian1,2,3,4, Bingmin Li2,3,4, Jie Yang2,3,4
1Tianjin Medical University, No. 22, Qixiangtai Road, Heping District, Tianjin, 300070, People's Republic of China.
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.
Insights
Decidual mesenchymal stem cell-derived small extracellular vesicles (dMSC-sEVs) promote fibroblast function and accelerate diabetic wound healing by modulating RAGE and Smad pathways. These findings highlight dMSC-sEVs as a potential therapy for diabetic wound complications.
Area of Science:
- Regenerative Medicine
- Wound Healing Research
- Cellular Senescence
Background:
- Fibroblast dysfunction in high-glucose (HG) environments impairs diabetic wound healing.
- Small extracellular vesicles (sEVs) show promise for skin wound regeneration.
- Decidual mesenchymal stem cell-derived sEVs (dMSC-sEVs) are investigated for therapeutic potential.
Purpose of the Study:
- To evaluate the impact of dMSC-sEVs on high-glucose (HG)-induced human dermal fibroblast (HDF) senescence.
- To investigate the efficacy of dMSC-sEVs in promoting diabetic wound healing.
- To elucidate the underlying molecular mechanisms involving RAGE and Smad pathways.
Main Methods:
- Established an in vitro HDF senescence model using HG.
- Treated HG-induced HDFs with dMSC-conditioned medium and dMSC-sEVs.
- Assessed fibroblast proliferation, migration, differentiation, and senescence markers; analyzed RAGE and Smad2/3 signaling; utilized a Smad pathway inhibitor (SB431542); evaluated dMSC-sEVs in a diabetic mouse wound model.
Main Results:
- HG impaired HDF function and accelerated senescence; dMSC-sEVs reversed these effects, promoting proliferation, migration, and differentiation.
- dMSC-sEVs inhibited RAGE expression and activated the Smad signaling pathway.
- Inhibition of Smad signaling partially reversed the anti-senescent effects of dMSC-sEVs; dMSC-sEVs accelerated wound healing and collagen deposition in diabetic mice.
Conclusions:
- dMSC-sEVs exhibit regenerative and protective effects on senescent fibroblasts in a high-glucose milieu.
- These effects are mediated by suppressing the RAGE pathway and activating the Smad pathway.
- dMSC-sEVs represent a promising therapeutic candidate for accelerating diabetic wound healing.
