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

Abstract

Change of actin filament organization at the early stage of cell differentiation directs cell fate commitment of mesenchymal stem cells (MSCs). Thymosin beta-4 (Tb 4 ), a major G-actin sequestering peptide, is known to regulate the cytoskeleton. The study investigated the ways in which Tb 4 regulates cell fate determination in MSCs upon differentiation induction. It was found that Tb 4 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, Tb 4 reciprocally facilitated adipogenic differentiation. Tb 4 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 receptor gamma during the first week of adipogenic induction. In summary, Tb 4 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 Tb 4, a ubiquitous peptide, may be involved in osteoporosis when its intracellular concentration is elevated. Further investigation of targeting Tb 4 for future osteoporosis treatment is warranted. ß

Modulation of osteogenic differentiation in hMSCs cells by submicron topographically-patterned ridges and grooves

“…These data demonstrate that ridges and grooves as low as 400 nm pitch modify alignment and/or morphology of hMSCs. It is known that changes in cell morphology affect gene expression profiles and cell differentiation [31–33]. In particular, hMSCs differentiate into osteoblasts when allowed to spread and flatten, whereas restricting the surface area upon which to grow promotes adipogenic differentiation of hMSCs [4].…”

Regulation of PTEN/Akt Pathway Enhances Cardiomyogenesis and Attenuates Adverse Left Ventricular Remodeling following Thymosin β4 Overexpressing Embryonic Stem Cell Transplantation in the Infarcted Heart

“…It has been suggested that Tβ4 is a novel signaling molecule, which activates various cell type differentiation [15,16,21,31]. However, its role in the differentiation of ES or adult stem cells into cardiac myocytes has not been examined.…”

The Mechanobiology of the Actin Cytoskeleton in Stem Cells during Differentiation and Interaction with Biomaterials

“…Tβ4 plays a role in human bone marrow-derived MSC differentiation. Tβ4 is known to suppress osteogenic differentiation by sequestering G-actin and preventing its polymerization [ 23 ]. It has shown a biophysical effect using exogenous Tβ4, without altering gene expression, measured by monitoring Runt-related transcription factor 2 (Runx2) and peroxisome proliferator-activated receptor gamma (PPARγ) genes during early osteogenic differentiation.…”

“…Despite a lack of change in gene expression, one cannot rule out the possibility of alteration in other genes not included in this study, since alteration in the actin cytoskeleton may modify gene expression via mechanotransduction. On the other hand, this study has shown that in these conditions, the adipogenic differentiation was promoted, but chondrogenic differentiation was not altered, pointing out the difference in requirements and importance of F-actin during these processes [ 23 ].…”