*Article* **Sphingosine-1-Phosphate Facilitates Skin Wound Healing by Increasing Angiogenesis and Inflammatory Cell Recruitment with Less Scar Formation**

**Masayo Aoki 1,2, Hiroaki Aoki 2,3, Partha Mukhopadhyay 2, Takuya Tsuge 1, Hirofumi Yamamoto 4, Noriko M. Matsumoto 1, Eri Toyohara 1, Yuri Okubo 1, Rei Ogawa 1 and Kazuaki Takabe 2,5,6,\***


Received: 11 June 2019; Accepted: 8 July 2019; Published: 10 July 2019

**Abstract:** Wound healing starts with the recruitment of inflammatory cells that secrete wound-related factors. This step is followed by fibroblast activation and tissue construction. Sphingosine-1-phosphate (S1P) is a lipid mediator that promotes angiogenesis, cell proliferation, and attracts immune cells. We investigated the roles of S1P in skin wound healing by altering the expression of its biogenic enzyme, sphingosine kinase-1 (SphK1). The murine excisional wound splinting model was used. Sphingosine kinase-1 (SphK1) was highly expressed in murine wounds and that SphK1−/− mice exhibit delayed wound closure along with less angiogenesis and inflammatory cell recruitment. Nanoparticle-mediated topical SphK1 overexpression accelerated wound closure, which associated with increased angiogenesis, inflammatory cell recruitment, and various wound-related factors. The SphK1 overexpression also led to less scarring, and the interaction between transforming growth factor (TGF)-β1 and S1P receptor-2 (S1PR2) signaling is likely to play a key role. In summary, SphK1 play important roles to strengthen immunity, and contributes early wound healing with suppressed scarring. S1P can be a novel therapeutic molecule with anti-scarring effect in surgical, trauma, and chronic wound management.

**Keywords:** sphingosine-1-phosphate; sphingosine kinase-1; sphingosine1-phosphate receptor-2; skin wound healing
