Thymosin beta-4 directs cell fate determination of human mesenchymal stem cells through biophysical effects

Change of actin filament organization at the early stage of cell differentiation directs cell fate commitment of mesenchymal stem cells (MSCs). Thymosin beta-4 (Tβ₄), a major G-actin sequestering peptide, is known to regulate the cytoskeleton. The study investigated the ways in whichTβ₄ regulates cell fate determination inMSCsupon differentiation induction. It was found thatTβ₄ decreased F-actin formation, reduced the F-actin/G-actin ratio, and inhibited osteogenic differentiation; such actin reorganization was not associated with the change of Runt-related transcription factor 2 gene expression during early osteogenic induction. Besides, Tβ₄ reciprocally facilitated adipogenic differentiation. Tβ₄ treatment was found to up-regulate gene as well as promote surface expression of adipocyte adhesion molecule during early adipogenic differentiation, which accompanied acceleration of adipocyte phenotypic maturation but was not associated with differential expression of peroxisome proliferator-activated receptorgammaduring the first week of adipogenic induction. In summary, Tβ₄ initiated cell fate determination of MSCs through biophysical effects exerted by cytoskeleton reorganization and altered cellcell adhesion rather than direct regulation of lineage-determining transcriptional factors. Such findings suggest that Tβ₄, a ubiquitous peptide, may be involved in osteoporosis when its intracellular concentration is elevated. Further investigation of targeting Tβ₄ for future osteoporosis treatment is warranted.