Receptor for hyaluronan mediated motility (RHAMM/HMMR) is a novel target for promoting subcutaneous adipogenesis

Abstract

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 mm2 versus 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.

Hyaluronan in adipogenesis, adipose tissue physiology and systemic metabolism

“…CD44 is one of major cell surface binding proteins for HA [39], and the PDGFRɑ + CD44+ subpopulation of preadipocyte is highly proliferative [40]. Activation of RHAMM/HMMR receptor antagonizes the CD44 signaling and suppresses adipogenesis [41]. The adipogenic potential of HA combined with its physical properties makes it the top choice of supporting matrices for in vivo transplantation of preadipocytes or adipocyte stem cells (ASCs) [42–46].…”

Improvement of hydration and epidermal barrier function in human skin by a novel compound isosorbide dicaprylate

“…CD44 is an important cell‐surface glycoprotein involved in cell–cell interactions, ECM adhesion and migration, resulting in the increased resilience of the skin . This receptor for hyaluronic acid (HA) can also interact with other ligands, such as osteopontin, collagens and matrix metalloproteinases (MMPs) not only in dermis and epidermis, but also in the hypodermis, which is an essential component of the skin . Downregulation of CD44 in cultured keratinocytes (using CD44 siRNA) significantly inhibits HA‐mediated keratinocyte differentiation and lipid synthesis .…”

Identification of genes and pathways involved in malignant pleural mesothelioma using bioinformatics methods

“…In clinic practice, highly expressed EZH2 and deletion of BAP1 and MTAP can be detected by immunohistochemistry and may be used to distingush MPM from mesothelial hyperplasia [ 21 ]. HMMR (Hyaluronan Mediated Motility Receptor) is a protein coding gene influencing in cell motility [ 26 ]. The protein is detected in breast tissue and complexes with BRCA1 and BRCA2.…”