Inflammatory Chemokines MIP-1δ and MIP-3α Are Involved in the Migration of Multipotent Mesenchymal Stromal Cells Induced by Hepatoma Cells

Lejmi, Esma; Perriraz, Nadja; Clément, Sophie; Morel, Philippe; Baertschiger, Reto M.; Christofilopoulos, Panayiotis; Meier, Raphaël; Bosco, Domenico; Bühler, Léo H.; Gonelle‐Gispert, Carmen

doi:10.1089/scd.2014.0176

Cited by 32 publications

(23 citation statements)

References 82 publications

(105 reference statements)

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“…Both histological and FACS analysis showed that significantly fewer hMSCs localized within 97H‐CCL15‐shRNA xenografts compared with 97H‐GFP xenografts after intravenous delivery, demonstrating a direct and specific role of CCL15 in hMSCs trafficking to HCC tumors in vivo. Just recently, Lejmi et al also reported that MIP‐1δ/CCL15 and MIP‐3α/CCL20 can promote the directed migration of hMSCs to HCC cells in vitro . The results of our study help to further clarify the molecular signaling mechanism underlying the homing capacity of hMSCs toward tumors.…”

Section: Discussionsupporting

confidence: 66%

Chemokine CCL15 Mediates Migration of Human Bone Marrow-Derived Mesenchymal Stem Cells Toward Hepatocellular Carcinoma

Gao

Zhou

et al. 2016

Stem Cells

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Mesenchymal stem cells (MSCs) possess the ability to migrate toward tumor sites and are regarded as promising gene delivery vehicles for cancer therapeutics. However, the factors that mediate this tropism have yet to be completely elucidated. In this study, through cytokine array analysis, chemokine CCL15 was found to be the most abundant protein differentially expressed in hepatocellular carcinoma (HCC) cell lines compared with a normal liver cell line. Serum CCL15 levels in HCC patients determined by enzyme linked immunosorbent assay were shown to be profoundly elevated compared with healthy controls. Immunohistochemical analysis indicated that CCL15 expression was much stronger in HCC tumor tissues than in adjacent nontumor tissues. Transwell migration assay suggested that CCL15 may be involved in chemotaxis of human MSCs (hMSCs) toward HCC in vitro and that this chemotactic effect of CCL15 is mediated via CCR1 receptors on hMSCs. Orthotopic animal models of HCC were established to investigate the role of CCL15 in hMSCs migration toward HCC in vivo. Both histological and flow cytometric analysis showed that significantly fewer hMSCs localized within 97H-CCL15-shRNA xenografts compared with 97H-green fluorescent protein xenografts after intravenous delivery. Finally, the possible effects of hMSCs on HCC tumor growth were also evaluated. Coculture experiments showed that hMSCs had no apparent effect on the proliferation of HCC cells in vitro In addition, systemic administration of hMSCs did not affect HCC tumor progression in vivo. Our data in this study help to elucidate the mechanism underlying the homing capacity of hMSCs toward HCC. STEM CELLS 2016;34:1112-1122 SIGNIFICANCE STATEMENTMesenchymal stem cells (MSCs) possess the ability to migrate toward tumor sites and are regarded as promising gene delivery vehicles for cancer therapeutics. In this study, HCC-derived CCL15 was demonstrated to be a chemoattractant for MSCs both in vitro and in vivo, and that this tropism of hMSCs for HCC is mainly mediated through the CCL15/CCR1 axis. Our data in the present study help to elucidate the mechanism underlying the homing capacity of hMSCs toward HCC and may be exploited to improve the therapeutic efficacy of hMSCs in the treatment of HCC.

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Section: Discussionsupporting

confidence: 66%

Chemokine CCL15 Mediates Migration of Human Bone Marrow-Derived Mesenchymal Stem Cells Toward Hepatocellular Carcinoma

Gao

Zhou

et al. 2016

Stem Cells

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“…After binding with its receptors, it is involved in the body's allergic reaction (28)(29)(30)(31). Most importantly, CCL4 and CCL13 have been revealed to enhance the migration of MSCs (32,33). Therefore, it was hypothesized that HMGB1 may enhance MSC migration by promoting the synthesis of CCL4 and CCL13, which would increase the mobility of MSCs.…”

Section: Discussionmentioning

confidence: 99%

HMGB1 promotes cellular chemokine synthesis and potentiates mesenchymal stromal cell migration via Rap1 activation

