High Mobility Group Box 1 Protein Inhibits the Proliferation of Human Mesenchymal Stem Cells and Promotes Their Migration and Differentiation along Osteoblastic Pathway

Abstract

Extracellular high mobility group box 1 (HMGB1) is a novel cytokine that takes part in the processes of in: ammation, tissue damage and regeneration. Mesenchymal stem cells (MSCs) are adult stem cells characterized by their inherently suppressive activities on inflammative and allo-immune reactions. In the present study, we have addressed whether HMGB1 could affect the biological properties of human bone marrow MSCs. Transwell experiments showed that HMGB1 induced MSC migration and this effect could not be hampered by a blocking antibody against the receptor for advanced glycation end products (RAGE). MSCs exposed to HMGB1 were negative for CD31, CD45, CD80, and HLA-DR, and displayed equal levels of CD73, CD166, and HLA-ABC compared with their counterparts, but HMGB1 profoundly suppressed MSC proliferation in a dose-dependent manner as evaluated by carboxyfluorescein diacetate succinmidyl ester dye dilution assay. Furthermore, HMGB1 triggered the differentiation of MSCs into osteoblasts as identified by histochemical staining, traditional RT-PCR and real-time RT-PCR analysis on mRNA expression of lineage-specific molecular markers. The differentiation-inductive activity could neither be inhibited by RAGE neutralizing antibody. Moreover, HMGB1-treated MSCs displayed unchanged suppressive activity on in vitro lymphocyte cell proliferation elicited by ConA. Collectively, the data suggest that MSCs are a target of HMGB1.