Abstract
ObjectiveBone marrow‐derived mesenchymal stem cells (MSCs) are recruited to the site of chronic inflammation during gastric cancer progression. Given that increased interferon‐gamma (IFNγ) and Sonic Hedgehog (Shh) expression contribute to cancer development, the role of the Shh signaling pathway as a mediator of IFNγ induced proliferation and recruitment of MSCs was studied.MethodsMSCs transduced with lentiviral particles expressing shRNA for Shh (MSCsShhKO) or empty vector (MSCsVect) were analyzed for cell cycle changes by flow cytometry. In vivo, MSCs tagged with RFP were transferred (via tail vein injection) into C57BL/6 mice and treated with either PBS or IFNγ (1μg/mouse/day) for 14 days. To identify the mechanism of recruitment, chemokine SDF‐1α was used in a chemotaxis assay with MSCsShhKO and MSCsVect.ResultsIFNγ significantly increased MSC proliferation, a response mediated by the secretion of Shh from cultured cells and blocked by Hedgehog signaling inhibitor cyclopamine. MSCsShhKO were arrested in G0/G1 phase compared to MSCsVect. Mice injected with IFNγ showed significant recruitment of RFP‐tagged MSCs to the gastric mucosa. Compared to MSCsVect, MSCsShhKO failed to migrate toward the SDF‐1α reflected by decreased CXCR4 expression.ConclusionIFNγ induces proliferation and initiates recruitment of MSCs, a mechanism mediated by Shh signaling.(Supported by start‐up funds, Zavros)
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