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Cellular and Molecular Life Sciences

, Volume 73, Issue 7, pp 1489–1501 | Cite as

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

  • Christian Mahl
  • Virginia Egea
  • Remco T. A. Megens
  • Thomas Pitsch
  • Donato Santovito
  • Christian Weber
  • Christian RiesEmail author
Original Article

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.

Keywords

RECK hMSC Chemotactic migration Osteogenic differentiation Canonical Wnt/β-catenin signaling 

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

Notes

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).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Basel 2015

Authors and Affiliations

  • Christian Mahl
    • 1
  • Virginia Egea
    • 1
  • Remco T. A. Megens
    • 1
    • 2
  • Thomas Pitsch
    • 1
  • Donato Santovito
    • 1
  • Christian Weber
    • 1
    • 2
    • 3
  • Christian Ries
    • 1
    Email author
  1. 1.Institute for Cardiovascular PreventionLudwig-Maximilians-University of MunichMunichGermany
  2. 2.Cardiovascular Research Institute MaastrichtMaastricht UniversityMaastrichtThe Netherlands
  3. 3.German Centre for Cardiovascular ResearchPartner Site Munich Heart AllianceMunichGermany

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