Mechanism of Divergent Growth Factor Effects in Mesenchymal Stem Cell Differentiation

  title={Mechanism of Divergent Growth Factor Effects in Mesenchymal Stem Cell Differentiation},
  author={Irina Kratchmarova and Blagoy S. Blagoev and Mandana Haack-S{\o}rensen and Moustapha Kassem and Matthias Mann},
  pages={1472 - 1477}
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… 
Platelet-derived growth factor receptor signaling is not involved in osteogenic differentiation of human mesenchymal stem cells.
PDGF receptor signaling sustains proliferation without affecting osteogenic differentiation of MSCs, and expression of other osteogenic marker genes such as osteocalcin, runt-related transcription factor 2, osteopontin, collagen type I, and bone sialoprotein was almost unaffected in perturbation studies.
Effects on Proliferation and Differentiation of Multipotent Bone Marrow Stromal Cells Engineered to Express Growth Factors for Combined Cell and Gene Therapy
Effects of overexpressing the growth factors, such as basic fibroblast growth factor (bFGF), platelet derived growth factor B (PDGF‐BB), transforming growth factor β1 (TGF‐β1), and vascular endothelial growth factors (VEGF), in human bone marrow‐derived MSCs are shown.
Cross-talk between EGF and BMP9 signalling pathways regulates the osteogenic differentiation of mesenchymal stem cells
It is found that EGF potentiates BMP9‐induced early and late osteogenic markers of MSCs in vitro, which can be effectively blunted by EGFR inhibitors Gefitinib and Erlotinib or receptor tyrosine kinase inhibitors AG‐1478 and AG‐494 in a dose‐ and time‐dependent manner.
Differential expression of cell surface proteins in human bone marrow mesenchymal stem cells cultured with or without basic fibroblast growth factor containing medium
The results indicate that the expression levels of F‐actin‐capping protein subunit alpha‐1, actin‐related protein 2/3 complex subunit 2, and myosin regulatory light chain 2 are important in bFGF‐induced morphological change of MSCs.
Inhibition of platelet‐derived growth factor receptorβ by imatinib mesylate suppresses proliferation and alters differentiation of human mesenchymal stem cells in vitro
Imatinib mesylate has a significant impact on proliferation and differentiation of human MSC in vitro and screening the activity of 42 receptor tyrosine kinases revealed an exclusive inhibition of platelet‐derived growth factor receptorβ (PDGFRβ).
Involvement of PI3K and MMP1 in PDGF-induced Migration of Human Adipose-derived Stem Cells
The results suggest that PDGF might signal hADSCs through PI3K, and MMP1 activity could play an important role in this PDGF-induced migration in vitro.
PDGF Receptor β Is a Potent Regulator of Mesenchymal Stromal Cell Function
  • A. TokunagaT. Oya M. Sasahara
  • Biology, Medicine
    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
  • 2008
PDGFRβ signaling distinctively induces proliferative and migratory responses but strongly inhibits osteogenic differentiation of MSCs, which could represent an important target for guided tissue regeneration or tissue engineering of bone.
Role of the EGFR ligand/receptor system in the secretion of angiogenic factors in mesenchymal stem cells
It is found that both MEK/MAPK and the PI3K/AKT signaling pathways mediate the ability of TGF‐α to induce secretion of angiogenic factors in MSCs.
Epidermal Growth Factor as a Candidate for Ex Vivo Expansion of Bone Marrow–Derived Mesenchymal Stem Cells
Findings suggest that EGFR ligands could be used for ex vivo expansion and direction of BMMSCs, and that PDGF did interfere with the differentiation of these BMMSC lineages.
Akt- and Erk-mediated regulation of proliferation and differentiation during PDGFRβ-induced MSC self-renewal
The data suggest that PDGFRβ‐induced Akt and Erk pathways regulate opposing fate decisions of proliferation and differentiation to promote MSC self‐renewal, and activation of multiple intracellular cascades is required for successful and sustainable MSCSelf‐Renewal strategies.


Adult Human Mesenchymal Stem Cell Differentiation to the Osteogenic or Adipogenic Lineage Is Regulated by Mitogen-activated Protein Kinase*
Observations provide a potential mechanism involving MAP kinase activation in osteogenic differentiation of adult stem cells and suggest that commitment of hMSCs into osteogenic or adipogenic lineages is governed by activation or inhibition of ERK, respectively.
Identification of genes responsible for osteoblast differentiation from human mesodermal progenitor cells
The studies indicate that in vitro differentiation cultures in which MPCs are induced to one of multiple cell fates should be very useful for defining signals important for lineage-specific differentiation.
Erk Is Essential for Growth, Differentiation, Integrin Expression, and Cell Function in Human Osteoblastic Cells*
The data suggest that Erks are not only essential for the growth and differentiation of osteoblasts but also are important for osteoblast adhesion, spreading, migration, and integrin expression.
Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells
It is suggested that ectopic expression of telomerase in hMSCs prevents senescence-associated impairment of osteoblast functions.
Multilineage potential of adult human mesenchymal stem cells.
Adult stem cells isolated from marrow aspirates of volunteer donors could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages.
Requirement of BMP-2-induced Phosphatidylinositol 3-Kinase and Akt Serine/Threonine Kinase in Osteoblast Differentiation and Smad-dependent BMP-2 Gene Transcription*
Together these data provide the first evidence that activation of BMP receptor serine/threonine kinase stimulates the PI 3 kinase/Akt pathway and define a role for this signal transduction pathway in BMP-specific Smad function during osteoblast differentiation.
Temporal analysis of phosphotyrosine-dependent signaling networks by quantitative proteomics
A mass spectrometric method is developed that converts temporal changes to differences in peptide isotopic abundance and provides an informative perspective on cell signaling and will be crucial to modeling signaling networks in a systems biology approach.