Mechanism of Divergent Growth Factor Effects in Mesenchymal Stem Cell Differentiation

TLDR

Closely related signals often lead to very different cellular outcomes. The study employed mass spectrometry‑based proteomics to compare tyrosine‑phosphorylated proteins and their partners in response to EGF and PDGF. EGF, but not PDGF, stimulates osteogenic differentiation of human mesenchymal stem cells; proteomics revealed that although most signaling proteins are shared, PI3K activation is exclusive to PDGF, and PI3K inhibition restores PDGF’s differentiation capacity, demonstrating that quantitative proteomics can uncover critical signaling differences that alter cell fate.

Abstract

Closely related signals often lead to very different cellular outcomes. We found that the differentiation of human mesenchymal stem cells into bone-forming cells is stimulated by epidermal growth factor (EGF) but not platelet-derived growth factor (PDGF). We used mass spectrometry-based proteomics to comprehensively compare proteins that were tyrosine phosphorylated in response to EGF and PDGF and their associated partners. More than 90% of these signaling proteins were used by both ligands, whereas the phosphatidylinositol 3-kinase (PI3K) pathway was exclusively activated by PDGF, implicating it as a possible control point. Indeed, chemical inhibition of PI3K in PDGF-stimulated cells removed the differential effect of the two growth factors, bestowing full differentiation effect onto PDGF. Thus, quantitative proteomics can directly compare entire signaling networks and discover critical differences capable of changing cell fate.