Inhibition of platelet‐derived growth factor receptorβ by imatinib mesylate suppresses proliferation and alters differentiation of human mesenchymal stem cells <i>in vitro</i>

Fierro, Fernando A.; Illmer, Thomas; Jing, Duohui; Schleyer, Eberhard; Ehninger, Gerhard; Boxberger, Sabine; Bornhäuser, Martin

doi:10.1111/j.1365-2184.2007.00438.x

Cited by 88 publications

(80 citation statements)

References 31 publications

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“…(39) In cultures of human stromal cells isolated from bone biopsies, treatment with imatinib significantly increased mineral deposi- tion (17,21) and decreased proliferation of stromal cells. (17,18) Similarly, imatinib increased mineralization (19) and partially inhibited proliferation (19,20) in primary rat stromal cells and murine cell lines. The proliferation, differentiation, and maturation of OBs are influenced by signaling pathways, including PDGFR, that are inhibited by dasatinib.…”

Section: Discussionmentioning

confidence: 94%

“…(17)(18)(19)(20) To determine whether OBs are similarly sensitive to dasatinib, we examined the effect of dasatinib on cell proliferation and mineral formation in rodent stromal cell cultures in vitro.…”

Section: In Vitro Ob Activitymentioning

confidence: 99%

“…PDGF is a potent mitogen for OB precursors that also inhibits OB differentiation in vitro. (13)(14)(15)(16) Studies from our laboratory (17) and those of others (18)(19)(20)(21) have shown that imatinib activates OB activity while inhibiting cell proliferation at least in part through the inhibition of PDGFR. In cultures of human and murine stromal cells and cell lines, treatment with therapeutically achievable concentrations of imatinib significantly increased mineral deposition (17,19,21) and decreased cell proliferation.…”

mentioning

confidence: 97%

“…In cultures of human and murine stromal cells and cell lines, treatment with therapeutically achievable concentrations of imatinib significantly increased mineral deposition (17,19,21) and decreased cell proliferation. (17)(18)(19)(20) In addition, imatinib treatment prevented the inhibitory effects of PDGF on mineralized matrix formation in vitro. (17,19) These results suggest that tyrosine kinase inhibitors could inhibit OB proliferation and activate their differentiation in vitro.…”

mentioning

confidence: 98%

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The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

Vandyke

Dewar

Diamond

et al. 2010

Journal of Bone and Mineral Research

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Dasatinib is a potent tyrosine kinase inhibitor that is used to treat chronic myeloid leukemia in patients resistant or intolerant to imatinib mesylate. While designed to inhibit Abl and Src kinases, dasatinib shows multitarget effects, including inhibition of the macrophage colony-stimulating factor (M-CSF) receptor c-fms. We have shown previously that dasatinib abrogates osteoclast formation and activity in vitro owing, in part, to its specificity for c-fms. In this study we examined whether dasatinib could significantly alter bone volume in a model of physiologic bone turnover. Sprague-Dawley rats were administered dasatinib (5 mg/kg/day) or vehicle by gavage or zoledronic acid (ZOL; 100 mg/kg/6 weeks) subcutaneously. Following 4, 8, and 12 weeks of treatment, serum biochemical, bone morphometric, and histologic analyses were performed. Whole-body bone mineral density and tibial cortical thickness where unchanged in the dasatinib-or ZOL-treated animals relative to controls. However, micro-computed tomographic (mCT) analysis of cancellous bone at the proximal tibias showed that trabecular volume (BV/TV) and thickness (Tb.Th) were increased in dasatinib-treated animals at levels comparable with those of the ZOL-treated group. These changes were associated with a decrease in osteoclast numbers (N.Oc/B.Pm) and surface (Oc.S/BS) and decreased serum levels of the osteoclast marker c-terminal collagen crosslinks (CTX-1). Mineral apposition rate (MAR), bone-formation rate (BFR), and levels of the serum osteoblast markers osteocalcin and N-terminal propeptide of type I procollagen (P1NP) were not altered significantly in the dasatinib-treated animals relative to controls. These studies show that dasatinib increases trabecular bone volume at least in part by inhibiting osteoclast activity, suggesting that dasatinib therapy may result in dysregulated bone remodeling. ß

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Section: Discussionmentioning

confidence: 94%

Section: In Vitro Ob Activitymentioning

confidence: 99%

mentioning

confidence: 97%

mentioning

confidence: 98%

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The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

Vandyke

Dewar

Diamond

et al. 2010

Journal of Bone and Mineral Research

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“…In various scenarios, activation of ERK1/2 and Akt in MSCs was important for cell proliferation (73) and protection from apoptosis (74). Prolonged inhibition of ERK1/2 has furthermore been shown to lead to adipogenic differentiation (75).…”

