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Sonic Hedgehog signaling mediates bone marrow‐derived mesenchymal stem cell proliferation and recruitment
Author(s) -
Donnelly Jessica M,
Chawla Ambreesh,
Houghton JeanMarie,
Zavros Yana
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1007.8
Subject(s) - mesenchymal stem cell , cyclopamine , microbiology and biotechnology , cancer research , sonic hedgehog , hedgehog , chemokine , bone marrow , cell growth , hedgehog signaling pathway , biology , chemistry , immunology , signal transduction , inflammation , biochemistry
Objective Bone 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. Methods MSCs transduced with lentiviral particles expressing shRNA for Shh (MSCs ShhKO ) or empty vector (MSCs Vect ) 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 MSCs ShhKO and MSCs Vect . Results IFNγ significantly increased MSC proliferation, a response mediated by the secretion of Shh from cultured cells and blocked by Hedgehog signaling inhibitor cyclopamine. MSCs ShhKO were arrested in G 0 /G 1 phase compared to MSCs Vect . Mice injected with IFNγ showed significant recruitment of RFP‐tagged MSCs to the gastric mucosa. Compared to MSCs Vect , MSCs ShhKO failed to migrate toward the SDF‐1α reflected by decreased CXCR4 expression. Conclusion IFNγ induces proliferation and initiates recruitment of MSCs, a mechanism mediated by Shh signaling. (Supported by start‐up funds, Zavros)