Mesenchymal stem cells (MSC) are multipotent adult stem cells that are present in multiple tissues including umbilical cord, bone marrow and fat tissue. MSCs can self-renew by dividing and can differentiate into multiple tissues including bone, cartilage, adipose tissue, and connective tissue. Platelet-derived growth factor (PDGF) isoforms are important signaling molecules for different types of mesenchymal cells, and these isoforms stimulate the proliferation, migration and survival of cells including MSCs. The PDGF family consists of two transmembrane receptor tyrosine kinase subunits (PDGF receptor alpha [α-PDGFR] and PDGF receptor beta [β-PDGFR]) and four ligands (PDGF A, B, C, and D). Little is currently known about how PDGF controls the differentiation of MSCs into certain lineages.
In a new study published in the Journal of Biological Chemistry: Tri Pham, Abdo Najy, and led by Professor Hyeong-Reh Choi Kim from Wayne State University School of Medicine and the Barbara Ann Karmanos Cancer Institute demonstrated that PDGF D stimulates the differentiation of human bone marrow mesenchymal stem cells (hBMSCs) into osteoblasts and prevents hBMSC differentiation into adipocytes.
The research team reported the unique function of PDGF D in bone formation by concurrently promoting the commitment of osteoblastic differentiation of BMSCs while blocking their commitment to adipogenesis using the growth factor domain dimers of recombinant PDGF D (rPDGF D) proteins. This is the first study to show that PDGF may control MSC development into a certain lineage directly. Importantly, the authors offer proof that PDGF D-activated β-PDGFR inhibits MSCs from differentiating into adipocytes by preserving the actin cytoskeleton and downregulating the expression of adipogenic genes. PDGF D facilitates remodeling of the actin cytoskeleton, coupled with the manifestation of osteogenic gene expression. According to the authors, PDGF D induces hBMSCs to differentiate into osteoblasts via increasing cytoskeleton tension, presumably involving networks of RhoA-ROCK-MCL-actin.
The authors further reported that PDGF D induces massive polyubiquitination of β-PDGFR mediated by the E3 ligase HUWE1 and demonstrated that HUWE1 expression is critical for PDGF D regulation of hBMSCs’ osteogenic differentiation. Even in the absence of a ubiquitin-proteasome system inhibitor, HUWE1-mediated polyubiquitination of β-PDGFR was easily detected by immunoblot analysis of whole cell lysates. Contrary to the Cbl family, HUWE1-mediated β-PDGFR extends the protein stability of β-PDGFR and its osteogenic signals by keeping β-PDGFR on the cell surface. The findings clearly illustrated the functional significance of HUWE1 in the regulation of PDGFR-mediated osteogenic differentiation of hBMSCs. Taken together, the discovery made by Professor Hyeong-Reh Kim and her research team widens our understanding on the detailed molecular mechanism by which PDGF D controls the commitment of hBMSCs to the osteoblastic lineage and opens up the potential of the use of rPDGF D for promoting bone repair and regeneration.
Pham T, Najy AJ, Kim HR. E3 ligase HUWE1 promotes PDGF D-mediated osteoblastic differentiation of mesenchymal stem cells by effecting polyubiquitination of β-PDGFR. Journal of Biological Chemistry. 2022 ;298(6).