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CCN4/WISP1 controls cutaneous wound healing by modulating proliferation, migration and ECM expression in dermal

Mitsuaki Ono1, Asuka Masaki2, Azusa Maeda3

  • 1Department of Oral and Maxillofacial Rehabilitation, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan; Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.

Matrix Biology : Journal of the International Society for Matrix Biology
|January 14, 2018
PubMed

Insights

CCN4, a novel extracellular matrix component, promotes skin wound healing by enhancing dermal fibroblast migration and proliferation. It also counteracts TNF-α

Area of Science:

  • Dermatology and Regenerative Medicine
  • Extracellular Matrix Biology
  • Cellular Signaling Pathways

Background:

  • Cutaneous wound healing is a complex process involving inflammation, cell migration, and proliferation.
  • Extracellular matrix (ECM) components play critical roles in regulating these healing mechanisms.
  • Identifying novel ECM factors is essential for improving wound repair strategies.

Purpose of the Study:

  • To investigate the role of CCN4, a novel ECM component, in regulating cutaneous wound healing.
  • To elucidate the molecular mechanisms by which CCN4 influences dermal fibroblast behavior.
  • To explore the interaction between CCN4 and TNF-α in the context of wound repair.

Main Methods:

  • Creation of full-thickness skin defects in mice to assess wound closure and ECM gene expression.
  • Utilized Ccn4-knockout (Ccn4-KO) mice to evaluate the necessity of CCN4 in wound healing.
  • Performed Boyden chamber assays and siRNA/adenoviral transduction on human adult dermal fibroblasts (hADFs) to study cell migration and proliferation.
  • Investigated downstream signaling pathways including α5β1 integrin, ERK/JNK, and NF-κB/p-65.

Main Results:

  • CCN4 expression was upregulated early in wound healing in mice.
  • Ccn4-KO mice exhibited delayed wound closure with reduced Col1a1 and Fn mRNA expression.
  • Ccn4-deficient dermal fibroblasts showed impaired migration and proliferation.
  • CCN4 enhanced hADF migration and proliferation via α5β1 integrin and downstream ERK/JNK signaling.
  • CCN4 counteracted TNF-α-induced inhibition of COL1A1 and FN mRNA and stimulation of MMP-1 and MMP3 mRNA by inhibiting NF-κB/p-65 signaling.

Conclusions:

  • CCN4 is a key regulator of cutaneous wound healing, promoting dermal fibroblast migration and proliferation.
  • CCN4 functions by activating α5β1 integrin and downstream signaling pathways.
  • CCN4 mitigates the negative effects of TNF-α on ECM production and inflammation, further supporting its role in wound repair.

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