Dermal fibroblasts (DF) obtained from the superficial dermal layer and those from the deep dermal layer have different cellular functions. These differences are often associated with excessive scarring; they also influence early wound healing. We therefore investigated the differences between superficial and deep dermal fibroblasts with special emphasis on their contractile properties, and ability to produce connective tissue. We investigated their proliferation kinetics, ability to contract collagen lattices, and chronological mRNA expression of eight genes associated with wound healing. To estimate the changes in the differences between them during the early phase of wound healing, we investigated mRNA expression in bFGF supplemented medium because bFGF is a representative cytokine that is familiar to clinicians. Superficial DF proliferate faster than deep DF in culture, whereas deep DF are better at contracting collagen lattices than superficial ones. In realtime analysis of polymerase chain reaction, the expression of type I and III collagen, fibronectin, TGF β1 and β3, and connective tissue growth factor were higher in deep DF than in superficial DF, while the expression of TGF β2 was higher in superficial DF. After bFGF supplementation, the relative dominance of mRNA expression between superficial and deep DF remained constant except for the expression of collagenase. According to our analysis, deep DF are superior to superficial DF at promoting wound healing (particularly contraction and production of connective tissue). The intradermal distribution of DF is appropriate for efficient wound healing.
Tongue reconstruction was performed using a deep inferior epigastric perforator (DIEP) free flap in a 6-year-old girl with undifferentiated sarcoma of the tongue. After hemi-glossectomy with upper neck dissection, a 3-lobed DIEP free flap was used for the reconstruction. Donor site was closed primarily with suturing umbilicus in proper position. No flap loss, leakage, or infection occurred. Postoperatively, the patient was able to consume a normal diet without difficulty or aspiration and displayed good speech function. No donor site morbidity, e.g., herniation or bulging, was observed, and the patient was able to perform their normal daily activities. DIEP flaps provide a pliable skin paddle, an adequate amount of adipose tissue, and reduced donor site morbidity, even in children. We did not have any difficulty harvesting the DIEP flap or with the microvascular anastomosis. We consider DIEP free flaps to be the ideal option for pediatric tongue reconstruction.
Objective: Non-alcoholic fatty liver disease (NAFLD) with excessive triglyceride accumulation in the liver prevails in approximately 24% of adults worldwide. Prolonged fasting rapidly causes hepatic steatosis. However, the etiology of hepatic steatosis during starvation is unclear. During starvation, skeletal muscle, the central tissue for metabolism, physical exercise, and storage for protein/amino acids, adapts to energy deficit by promoting muscle proteolysis, which leads to muscle atrophy. The critical factors that cause muscle atrophy are the Forkhead Box O family transcription factors (FoxO1, 3 and 4). Although skeletal muscle FoxOs are necessary to adapt to starvation, the specific function of skeletal muscle FoxOs at the whole-body level is unclear. We hypothesized that skeletal muscle atrophy and/or metabolism would be associated with the etiology of starvation-induced fatty liver and aimed to elucidate the inter-organ crosstalk from skeletal muscle to liver via FoxOs signaling pathway. Methods: We previously generated skeletal muscle-specific FoxO1,3,4-triple knockout mice (mFoxO1,3,4-/-) using human skeletal α-actin promoter-driven Cre recombinase expression (Oyabu et al. 2022. FASEB J 36: e22152). The control FoxO1,3,4flox/flox mice (wild-type mice) and mFoxO1,3,4-/- mice were fasted for 48 h to mimic prolonged fasting. Results: Skeletal muscle mass was significantly reduced in 48 h-fasted wild-type mice. This reduction was prevented by the skeletal muscle FoxO-triple deletion. Fasted mFoxO1,3,4-/- mice showed reduced blood glucose levels, suggesting the lack of energy in 48 h-fasted mFoxO1,3,4-/- mice. Interestingly, starvation-induced lipid-droplet formation in the liver, accumulation of hepatic triglyceride, and the expression of hepatic lipid-droplet-marker protein (Plin2) were significantly increased in 48 h-fasted mFoxO1,3,4-/- mice compared to fasted wild-type mice, indicating that hepatic steatosis was accelerated by skeletal muscle FoxO-triple deletion, despite of the retention from skeletal muscle loss. This suggests that skeletal muscle FoxOs are essential for protection against starvation-induced hepatic steatosis for adaptation to starvation. Starvation induced the upregulation of genes involved in not only muscle proteolysis, but also triglyceride uptake and metabolism in skeletal muscle, which were abrogated by the skeletal muscle-specific FoxO-triple deletion. In addition, the muscle triglyceride level was lower in 48 h-fasted mFoxO1,3,4-/- mice than fasted wild-type mice. Conclusion: Here, we demonstrated a critical connection between liver and skeletal muscle via FoxOs transcription factors. Our data indicate that healthy skeletal muscle atrophy and/or metabolism via FoxOs signaling pathway is critical for prevention of starvation-induced hepatic steatosis. This study sheds light on the skeletal muscle-liver inter-organ crosstalk as the potential therapeutic targets of malnutrition-induced NAFLD. This study was supported by Grants-in-Aids for Scientific Research KAKENHI from the Japan Society for the Promotion of Science. This study was also supported by Mishima Kaiun Memorial Foundation and Grants-in-Aids for the Second Dream Challenge Planning Awards from JSBBA. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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