Dataset Information

Thyroid Transcription Factor 1 Reprograms Angiogenic Activities of Secretome.

ABSTRACT: Through both gain- and loss-of-TTF-1 expression strategies, we show that TTF-1 positively regulates vascular endothelial growth factor (VEGF) and that the VEGF promoter element contains multiple TTF-1-responsive sequences. The major signaling receptor for VEGF, i.e VEGFR2, also appears to be under a direct and positive regulation of TTF-1. The TTF-1-dependent upregulation of VEGF was moderately sensitive to rapamycin, implicating a partial involvement of mammalian target of rapamycin (mTOR). However, hypoxia did not further increase the secreted VEGF level of the TTF-1(+) lung cancer cells. The TTF-1-induced VEGF upregulation occurs in both compartments (exosomes and exosome-depleted media (EDM)) of the conditioned media. Surprisingly, the EDM of TTF-1(+) lung cancer cells (designated EDM-TTF-1(+)) displayed an anti-angiogenic activity in the endothelial cell tube formation assay. Mechanistic studies suggest that the increased granulocyte-macrophage colony-stimulating factor (GM-CSF) level in the EDM-TTF-1(+) conferred the antiangiogenic activities. In human lung cancer, the expression of TTF-1 and GM-CSF exhibits a statistically significant and positive correlation. In summary, this study provides evidence that TTF-1 may reprogram lung cancer secreted proteome into an antiangiogenic state, offering a novel basis to account for the long-standing observation of favorable prognosis associated with TTF-1(+) lung adenocarcinomas.

SUBMITTER: Wood LW

PROVIDER: S-EPMC4766481 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Thyroid Transcription Factor 1 Reprograms Angiogenic Activities of Secretome.

Wood Lauren W LW Cox Nicole I NI Phelps Cody A CA Lai Shao-Chiang SC Poddar Arjun A Talbot Conover C Mu David D

Scientific reports 20160225

Through both gain- and loss-of-TTF-1 expression strategies, we show that TTF-1 positively regulates vascular endothelial growth factor (VEGF) and that the VEGF promoter element contains multiple TTF-1-responsive sequences. The major signaling receptor for VEGF, i.e VEGFR2, also appears to be under a direct and positive regulation of TTF-1. The TTF-1-dependent upregulation of VEGF was moderately sensitive to rapamycin, implicating a partial involvement of mammalian target of rapamycin (mTOR). How ...[more]

PMID: 26912193

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Project description:Tissue (re)vascularization strategies face various challenges, as therapeutic cells do not survive long enough in situ, while the administration of pro-angiogenic factors is hampered by fast clearance and insufficient ability to emulate complex spatiotemporal signaling. Here, we propose to address these limitations by engineering a functional biomaterial capable of capturing and concentrating the pro-angiogenic activities of mesenchymal stem cells (MSCs). In particular, dextran sulfate, a high molecular weight sulfated glucose polymer, supplemented to MSC cultures, interacts with MSC-derived extracellular matrix (ECM) components and facilitates their co-assembly and accumulation in the pericellular space. Upon decellularization, the resulting dextran sulfate-ECM hybrid material can be processed into MIcroparticles of SOlidified Secretome (MIPSOS). The insoluble format of MIPSOS protects protein components from degradation, while facilitating their sustained release. Proteomic analysis demonstrates that MIPSOS are highly enriched in pro-angiogenic factors, resulting in an enhanced pro-angiogenic bioactivity when compared to naïve MSC-derived ECM (cECM). Consequently, intravital microscopy of full-thickness skin wounds treated with MIPSOS demonstrates accelerated revascularization and healing, far superior to the therapeutic potential of cECM. Hence, the microparticle-based solidified stem cell secretome provides a promising platform to address major limitations of current therapeutic angiogenesis approaches. Graphical abstract A high molecular weight sulfated polyglucose polymer, dextran sulfate, co-assembles with mesenchymal stem cell derived secretome into insoluble microparticles (named MIPSOS). Simultaneously, dextran sulfate's ability to mimic heparan sulfate promotes the accumulation of a plethora of pro-angiogenic factors, resulting in superior pro-angiogenic properties and thus therapeutic potential.Image 1 Highlights • Dextran sulfate assembles with mesenchymal stem cell secretome.• As a result, microparticles of solidified stem cell secretome (MIPSOS) are formed.• The insoluble MIPSOS format protects proteins from premature degradation.• MIPSOS are enriched in pro-angiogenic factors and exhibit gradual release kinetics.• MIPSOS demonstrate superior pro-angiogenic properties and thus therapeutic potential.

Dataset Information

Thyroid Transcription Factor 1 Reprograms Angiogenic Activities of Secretome.

Publications

Thyroid Transcription Factor 1 Reprograms Angiogenic Activities of Secretome.

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