Forum for Nordic Dermato-Venereology Nr1,2019 | Page 20

Dissertation The Roles of MicroRNAs in Skin Wound Healing X i L i Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. E-mail: [email protected] Xi Li defended her PhD thesis on February 8, 2019 at Karolinska Institutet, Stockholm, Sweden. The opponent was Professor Marjana Tomic-Canic, from Department of Dermatology and Cutaneous Surgery, University of Miami, USA and Principal supervisor was Ning Xu Landén, Department of Medicine Solna, Unit of Derma- tology and Venereology, Karolinska Institutet, Stockholm, Sweden. The dissertation is available at: https:// openarchive.ki.se/xmlui/handle/10616/46604 S kin is an essential biological barrier of the human body, and wound healing is the funda- mental physiological process to keep its integrity. Chronic non-healing wounds are growing socioec- onomic and health concerns, which longs for more understanding of their pathophysiology to discover effective treatments. In this thesis, we focused on how microRNAs (miR) work together with their target protein-coding genes to regulate the complex wound healing process, and by exploring the roles they play in chronic wounds we aimed to discover potential therapeutic targets. In paper I, a distinct up-regulation of miR-31 in human acute wounds was identified from profiling analysis. We discovered miR-31 as a pivotal regula- tor in promoting keratinocyte proliferation and mi- gration by targeting EMP1 during wound healing, emphasizing its importance in re-epithelialization. In paper II, miR-34 family, as a famous tumour Fig. 1. From left: Lena Eliasson (examination board), Gunnar Kratz (examination suppressor, popped out amidst the top upregulated board), Ning Xu Landén (principal supervisor), Ole E Sørensen (examination board), miRs in venous ulcer. In vitro, miR-34a and miR-34c Mona Ståhle (co-supervisor), Xi Li (defendent), Andor Pivarcsi (co-supervisor), Enikö enhanced inflammatory response of epidermal Sonkoly (Co-supervisor) and Marjana Tomic-Canic (Opponent). keratinocytes via targeting LGR4 and positively regulating NF-κB signalling pathway. In vivo, mouse through targeting RASA1 and regulating Ras signalling. Since model of either miR-34 local overexpression or Lgr4 fibroblasts derived from chronic wounds are non-migratory, knockout displayed impaired wound healing with excessive our study suggests the miR-132-RASA1-Ras axis with potential inflammation and suppressed cell growth. These suggest that therapeutic impact. miR-34 plays a pathological role in chronic wounds by con- tributing to the excessive inflammation. In paper III, in continuity with our previous report that miR-132 displays anti-inflammatory and pro-proliferative roles in keratinocytes, we studied the function of miR-132 in another major skin resident cell type fibroblasts. By both overexpression and inhibition, miR-132 was proved to facilitate migration of primary human dermal fibroblasts, 18 In paper IV, we tested the therapeutic potential of miRs, taken miR-132 as an example. A significant downregulation of miR- 132 was revealed in diabetic foot ulcer. Intradermal injection of liposome-encapsulated miR-132 mimics effectively accelerated wound healing. Moreover, ex vivo human model exhibited ameliorated re-epithelialization upon miR-132 topical ap- plication, denoting that local treatment of miR-132 deserves Forum for Nord Derm Ven 2019, Vol. 24, No. 1