The tyrosine kinase inhibitor dasatinib induces a marked adipogenic differentiation of human multipotent mesenchymal stromal cells.
The tyrosine kinase inhibitor dasatinib induces a marked adipogenic differentiation of human multipotent mesenchymal stromal cells.
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DOI：
10.1371/journal.pone.0028555
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Oliva A
中科院分区：
文献类型：
--
作者：
Borriello A;Caldarelli I;Basile MA;Bencivenga D;Tramontano A;Perrotta S;Della Ragione F;Oliva A
在慢性粒细胞白血病治疗中引入特异性BCR-ABL抑制剂已经完全改变了这种血液学癌症的预后，从致命性疾病转变为慢性疾病。由于酪氨酸激酶抑制剂（TKI）可能长期持续治疗，因此了解其对正常细胞的影响至关重要。我们研究了达沙替尼治疗对人骨髓间充质干细胞（MSCs）的影响。我们的研究结果首次表明，达沙替尼诱导MSC脂肪细胞分化。特别地，当TKI加入诱导成骨分化的培养基中时，高百分比的MSC获得脂肪细胞形态并过表达脂肪细胞特异性基因，包括PPARγ、CEBPα、LPL和SREBP 1c。达沙替尼还抑制碱性磷酸酶（一种成骨标志物）的活性，并显著降低基质矿化。在蛋白水平上也证实了PPARγ的增加。达沙替尼诱导脂肪形成所需的成骨培养基组分是地塞米松。有趣的是，在单独用达沙替尼处理的MSC中也观察到脂肪细胞标志物的增加。TKI效应具有表型特异性，因为成纤维细胞不发生脂肪细胞分化或PPARγ增加。我们的数据表明，达沙替尼治疗影响骨髓间充质干细胞的承诺，并表明TKI治疗可能会改变正常的表型与潜在的显着的负面后果。
The introduction of specific BCR-ABL inhibitors in chronic myelogenous leukemia therapy has entirely mutated the prognosis of this hematologic cancer from being a fatal disorder to becoming a chronic disease. Due to the probable long lasting treatment with tyrosine-kinase inhibitors (TKIs), the knowledge of their effects on normal cells is of pivotal importance. We investigated the effects of dasatinib treatment on human bone marrow-derived mesenchymal stromal cells (MSCs). Our findings demonstrate, for the first time, that dasatinib induces MSCs adipocytic differentiation. Particularly, when the TKI is added to the medium inducing osteogenic differentiation, a high MSCs percentage acquires adipocytic morphology and overexpresses adipocytic specific genes, including PPARγ, CEBPα, LPL and SREBP1c. Dasatinib also inhibits the activity of alkaline phosphatase, an osteogenic marker, and remarkably reduces matrix mineralization. The increase of PPARγ is also confirmed at protein level. The component of osteogenic medium required for dasatinib-induced adipogenesis is dexamethasone. Intriguingly, the increase of adipocytic markers is also observed in MSCs treated with dasatinib alone. The TKI effect is phenotype-specific, since fibroblasts do not undergo adipocytic differentiation or PPARγ increase. Our data demonstrate that dasatinib treatment affects bone marrow MSCs commitment and suggest that TKIs therapy might modify normal phenotypes with potential significant negative consequences.
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影响因子：
8.8
作者：
通讯作者：
--
SRC抑制剂dasatinib加速了人骨骨髓衍生的间充质基质细胞分化成成骨细胞。
影响因子：
3.8
作者：
Id Boufker H;Lagneaux L;Najar M;Piccart M;Ghanem G;Body JJ;Journé F
通讯作者：
Journé F
影响因子：
158.5
作者：
Druker, Brian J.;Guilhot, Francois;Larson, Richard A.
通讯作者：
Larson, Richard A.
影响因子：
4.8
作者：
Jaiswal, RK;Jaiswal, N;Pittenger, MF
通讯作者：
Pittenger, MF
影响因子：
4.7
作者：
Borriello, Adriana;Caldarelli, Ilaria;Della Ragione, Fulvio
通讯作者：
Della Ragione, Fulvio