Hyaluronan, CD44 and the Receptor for Hyaluronan-Mediated Motility (RHAMM, gene name HMMR) regulate stem cell differentiation including mesenchymal progenitor differentiation. Here, we show that CD44 expression is required for subcutaneous adipogenesis, whereas RHAMM expression suppresses this process. We designed RHAMM function blocking peptides to promote subcutaneous adipogenesis as a clinical and tissue engineering tool. Adipogenic RHAMM peptides were identified by screening for their ability to promote adipogenesis in culture assays using rat bone marrow mesenchymal stem cells, mouse pre-adipocyte cell lines and primary human subcutaneous pre-adipocytes. Oil red O uptake into fat droplets and adiponectin production were used as biomarkers of adipogenesis. Positive peptides were formulated in either collagen I or hyaluronan (Orthovisc) gels then assessed for their adipogenic potential in vivo following injection into dorsal rat skin and mammary fat pads. Fat content was quantified and characterized using micro CT imaging, morphometry, histology, RT-PCR and ELISA analyses of adipogenic gene expression. Injection of screened peptides increased dorsal back subcutaneous fat pad area (208.3 ± 10.4 mm2versus control 84.11 ± 4.2 mm2; p < 0.05) and mammary fat pad size (45 ± 11 mg above control background, p = 0.002) in female rats. This effect lasted >5 weeks as detected by micro CT imaging and perilipin 1 mRNA expression. RHAMM expression suppresses while blocking peptides promote expression of PPARγ, C/EBP and their target genes. Blocking RHAMM function by peptide injection or topical application is a novel and minimally invasive method for potentially promoting subcutaneous adipogenesis in lipodystrophic diseases and a complementary tool to subcutaneous fat augmentation techniques.

中文翻译：

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透明质酸介导的运动（RHAMM / HMMR）的受体是促进皮下脂肪形成的新目标。

透明质酸，CD44和透明质酸介导的运动受体（RHAMM，基因名称HMMR）调节干细胞分化，包括间充质祖细胞分化。在这里，我们显示皮下脂肪形成需要CD44表达，而RHAMM表达抑制了这一过程。我们设计了RHAMM功能阻断肽来促进皮下脂肪形成，作为一种临床和组织工程工具。通过使用大鼠骨髓间充质干细胞，小鼠前脂肪细胞系和原代人皮下前脂肪细胞在培养试验中筛选其促脂肪形成的能力，从而鉴定了成脂肪的RHAMM肽。脂肪小滴中油红O的吸收和脂联素的产生被用作脂肪生成的生物标志物。将阳性肽配制在胶原蛋白I或透明质酸（Orthovisc）凝胶中，然后在注射到大鼠背侧皮肤和乳腺脂肪垫中后评估其体内的成脂潜能。使用微CT成像，形态学，组织学，RT-PCR和成脂基因表达的ELISA分析对脂肪含量进行定量和表征。在雌性大鼠中，注射筛选出的肽可增加背背皮下脂肪垫的面积（208.3±10.4 mm2，相对于对照的84.11±4.2 mm2； p <0.05）和乳腺脂肪垫的大小（相对于对照背景高45±11 mg，p = 0.002）。通过微型CT成像和periplipin 1 mRNA表达检测到，该作用持续> 5周。RHAMM表达受到抑制，而封闭肽则促进PPARγ，C / EBP及其靶基因的表达。