Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/β-catenin signaling

Egea, Virginia; Zahler, Stefan; Rieth, Nicole; Neth, Peter; Popp, Tanja; Kehe, Kai; Jochum, Marianne; Ries, Christian

doi:10.1073/pnas.1115083109

Cited by 116 publications

(111 citation statements)

References 45 publications

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“…43 Effects of TIMP-1 on proliferation and differentiation have been described for several cell types, including tumor cells, 44 neuronal cells, 45 and mesenchymal stem cells. 17 Interestingly, TIMP-1 was concurrently discovered as erythroid potentiating activity (EPA), 46 a factor that stimulated proliferation of human erythroid progenitors, 47 and this effect was found to be independent of protease inhibition. 48 Furthermore, the hematopoietic stem cell (HSC) compartment was shown to be functionally impaired in TIMP-1 knockout mice 49 and engraftment of HSPCs after BM transplantation was promoted by TIMP-1.…”

Section: Discussionmentioning

confidence: 99%

“…N-TIMP-1 is sufficient to inhibit almost the full spectrum of TIMP-1 substrates, 9 but lacks the cytokine domain. TIMP-1/T2G 16 and vvTIMP-1 17 carry amino acid mutations in the N-terminus that impair or abolish the capability to bind proteases but retain full signaling function. Adenoviral transduction of mice with these variants revealed that N-TIMP-1 did not increase, but rather slightly decreased the numbers of circulating neutrophils, indicating that MMP inhibition was not sufficient to induce neutrophilia.…”

Section: Timp-1 Signaling But Not Protease Inhibition Triggers Granulmentioning

confidence: 99%

“…9 Due to this two-pronged functional activity, TIMP-1 exerts a wide range of effects on tissue homeostasis, as well as cell behavior including inhibition of apoptosis, 13 promotion of cell proliferation and differentiation or the metastatic potential of tumor cells. 14,15 Separate investigation of the two functions of TIMP-1 can be achieved by employing variants either lacking the C-terminus (N-TIMP-1 9 ) or with mutations in the N-terminal domain that diminish protease binding but retain signaling capacity (TIMP-1/T2G, 16 vvTIMP-1 17 ). Although investigation of such variants helped to explain physiological effects of TIMP-1 in vitro, so far only limited knowledge is available on the relevance of signaling or protease inhibition for tissue homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nrent study, we investigated whether TIMP-1 affects neutrophil homeostasis. We show that TIMP-1 signaling via CD63 triggered granulopoiesis in the bone marrow (BM) resulting in increased systemic neutrophil blood counts. Our findings reveal a new function of TIMP-1 on immune cell homeostasis, and may provide a link to the frequently described correlation of high TIMP-1 levels with inflammatory diseases in the clinic. Methods Animal experimentsAnimal experiments were performed in compliance with the guidelines of the Tierschutzgesetz des Freistaates Bayern and approved by the Regierung von Oberbayern. For TIMP-1-secreting tumors, 2x10 6 HT1080 cells were subcutaneously injected into the nuchal fold of CD1 nu/nu mice and tumors were grown over ten days to a diameter of approximately 1 cm. Tumor size was monitored with a caliper. For adenoviral transduction, 3x10 9 ifu were intravenously injected, as previously described. 22 Recombinant TIMP-1 protein was applied in LPS-free PBS by a single intraperitoneal (i.p.) injection of 2 mg/kg, as previously described. 22 Mice were killed with CO 2 , blood was collected from the vena cava inferior using EDTA-coated syringes, and BM cells were obtained by flushing femurs and tibias with PBS. Flow cytometryAbsolute quantification of blood neutrophils occurred in BD trucount TM tubes according to the manufacturer´s instructions. Briefly, antibody-cocktail was mixed with 50 mL fresh blood in trucount TM tubes and incubated for 15 min at RT. Subsequently, 450 mL FACS TM lysing solution (BD Bioscience) were added and incubated for 30 min at RT to lyse erythrocytes and fix the sample. For staining of BM, femurs and tibias were flushed with PBS and the obtained cell suspension was stained as blood. Samples were measured on a FACS Canto TM II flow cytometer (BD) and analyzed using FlowJo software. Immunohistochemical staining of neutrophilsFor immunohistochemical analysis of BM, femurs were freed from tissue, fixed in 4% paraformaldehyde for 20 h, de-calcified in 0.5 M EDTA for five days, dehydrated and embedded into paraffin. Ly6G-positive cells were stained on 4 mm sections, as previously described. 22 Colony formation assayBone marrow cells were harvested from AdCtrl or AdT1-transduced mice and erythrocytes were removed with RBC lysis buffer (eBioscience). 1x10 4 BM cells were seeded in MethoCult TM medium (StemCell Technologies) containing 50 ng/mL murine rSCF, 10 ng/mL murine rIL-3, and 10 ng/mL murine rIL-6 into 6-well plates. Cells were incubated at 37°C for seven days and colonies per well were counted. For each mouse, analysis was performed in duplicates, and a total of 5 mice per group were analyzed. 32Dcl3 differentiation assay 32Dcl3 cells were seeded at a density of 8x10 5 cells/mL in IL3-free medium supplemented with 100 ng/mL murine G-CSF (Peptrotech) +/-1000 ng/mL rTIMP-1. Every two days, medium was replaced by fresh medium containing 50 ng/mL G-CSF +/-1000 ng/mL rTIMP-1. At the indicated time points, cells were c...

