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Leptin Induces Sca-1+ Progenitor Cell Migration Enhancing Neointimal Lesions in Vessel-Injury Mouse Models

Student thesis: Doctoral ThesisDoctor of Philosophy

Leptin is a hormone predominantly secreted by white adipose tissue which was initially believed to be solely a metabolic factor. Recent publications showed that leptin also played a role in inflammation and vascular disease, to which Sca-1+ vascular progenitor cells within the vessel wall may contribute. However, the effect of leptin on vascular progenitor cells remains unknown. In the present study, we sought to elucidate the effect of leptin on Sca-1+ progenitor cells and neointimal formation, and to understand the underlying mechanisms.

Sca-1+ progenitor cells from the vessel wall of C57BL/6J (Lepr+/+) and db/db (Lepr-/-) mice were cultured and purified with microbeads. The migration of Sca-1+ progenitor cells in vitro derived from Lepr+/+ mice was markedly induced by leptin. Western blotting and kinase assays revealed that leptin induced phosphorylation of STAT3, ERK1/2, FAK, and Rac1/Cdc42. Guide-wire injury of the femoral artery was performed in wild-type mice with neointimal development in a time-dependent manner. An increased expression of leptin in both injured vessels and serum was observed at 24 hours post-surgery. Red fluorescent protein (RFP) labelled-Sca-1+ progenitor cells in Matrigel were applied to the adventitia of the injured femoral artery, RFP+ cells were observed in the intima at 24 hours post-surgery, which significantly enhanced neointimal lesions at 2 weeks. This increase in neointimal lesions was reduced by pre-treatment of Sca-1+ cells with CYT-354 (leptin antagonist). Moreover, guide-wire injury could only induce minor neointima in Lepr-/- mice at 2 and 4 weeks post-surgery. However, transplantation of Lepr+/+ Sca-1+ progenitor cells into the adventitial side of the injured femoral arteries of Lepr-/- mice significantly enhanced the neointimal formation.

In summary, upregulation of leptin levels in both the vessel wall and the circulation following vessel injury resulted in the migration of Sca-1+ progenitor cells, which enhanced neointimal formation via leptin receptor-dependent STAT3- Rac1/Cdc42-ERK-FAK pathways.

Key words: Leptin, Sca-1+ progenitor, smooth muscle cells, neointimal formation, animal models
Original languageEnglish
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Award date2017

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