title: WISP 1 is an important survival factor in human mesenchymal stromal cells.
abstract: WNT-induced secreted protein 1 (WISP1/CCN4), a member of the CCN protein family, acts as a downstream factor of the canonical WNT signaling pathway. Its expression is known to affect proliferation and differentiation of human mesenchymal stromal cells (hMSCs), which are fundamental for the development and maintenance of the musculoskeletal system. Whereas a dysregulated, excessive expression of WISP1 often reflects its oncogenic potential via the inhibition of apoptosis, our study emphasizes the importance of WISP1 signaling for the survival of primary human cells. We have established the efficient and specific down-regulation of endogenous WISP1 transcripts by gene silencing in hMSCs and observed cell death as a consequence of WISP1 deficiency. This was confirmed by Annexin V staining for apoptotic cells. DNA microarray analyses of WISP1 down-regulated versus control samples revealed several clusters of differentially expressed genes important for apoptosis induction such as TNF-related apoptosis-inducing ligand 1 (TRAIL) and the corresponding apoptosis-inducing receptors TRAIL-R1 and -R2. An increased expression of TRAIL and its receptors TRAIL-R1 and -R2 in WISP1-deficient hMSCs was confirmed by immunocytofluorescence. Accordingly, WISP1 deficiency is likely to cause TRAIL-induced apoptosis. This is an important novel finding, which suggests that WISP1 is indispensable for the protection of healthy hMSCs against TRAIL-induced apoptosis.
authors.affiliation: Orthopedic Center for Musculoskeletal Research, University of Würzburg, Germany. Electronic address: katrin.schlegelmilch@fmz.uni-wuerzburg.de.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schlegelmilch
authors.affiliation: DNA-Analytics Core Facility, Biocenter and Department of Animal Ecology and Tropical Biology, University of Würzburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Keller
authors.affiliation: Orthopedic Center for Musculoskeletal Research, University of Würzburg, Germany.
authors.forename: Viola
authors.initials: V
authors.lastname: Zehe
authors.affiliation: Orthopedic Center for Musculoskeletal Research, University of Würzburg, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Hondke
authors.affiliation: Orthopedic Center for Musculoskeletal Research, University of Würzburg, Germany.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Schilling
authors.affiliation: Orthopedic Center for Musculoskeletal Research, University of Würzburg, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Jakob
authors.affiliation: Center for Medical Biotechnology, University of Duisburg-Essen, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Klein-Hitpass
authors.affiliation: Orthopedic Center for Musculoskeletal Research, University of Würzburg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Schütze
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D055511:CCN Intercellular Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D063990:Gene Ontology; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D018613:Microscopy, Confocal; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D016877:Oxidants / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; D016877:Oxidants; D011518:Proto-Oncogene Proteins; D006861:Hydrogen Peroxide
keywords: Apoptosis; Cancer; Death receptors; Human stem cell; Musculoskeletal system; TRAIL; WNT-signalling