Improved wound healing by dual inhibition of miR-146a-5p and miR-29a-3p supports a network action of dysregulated miRNAs in diabetic skin

ABSTRACT: MiRNA-146a-5p, and -29-3p are repeatedly reported to be dysregulated in wound healing, however, not much is known about their roles in in the immune inflammatory responses and skin regeneration within cellular networks. We tested our hypothesis that suppressing the two over-expressed miRNAs would address wound healing impairments, using two distinct models of wound healing: Immortalised keratinocytes (HaCaT cells) transfected with LNA (locked nucleic acid)-spiked fully phosphorothioate modified antisense miR-146a-5p (5’-TGgaauucAgTuCucA-3’), miR-29a-3p (5’-AuuTcaGauGguGcuA-3’) oligos (LNA bases are written in capital letters while 2′-O-methyl RNA bases in small letters) and a scramble (Scr) control oligo (5’-CaaTagGguCaaGauT-3’) individually or in combination, and STZ induced type 1 diabetes animal model of wound healing. We observed significant corrections of dysfunctional cell migration (p<0.01 on day 8; and p<0.05 on day 9), decreased inflammation at day 3 (p<0.01) and day 10 (p<0.0001), reduction of excessive production of reactive oxygen species (p<0.01) 3 days post-wounding while increasing the density of blood vessel networks on day 3 (p<0.01) and day 10 (p<0.0001). This was consistent with cytoskeletal rearrangements and collagen alterations observed with proteome profiling. Our data suggest that synergetic potential of dual inhibition of the two miRNAs is a superior approach compared to individual miRNA inhibition, and a potential treatment for a multitude of wound healing impairments observed in diabetic wounds.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Skin, Hacat Cell

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: Marcus Nielsen  

LAB HEAD: Louise Torp Dalgaard

PROVIDER: PXD060087 | Pride | 2025-12-15

REPOSITORIES: Pride