PTEN, a master driver of nonhealing phenotype in venous leg ulcers, suppresses immune response, angiogenesis and lymphangiogenesis

RNA-Seq was performed on healing and non-healing venous leg ulcers, and transcriptomes were compared to those of human acute wounds (AW). A robust suppression of inflammatory response, lymphangiogenesis and angiogenesis was hallmark of non-healing, in contrast to healing VLUs that showed similarity to physiological healing. Diminished inflammatory response in non-healing VLUs was due to impaired leukocyte transmigration and egression, with suppression of kinases' activity, including AKT, ERK, JNK1/2, SRC, and PDGFR, underlining the non-healing signature. Bioinformatic analyses pinpointed PTEN as a master negative regulator of the processes and signaling pathways suppressed in non-healing VLU. Indeed, increased PTEN was confirmed in non-healing compared to healing VLUs on scRNA-Seq and protein level. Functional in vivo murine studies confirmed that pharmacological PTEN inhibition enhances immune response, and proinflammatory signals, leading to accelerated wound closure. We identify PTEN as a master regulator of non-healing VLU phenotype that orchestrates multiple key processes responsible for impaired healing. Targeting PTEN as a therapeutic approach may shift non-healing VLUs into healing trajectory allowing for progression of wound closure. Overall design: Transcriptome profiles from patients with healing and non-healing venous leg ulcers generated by deep sequencing using Illumina Novaseq 6000