Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 73, Issue 7, Pages 1489-1501Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-015-2054-4
Keywords
RECK; hMSC; Chemotactic migration; Osteogenic differentiation; Canonical Wnt/beta-catenin signaling
Categories
Funding
- Institute of Cardiovascular Prevention, Ludwig-Maximilians-University of Munich
- Deutsche Forschungsgemeinschaft [SFB 1123-A1, SFB 1123-Z1]
Ask authors/readers for more resources
The membrane-anchored glycoprotein RECK (reversion-inducing cysteine-rich protein with Kazal motifs) inhibits expression and activity of certain matrix metalloproteinases (MMPs), thereby suppressing tumor cell metastasis. However, RECK's role in physiological cell function is largely unknown. Human mesenchymal stem cells (hMSCs) are able to differentiate into various cell types and represent promising tools in multiple clinical applications including the regeneration of injured tissues by endogenous or transplanted hMSCs. RNA interference of RECK in hMSCs revealed that endogenous RECK suppresses the transcription and biosynthesis of tissue inhibitor of metalloproteinases (TIMP)-2 but does not influence the expression of MMP-2, MMP-9, membrane type (MT)1-MMP and TIMP-1 in these cells. Knockdown of RECK in hMSCs promoted monolayer regeneration and chemotactic migration of hMSCs, as demonstrated by scratch wound and chemotaxis assay analyses. Moreover, expression of endogenous RECK was upregulated upon osteogenic differentiation and diminished after adipogenic differentiation of hMSCs. RECK depletion in hMSCs reduced their capacity to differentiate into the osteogenic lineage whereas adipogenesis was increased, demonstrating that RECK functions as a master switch between both pathways. Furthermore, knockdown of RECK in hMSCs attenuated the Wnt/beta-catenin signaling pathway as indicated by reduced stability and impaired transcriptional activity of beta-catenin. The latter was determined by analysis of the beta-catenin target genes Dickkopf1 (DKK1), axis inhibition protein 2 (AXIN2), runt-related transcription factor 2 (RUNX2) and a luciferase-based beta-catenin-activated reporter (BAR) assay. Our findings demonstrate that RECK is a regulator of hMSC functions suggesting that modulation of RECK may improve the development of hMSC-based therapeutical approaches in regenerative medicine.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available