Exosomes derived from human umbilical cord blood mesenchymal stem cells stimulate regenerative wound healing via transforming growth factor-β receptor inhibition

  • Stem Cell Res Ther. 2021 Aug 3;12(1):434. doi: 10.1186/s13287-021-02517-0.
Yan Zhang  1  2 ,  Yingjin Pan  3 ,  Yanhong Liu  4 ,  Xiheng Li  1  2 ,  Liang Tang  1  2 ,  Mengna Duan  5 ,  Jiang Li  6  7 ,  Guokun Zhang  8  9
Affiliations
  • 1. Hospital of Stomatology, Jilin University, 1500 Qinghua Rd., Changchun, Jilin, 130021, China.
  • 2. Jilin Provincial Laboratory of Biomedical Engineering, Jilin University, Changchun, China.
  • 3. Center of Prosthodontics and Oral Implantology, Foshan Stomatology Hospital, School of Stomatology and Medicine, Foshan University, Foshan, 528000, China.
  • 4. Center for Reproductive Medicine, Center for Prenatal Diagnosis, First Hospital, Jilin University, Changchun, China.
  • 5. Hospital of Stomatology, Jilin University, 1500 Qinghua Rd., Changchun, Jilin, 130021, China. [email protected].
  • 6. Hospital of Stomatology, Jilin University, 1500 Qinghua Rd., Changchun, Jilin, 130021, China. [email protected].
  • 7. Affiliated Stomatology Hospital of Guangzhou Medical University, 39 Huangsha Ave., Guangzhou, 510080, Guangdong, China. [email protected].
  • 8. Institute of Antler Science and Product Technology, Changchun Sci-Tech University, 1345 Pudong Rd., Changchun, Jilin, 130600, China. [email protected].
  • 9. Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences (CAAS), 4899 Juye St., Changchun, Jilin, 130112, China. [email protected].
PMID: 34344478 DOI: 10.1186/s13287-021-02517-0
Abstract

Background: Scar formation is a common consequence of skin wound healing, and no effective treatment exists. Umbilical cord blood mesenchymal stem cells (UCB-MSCs) can improve wound healing; however, the role of UCB-MSCs remains unclear and whether they can ameliorate scar formation has not been fully elucidated.

Methods: To determine the function of UCB-MSCs, we examined and compared the therapeutic effects of UCB-MSCs and UCB-MSC-derived exosomes (UCB-MSC-exo) on skin healing in rats. Moreover, UCB-MSC-exo-specific miRNAs were identified and their effects in inhibiting the human dermal fibroblast (HDF) differentiation into myofibroblasts were investigated.

Results: Both UCB-MSCs and UCB-MSC-exo accelerated wound closure; reduced scar formation; improved the regeneration of skin appendages, nerves, and vessels; and regulated the natural distribution of Collagen fibers in wound healing. Additionally, UCB-MSC-exo suppressed the excessive formation of myofibroblasts and Collagen I and increased the proliferation and migration of skin cells in vivo and in vitro. Functional analysis showed that UCB-MSC-derived miRNAs were closely related to the transforming growth factor-β (TGF-β) signaling pathway, which could induce myofibroblast differentiation. We identified abundant miRNAs that were highly expressed in UCB-MSC-exo. miR-21-5p and miR-125b-5p were predicted to contribute to TGF-β Receptor type II (TGFBR2) and TGF-β Receptor type I (TGFBR1) inhibition, respectively. Using miRNA mimics, we found that miR-21-5p and miR-125b-5p were critical for anti-myofibroblast differentiation in the TGF-β1-induced HDF.

Conclusion: The effect of UCB-MSCs in stimulating regenerative wound healing might be achieved through exosomes, which can be, in part, through miR-21-5p- and miR-125b-5p-mediated TGF-β Receptor inhibition, suggesting that UCB-MSC-exo might represent a novel strategy to prevent scar formation during wound healing.

Keywords
Cord blood stem cell transplantation; Exosomes; MicroRNAs; Myofibroblasts; Regeneration; Transforming growth factor beta; Wound healing.
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