Lin

Xue

Xie

et al. 2016

Molecular Medicine Reports

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The migration of mesenchymal stem cells (MSCs) and osteogenic differentiation occupy an important role in fracture healing. High mobility group box 1 (HMGB1), a widely distributed inflammatory factor in fractures, has been confirmed to act as a chemoattractant to MSCs. To investigate the effect of HMGB1 on MSC migration and the underlying mechanism, the synthesis of MSC chemokines, and the consequent activation of signaling pathways following HMGB1 stimulation, were evaluated. A Quantibody® array was performed to determine which chemokines were secreted from MSCs with or without treatment with HMGB1. The results indicated differential chemokine synthesis by MSCs following treatment with HMGB1, including that of CCL4 and CCL13. In addition, the Ras‑associated protein‑1 (Rap1) signaling pathway was markedly activated in the HMGB1‑treated groups, suggesting that HMGB1 may enhance the migrational ability of MSCs via Rap1 activation. Furthermore, HMGB1 was able to promote the secretion of various chemokines derived from MSCs, which would, in turn, increase the mobility of MSCs. Taken together, these results provide a mechanistic basis for developing novel approaches to promote fracture healing.

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“…Informed consent was given by all patients and the experimental procedure was approved by the local ethical committee of the University Hospitals of Geneva (NAC 01-015). Briefly, MSC were purified from crushed bone marrow by gradient centrifugation, and then cultured in Iscove’s modified Dulbecco’s medium (Cambrex, Verviers, Belgium) supplemented with 10% FCS, P-S, and 10 ng/ml platelet-derived growth factor BB (PDGF-BB; PeproTech EC Ltd, London, UK) [ 28 ]. MSC from three different donors between passages 2 and 4 were used and were cultured at 37 °C in humidified air containing 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Multipotent mesenchymal stromal cells enhance insulin secretion from human islets via N-cadherin interaction and prolong function of transplanted encapsulated islets in mice

et al. 2017

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BackgroundMultipotent mesenchymal stromal cells (MSC) enhance viability and function of islets of Langerhans. We aimed to examine the interactions between human MSC and human islets of Langerhans that influence the function of islets.MethodsHuman MSC and human islets (or pseudoislets, obtained after digestion and reaggregation of islet cells) were cocultured with or without cellular contact and glucose-stimulated insulin secretion assays were performed to assess cell function. The expression of several adhesion molecules, notably ICAM-1 and N-cadherin on islets and MSC, was investigated by qPCR. The role of N-cadherin was analyzed by adding an anti-N-cadherin antibody in islets cultured with or without MSC for 24 h followed by insulin measurements in static incubation assays. Islets and MSC were coencapsulated in new hydrogel microspheres composed of calcium alginate and covalently crosslinked polyethylene glycol. Encapsulated cells were transplanted intraperitoneally in streptozotocin-induced diabetic mice and glycemia was monitored. Islet function was evaluated by the intraperitoneal glucose tolerance test.ResultsIn vitro, free islets and pseudoislets cocultured in contact with MSC showed a significantly increased insulin secretion when compared to islets or pseudoislets cultured alone or cocultured without cell-to-cell contact with MSC (p < 0.05). The expression of ICAM-1 and N-cadherin was present on islets and MSC. Blocking N-cadherin prevented the enhanced insulin secretion by islets cultured in contact with MSC whereas it did not affect insulin secretion by islets cultured alone. Upon transplantation in diabetic mice, islets microencapsulated together with MSC showed significantly prolonged normoglycemia when compared with islets alone (median 69 and 39 days, respectively, p < 0.01). The intraperitoneal glucose tolerance test revealed an improved glycemic response in mice treated with islets microencapsulated together with MSC compared to mice transplanted with islets alone (p < 0.001).ConclusionsMSC improve survival and function of islets of Langerhans by cell-to-cell contact mediated by the adhesion molecule N-cadherin.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0646-7) contains supplementary material, which is available to authorized users.

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Inflammatory Chemokines MIP-1δ and MIP-3α Are Involved in the Migration of Multipotent Mesenchymal Stromal Cells Induced by Hepatoma Cells

Cited by 32 publications

References 82 publications

Chemokine CCL15 Mediates Migration of Human Bone Marrow-Derived Mesenchymal Stem Cells Toward Hepatocellular Carcinoma

Chemokine CCL15 Mediates Migration of Human Bone Marrow-Derived Mesenchymal Stem Cells Toward Hepatocellular Carcinoma

HMGB1 promotes cellular chemokine synthesis and potentiates mesenchymal stromal cell migration via Rap1 activation

Multipotent mesenchymal stromal cells enhance insulin secretion from human islets via N-cadherin interaction and prolong function of transplanted encapsulated islets in mice

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