Topical hADSCs-HA Gel Promotes Skin Regeneration and Angiogenesis in Pressure Ulcers by Paracrine Activating PPARβ/δ Pathway

Drug Des Devel Ther. 2024 Oct 26:18:4799-4824. doi: 10.2147/DDDT.S474628. eCollection 2024.

Abstract

Background: Pressure ulcer is common in the bedridden elderly with high mortality and lack of effective treatment. In this study, human-adipose-derived-stem-cells-hyaluronic acid gel (hADSCs-HA gel) was developed and applied topically to treat pressure ulcers, of which efficacy and paracrine mechanisms were investigated through in vivo and in vitro experiments.

Methods: Pressure ulcers were established on the backs of C57BL/6 mice and treated topically with hADSCs-HA gel, hADSCs, hyaluronic acid, and normal saline respectively. The rate of wound closure was observed continuously during the following 14 days and the wound samples were obtained for Western blot, histopathology, immunohistochemistry, and proteomic analysis. Human dermal fibroblasts (HDFs) and human venous endothelial cells (HUVECs) under normal or hypoxic conditions were treated with conditioned medium of human ADSCs (ADSC-CM), then CCK-8, scratch test, tube formation, and Western blot were conducted to evaluate the paracrine effects of hADSCs and to explore the underlying mechanism.

Results: The in vivo data demonstrated that hADSCs-HA gel significantly accelerated the healing of pressure ulcers by enhancing collagen expression, angiogenesis, and skin proliferation. The in vitro data revealed that hADSCs strengthened the proliferation and wound healing capabilities of HDFs and HUVECs, meanwhile promoted collagen secretion and tube formation through paracrine mode. ADSC-CM was also proved to exert protective effects on hypoxic HDFs and HUVECs. Besides, the results of proteomic analysis and Western blot elucidated that lipid metabolism and PPARβ/δ pathway mediated the healing effect of hADSCs-HA gel on pressure ulcers.

Conclusion: Our research showed that topical application of hADSCs-HA gel played an important role in dermal regeneration and angiogenesis. Therefore, hADSCs-HA gel exhibited the potential as a novel stem-cell-based therapeutic strategy of treating pressure ulcers in clinical practices.

Keywords: PPARβ/δ; human adipose derived stem cell; hydrogel; lipid metabolism; pressure ulcer; skin regeneration; wound healing.

MeSH terms

  • Adipose Tissue / drug effects
  • Administration, Topical
  • Angiogenesis
  • Animals
  • Cells, Cultured
  • Gels*
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Humans
  • Hyaluronic Acid* / chemistry
  • Hyaluronic Acid* / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL*
  • Neovascularization, Physiologic / drug effects
  • PPAR delta* / metabolism
  • PPAR-beta* / metabolism
  • Paracrine Communication / drug effects
  • Pressure Ulcer* / drug therapy
  • Pressure Ulcer* / metabolism
  • Pressure Ulcer* / pathology
  • Regeneration / drug effects
  • Skin / drug effects
  • Skin / metabolism
  • Wound Healing / drug effects

Substances

  • Gels
  • Hyaluronic Acid
  • PPAR-beta
  • PPAR delta

Grants and funding

This work was supported by Zhejiang Provincial Natural Science Foundation of China (Grant No. LGF22H150017), Zhejiang Provincial Military Medical Science and Technology Youth Cultivation Program (Grant No. 19QNP045), and Zhejiang Provincial Medical Science and Technology Program (Grant No. 2019315077).