title: SDF-1α induces PDGF-B expression and the differentiation of bone marrow cells into pericytes.
abstract: Platelet-derived growth factor B (PDGF-B) and its receptor, PDGFR-β, play a critical role in pericyte maturation; however, the mechanisms by which PDGF-B is upregulated in the tumor microenvironment remain unclear. We previously showed that upregulating stromal-derived factor, SDF-1α, in VEGF(165)-inhibited Ewing's sarcoma tumors (TC/siVEGF(7-1)) induced PDGF-B mRNA expression, increased infiltration and differentiation of bone marrow cells (BMC) into pericytes and, rescued tumor growth. The purpose of this study was to investigate the mechanism by which SDF-1α increased PDGF-B expression and the role of this pathway in BM-derived pericyte differentiation. We showed that SDF-1α induced expression of PDGF-B mRNA and protein both in vitro and in vivo. In contrast, inhibiting SDF-1α downregulated PDGF-B. We cloned the 2-kb pdgf-b promoter fragment and showed that SDF-1α activates PDGF-B via a transcriptional mechanism. Chromatin immunoprecipitation showed that the ELK-1 transcription factor binds to the pdgf-b promoter in response to SDF-1α. We confirmed the correlation between the SDF-1α/PDGF-B pathway and the differentiation of PDGFR-β+ BMCs into mature pericytes using an in vitro assay. These findings show that SDF-1α regulates PDGF-B expression and that this regulation plays a critical role in the differentiation of PDGFR-β+ BMCs into mature pericytes.
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Randala
authors.initials: R
authors.lastname: Hamdan
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhou
authors.forename: Eugenie S
authors.initials: ES
authors.lastname: Kleinerman
mesh_terms: D000818:Animals; D000941:Antigens / Q000096:biosynthesis; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D003893:Desmin / Q000096:biosynthesis; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008809:Mice, Inbred C3H; D020286:Pericytes / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011509:Proteoglycans / Q000096:biosynthesis; D020574:Proto-Oncogene Proteins c-sis / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic; D015854:Up-Regulation; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D054377:Chemokine CXCL12; D003893:Desmin; D011509:Proteoglycans; D020574:Proto-Oncogene Proteins c-sis; D020797:Receptor, Platelet-Derived Growth Factor beta; D011994:Recombinant Proteins; D050807:ets-Domain Protein Elk-1; D000099216:Chondroitin Sulfate Proteoglycan 4