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RECK (reversion-inducing cysteine-rich protein with Kazal motifs) regulates migration, differentiation and Wnt/β-catenin signaling in human mesenchymal stem cells

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Abstract

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/β-catenin signaling pathway as indicated by reduced stability and impaired transcriptional activity of β-catenin. The latter was determined by analysis of the β-catenin target genes Dickkopf1 (DKK1), axis inhibition protein 2 (AXIN2), runt-related transcription factor 2 (RUNX2) and a luciferase-based β-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.

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Abbreviations

ALP:

Alkaline phosphatase

AXIN2:

Axis inhibition protein 2

BAR:

β-Catenin-activated reporter

COM:

Displacement of the center of mass

DKK1:

Dickkopf1

ECM:

Extracellular matrix

FMI:

Forward migration index

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

hMSC:

Human mesenchymal stem cell

LEF:

Lymphoid enhancer factor

MMP:

Matrix metalloproteinase

MSCGM:

Mesenchymal stem cell growth medium

MT1-MMP:

Membrane-type 1 matrix metalloproteinase

PPARγ:

Peroxisome proliferator-activated receptor γ

qRT-PCR:

Quantitative real-time polymerase chain reaction

RECK:

Reversion-inducing cysteine-rich protein with Kazal motifs

RUNX2:

Runt-related transcription factor 2

siRNA:

Small interfering RNA

TCF:

T cell factor

TIMP:

Tissue inhibitor of metalloproteinase

Wnt:

Wingless-type mouse mammary tumor virus integration site

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Acknowledgments

Microscopic analysis and data evaluation of the scratch assay were performed with kind help from Maximilian Saller. The BAR was established and kindly provided by Randall T. Moon (University of Washington, USA). This work was funded by grants from the Institute of Cardiovascular Prevention, Ludwig-Maximilians-University of Munich and was supported by Deutsche Forschungsgemeinschaft (SFB 1123-A1 and Z1).

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Mahl, C., Egea, V., Megens, R.T.A. et al. RECK (reversion-inducing cysteine-rich protein with Kazal motifs) regulates migration, differentiation and Wnt/β-catenin signaling in human mesenchymal stem cells. Cell. Mol. Life Sci. 73, 1489–1501 (2016). https://doi.org/10.1007/s00018-015-2054-4

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