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Section: Discussionmentioning

confidence: 99%

Section: Timp-1 Signaling But Not Protease Inhibition Triggers Granulmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice

et al. 2015

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“…TIMPs and MMPs play a critical role in the formation, alteration, and degradation of matrix proteins [27][28][29] . TIMP-1 can combine with most MMP active sites, thus inhibiting enzyme activity [30][31] . However, some research has found that the expression of TIMP-1 is significantly higher in the scar tissue of patients with HS than in scar tissues of patients with normotrophic scars 32 .…”

Section: Discussionmentioning

confidence: 99%

Recombinant human endostatin reduces hypertrophic scar formation in rabbit ear model through down-regulation of VEGF and TIMP-1

2016

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Background: Recombinant human endostatin (Endostar) has been widely used to suppress angiogenesis in carcinoma patients. Hypertrophic scar (HS) tissue, much like a carcinoma, is often associated with angiogenesis. However, there have been few studies conducted on the effects of Endostar on HS or its mechanism. Objective: This paper investigated the effects Endostar on the HS of rabbit ears and studied the effects of Endostar on VEGF and TIMP-1 expression. Methods: Sixteen New Zealand white rabbits were used to establish HS models. Then, rabbit ears containing HS were randomly assigned to either the Endostar group or the control group. The changes of appearance and histology were evaluated using the naked eye, hematoxylin eosin staining, and a scar elevation index. The VEGF and TIMP-1 expressions were detected by immunohistochemical staining, RT-PCR, and western blot. Results: The thickness of the connective tissue in the Endostar group were thinner, the numbers of micro vessels and fibroblasts were fewer, and the collagen fibers were smoother. Moreover, the mRNA and protein expressions of VEGF and TIMP-1 in the Endostar group were significantly lower than those in the control group. Conclusion:The results suggested that Endostar reduced the formation of HS by down-regulation of VEGF and TIMP-1 expressions.

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“…In this context, several signal transduction pathways are involved in the maintenance of the stem cell fate or in triggering differentiation processes, in particular the Wnt/ β -catenin signal transduction pathway Willert et al , 2003 ;Neth et al , 2006Neth et al , , 2007Ling et al , 2009 ;Egea et al , 2012;Peröbner et al, 2012 ). In the absence of Wnt ligands, β -catenin is degraded by the destruction complex, which is formed by axin, adenomatosis polyposis coli (APC), glycogen-synthase-kinase-3 β , and casein kinase 1 α .…”

Section: Introductionmentioning

confidence: 99%

Dissecting the impact of Frizzled receptors in Wnt/β-catenin signaling of human mesenchymal stem cells

Kolben¹,

Peröbner²,

Fernsebner³

et al. 2012

Biological Chemistry

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Wnt/ β -catenin signaling is of fundamental importance in the regulation of self-renewal, migration/ invasion, and differentiation of human mesenchymal stem cells (hMSCs). Because little information is available about the function of Frizzled receptors (Fzds) as the main receptors of Wnt proteins in hMSCs, we first performed comparative Fzd mRNA expression profiling. Fzd9 and Fzd10 were not expressed in hMSCs. While Fzd3 was expressed at low levels in hMSCs, the other Fzds exhibited high expression rates. Activation and repression of Wnt signaling in hMSCs revealed that the expression levels of Fzd1, Fzd6, and Fzd7 are positively correlated with the Wnt/ β -catenin activation status, whereas Fzd8 exhibited an inverse relation. For studying the functional relevance of Fzds in Wnt/ β -catenin signaling, RNA interference, ectopic expression studies, and rescue approaches were performed in hMSCs carrying a highly sensitive TCF/LEF reporter gene system ( Gaussia luciferase). We found that, Fzd1, Fzd5, Fzd7, and Fzd8 are largely involved in Wnt/ β -catenin signaling of hMSCs. Moreover, the knockdown of Fzd5 can be compensated by the ectopic expression of Fzd7. Conversely, the ectopic expression of Fzd5 in Fzd7-knockdown hMSCs resulted in a rescue of Wnt/ β -catenin signaling, pointing to a functional redundancy of Fzd5 and Fzd7.

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Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/β-catenin signaling

Cited by 116 publications

References 45 publications

TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice

TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice

Recombinant human endostatin reduces hypertrophic scar formation in rabbit ear model through down-regulation of VEGF and TIMP-1

Dissecting the impact of Frizzled receptors in Wnt/β-catenin signaling of human mesenchymal stem cells

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