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Coupling growth-factor engineering with nanotechnology for therapeutic angiogenesis.

ABSTRACT: Therapeutic angiogenesis is an emerging paradigm for the management of ischemic pathologies. Proangiogenic Therapy is limited, however, by the current inability to deliver angiogenic factors in a sustained manner at the site of pathology. In this study, we investigated a unique nonglycosylated active fragment of hepatocyte growth factor/scatter factor, 1K1, which acts as a potent angiogenic agent in vitro and in a zebrafish embryo and a murine matrigel implant model. Furthermore, we demonstrate that nanoformulating 1K1 for sustained release temporally alters downstream signaling through the mitogen activated protein kinase pathway, and amplifies the angiogenic outcome. Merging protein engineering and nanotechnology offers exciting possibilities for the treatment of ischemic disease, and furthermore allows the selective targeting of downstream signaling pathways, which translates into discrete phenotypes.

SUBMITTER: Sinha Roy R

PROVIDER: S-EPMC2922257 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Coupling growth-factor engineering with nanotechnology for therapeutic angiogenesis.

Sinha Roy Rituparna R Soni Shivani S Harfouche Rania R Vasudevan Pooja R PR Holmes Oliver O de Jonge Hugo H Rowe Arthur A Paraskar Abhimanyu A Hentschel Dirk M DM Chirgadze Dimitri D Blundell Tom L TL Gherardi Ermanno E Mashelkar Raghunath A RA Sengupta Shiladitya S

Proceedings of the National Academy of Sciences of the United States of America 20100716 31

Therapeutic angiogenesis is an emerging paradigm for the management of ischemic pathologies. Proangiogenic Therapy is limited, however, by the current inability to deliver angiogenic factors in a sustained manner at the site of pathology. In this study, we investigated a unique nonglycosylated active fragment of hepatocyte growth factor/scatter factor, 1K1, which acts as a potent angiogenic agent in vitro and in a zebrafish embryo and a murine matrigel implant model. Furthermore, we demonstrate ...[more]

PMID: 20639469

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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

Coupling growth-factor engineering with nanotechnology for therapeutic angiogenesis.

Publications

Coupling growth-factor engineering with nanotechnology for therapeutic angiogenesis.

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