Dermal White Adipose Tissue (dWAT) Is Regulated by Foxn1 and Hif-1α during the Early Phase of Skin Wound Healing

Abstract

Dermal white adipose tissue (dWAT) is involved in the maintenance of skin homeostasis. However, the studies concerning its molecular regulation are limited. In the present paper, we ask whether the introduction of two transcription factors, Foxn1 and Hif-1α, into the post-wounded skin of Foxn1-/- mice regulates dWAT during wound healing (days 3 and 6). We have chosen lentivirus vectors (LVs) as a tool to deliver Foxn1 and Hif-1α into the post-wounded skin. We documented that combinations of both transgenes reduces the number, size and diameter of dermal adipocytes at the wound bed area. The qRT-PCR analysis of pro-adipogenic genes, revealed that LV-Hif-1α alone, or combined with LV-Foxn1, increases the mRNA expression of Pparγ, Glut 4 and Fasn at post-wounding day 6. However, the most spectacular stimulatory effect of Foxn1 and/or Hif-1α was observed for Igf2, the growth factor participating in adipogenic signal transduction. Our data also shows that Foxn1/Hif-1α, at post-wounding day 3, reduces levels of CD68 and MIP-1γ mRNA expression and the percentage of CD68 positive cells in the wound site. In conclusion, the present data are the first to document that Foxn1 and Hif-1α cooperatively (1) regulate dWAT during the proliferative phase of skin wound healing through the Igf2 signaling pathway, and (2) reduce the macrophages content in the wound site.

Proteoglycan 4 (PRG4) treatment improves skin wound healing in a porcine model

“…Yet, between 3 and 6 dpw there was a near complete loss of lipid and a vast reduction of adipocytes (in the control wounds). The role of lipolysis in wound healing is a recent concept and only a few studies have shown a mechanistic relationship between this phenomena and healing outcomes 38‐41 . Specifically, it has been shown that dermal adipocytes can shed their lipid content and change their fate to a myo‐fibroblast like phenotype 42 .…”

“…The role of lipolysis in wound healing is a recent concept and only a few studies have shown a mechanistic relationship between this phenomena and healing outcomes. [38][39][40][41] Specifically, it has been shown that dermal adipocytes can shed their lipid content and change their fate to a myofibroblast like phenotype. 42 This cells then produce ECM and fill in the wound.…”

Dermal white adipose tissue development and metabolism: The role of transcription factor Foxn1

“…The effect of Foxn1 activity on the increase in Igf2 expression observed in in vitro experiment was also detected in post‐wounded skin of Foxn1 +/+ mice. Furthermore, our recent in vivo studies showed that lentivirus carrying Foxn1 transgene introduced into post‐wounded skin of Foxn1 −/− mice increases Igf2 expression 78 . A number of studies have found that IGF2 promotes adipogenesis via the IGF‐1R and PI3K pathways, modulates composition of fatty acids in adipose tissue, and participates in CREG1‐mediated glucose uptake 79–81 .…”

“…Furthermore, our recent in vivo studies showed that lentivirus carrying Foxn1 transgene introduced into post-wounded skin of Foxn1 −/− mice increases Igf2 expression. 78 A number of studies have found that IGF2 promotes adipogenesis via the IGF-1R and PI3K pathways, modulates composition of fatty acids in adipose tissue, and participates in CREG1-mediated glucose uptake. [79][80][81] Interestingly, our recent proteomic analysis revealed that Foxn1 upregulates and stimulates the release of CREG1 protein into conditioned media collected from keratinocytes transduced with Ad-Foxn1.…”

Gender Differences in Post-Operative Human Skin

“…It was revealed that Foxn1 regulates reparative (scar-forming) wound healing by engaging in re-epithelialization, epithelial-to-mesenchymal transition (EMT), and dWAT regulation [8]. Our recent data based on a mouse model (Foxn1 +/− and Foxn1 −/− mice) also showed that Foxn1 controls adipogenic signaling that regulates skin homeostasis and wound healing and affects susceptibility to diet-induced obesity [8,24].…”