Section: Discussionmentioning

confidence: 99%

C3a and C5a Are Chemotactic Factors for Human Mesenchymal Stem Cells, Which Cause Prolonged ERK1/2 Phosphorylation

Schraufstätter

DiScipio

Zhao

et al. 2009

The Journal of Immunology

164

136

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Mesenchymal stem cells (MSCs) have a great potential for tissue repair, especially if they can be delivered efficiently to sites of tissue injury. Since complement activation occurs whenever there is tissue damage, the effects of the complement activation products C3a and C5a on MSCs were examined. Both C3a and C5a were chemoattractants for human bone marrow-derived MSCs, which expressed both the C3a receptor (C3aR) and the C5a receptor (C5aR; CD88) on the cell surface. Specific C3aR and C5aR inhibitors blocked the chemotactic response, as did pertussis toxin, indicating that the response was mediated by the known anaphylatoxin receptors in a Gi activation-dependent fashion. While C5a causes strong and prolonged activation of various signaling pathways in many different cell types, the response observed with C3a is generally transient and weak. However, we show herein that in MSCs both C3a and C5a caused prolonged and robust ERK1/2 and Akt phosphorylation. Phospho-ERK1/2 was translocated to the nucleus in both C3a and C5a-stimulated MSCs, which was associated with subsequent phosphorylation of the transcription factor Elk, which could not be detected in other cell types stimulated with C3a. More surprisingly, the C3aR itself was translocated to the nucleus in C3a-stimulated MSCs, especially at low cell densities. Since nuclear activation/translocation of G protein-coupled receptors has been shown to induce long-term effects, this novel observation implies that C3a exerts far-reaching consequences on MSC biology. These results suggest that the anaphylatoxins C3a and C5a present in injured tissues contribute to the recruitment of MSCs and regulation of their behavior.

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Coculture of endothelial progenitor cells and mesenchymal stem cells enhanced their proliferation and angiogenesis through PDGF and Notch signaling

et al. 2017

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The beneficial effects of combined use of mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) on tissue repair and regeneration after injury have been demonstrated, but the underlying mechanism remains incompletely understood. This study aimed to investigate the effects of direct contact coculture of human bone marrow‐derived EPCs (hEPCs)/human bone marrow‐derived MSCs (hMSCs) on their proliferation and angiogenic capacities and the underlying mechanism. hEPCs and hMSCs were cocultured in a 2D mixed monolayer or a 3D transwell membrane cell‐to‐cell coculture system. Cell proliferation was determined by Cell Counting Kit‐8. Angiogenic capacity was evaluated by in vitro angiogenesis assay. Platelet‐derived growth factor‐BB (PDGF‐BB), PDGF receptor neutralizing antibody (AB‐PDGFR), and DAPT (a γ‐secretase inhibitor) were used to investigate PDGF and Notch signaling. Cell proliferation was significantly enhanced by hEPCs/hMSCs 3D‐coculture and PDGF‐BB treatment, but inhibited by AB‐PDGFR. Expression of cyclin D1, PDGFR, Notch1, and Hes1 was markedly enhanced by PDGF‐BB but inhibited by DAPT. In vitro angiogenesis assay showed that hEPCs/hMSCs coculture and PDGF‐BB significantly enhanced angiogenic capacity, whereas AB‐PDGFR significantly reduced the angiogenic capacity. PDGF‐BB increased the expression of kinase insert domain receptor (KDR, an endothelial marker) and activated Notch1 signaling in cocultured cells, while DAPT attenuated the promoting effect of PDGF‐BB on KDR expression of hEPCs/hMSCs coculture. hEPCs/hMSCs coculture enhanced their proliferation and angiogenic capacities. PDGF and Notch signaling pathways participated in the promoting effects of hEPCs/hMSCs coculture, and there was crosstalk between these two signaling pathways. Our findings should aid understanding of the mechanism of beneficial effects of hEPCs/hMSCs coculture.

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Inhibition of platelet‐derived growth factor receptorβ by imatinib mesylate suppresses proliferation and alters differentiation of human mesenchymal stem cells in vitro

Abstract: In summary, inhibition of PDGFRbeta and downstream Akt and Erk signalling by IM has a significant impact on proliferation and differentiation of human MSC in vitro.

Cited by 88 publications

References 31 publications

The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

C3a and C5a Are Chemotactic Factors for Human Mesenchymal Stem Cells, Which Cause Prolonged ERK1/2 Phosphorylation

Coculture of endothelial progenitor cells and mesenchymal stem cells enhanced their proliferation and angiogenesis through PDGF and Notch signaling

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