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VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma.

ABSTRACT: Little is known about the factors that enable the mobilisation of human mesenchymal stem cells (MSC) from the bone marrow into the blood stream and their recruitment to and retention in the tumour. We found specific migration of MSC towards growth factors present in pancreatic tumours, such as PDGF, EGF, VEGF and specific inhibitors Glivec, Erbitux and Avastin interfered with migration. Within a few hours, MSC migrated into spheroids consisting of pancreatic cancer cells, fibroblasts and endothelial cells as measured by time-lapse microscopy. Supernatant from subconfluent MSC increased sprouting of HUVEC due to VEGF production by MSC itself as demonstrated by RT-PCR and ELISA. Only few MSCs were differentiated into endothelial cells in vitro, whereas in vivo differentiation was not observed. Lentiviral GFP-marked MSCs, injected in nude mice xenografted with orthotopic pancreatic tumours, preferentially migrated into the tumours as observed by FACS analysis of green fluorescent cells. By immunofluorescence and intravital microscopic studies, we found the interaction of MSC with the endothelium of blood vessels. Mesenchymal stem cells supported tumour angiogenesis in vivo, that is CD31(+) vessel density was increased after the transfer of MSC compared with siVEGF-MSC. Our data demonstrate the migration of MSC toward tumour vessels and suggest a supportive role in angiogenesis.

SUBMITTER: Beckermann BM

PROVIDER: S-EPMC2527820 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma.

Beckermann B M BM Kallifatidis G G Groth A A Frommhold D D Apel A A Mattern J J Salnikov A V AV Moldenhauer G G Wagner W W Diehlmann A A Saffrich R R Schubert M M Ho A D AD Giese N N Büchler M W MW Friess H H Büchler P P Herr I I

British journal of cancer 20080729 4

Little is known about the factors that enable the mobilisation of human mesenchymal stem cells (MSC) from the bone marrow into the blood stream and their recruitment to and retention in the tumour. We found specific migration of MSC towards growth factors present in pancreatic tumours, such as PDGF, EGF, VEGF and specific inhibitors Glivec, Erbitux and Avastin interfered with migration. Within a few hours, MSC migrated into spheroids consisting of pancreatic cancer cells, fibroblasts and endothe ...[more]

PMID: 18665180

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Project description:Human amniotic mesenchymal stem cells (hAMSCs) are multiple potent progenitor cells (MPCs) that can differentiate into different lineages (osteogenic, chondrogenic, and adipogenic cells) and have a favorable capacity for angiogenesis. Schnurri-3 (Shn3) is a large zinc finger protein related to Drosophila Shn, which is a critical mediator of postnatal bone formation. Bone morphogenetic protein 9 (BMP9), one of the most potent osteogenic BMPs, can strongly upregulate various osteogenesis- and angiogenesis-related factors in MSCs. It remains unclear how Shn3 is involved in BMP9-induced osteogenic differentiation coupled with angiogenesis in hAMSCs. In this investigation, we conducted a comprehensive study to identify the effect of Shn3 on BMP9-induced osteogenic differentiation and angiogenesis in hAMSCs and analyze the responsible signaling pathway. The results from in vitro and in vivo experimentation show that Shn3 notably inhibits BMP9-induced early and late osteogenic differentiation of hAMSCs, expression of osteogenesis-related factors, and subcutaneous ectopic bone formation from hAMSCs in nude mice. Shn3 also inhibited BMP9-induced angiogenic differentiation, expression of angiogenesis-related factors, and subcutaneous vascular invasion in mice. Mechanistically, we found that Shn3 prominently inhibited the expression of BMP9 and activation of the BMP/Smad and BMP/MAPK signaling pathways. In addition, we further found activity on runt-related transcription factor 2 (Runx2), vascular endothelial growth factor (VEGF), and the target genes shared by BMP and Shn3 signaling pathways. Silencing Shn3 could dramatically enhance the expression of Runx2, which directly regulates the downstream target VEGF to couple osteogenic differentiation with angiogenesis. To summarize, our findings suggested that Shn3 significantly inhibited the BMP9-induced osteogenic differentiation and angiogenesis in hAMSCs. The effect of Shn3 was primarily seen through inhibition of the BMP/Smad signaling pathway and depressed expression of Runx2, which directly regulates VEGF, which couples BMP9-induced osteogenic differentiation with angiogenesis.

Project description:Background/objectives:Accelerating the process of bone regeneration is of great interest for surgeons and basic scientists alike. Recently, umbilical cord mesenchymal stem cells (UCMSCs) are considered clinically applicable for tissue regeneration due to their noninvasive harvesting and better viability. Nonetheless, the bone regenerative ability of human UCMSCs (HUCMSCs) is largely unknown. This study aimed to investigate whether Wnt10b-overexpressing HUCMSCs have enhanced bone regeneration ability in a rat model. Method:A rat calvarial defect was performed on 8-week old male Sprague Dawley rats. Commercially purchased HUCMSCsEmp in hydrogel, HUCMSCsWnt10b in hydrogel and HUCMSCsWnt10b with IWR-1 were placed in the calvarial bone defect right after surgery on rats (N = 8 rats for each group). Calvaria were harvested for micro-CT analysis and histology four weeks after surgery. CFU-F and multi-differentiation assay by oil red staining, alizarin red staining and RT-PCR (real-time polymerase chain reaction) were performed on HUCMSCsEmp and HUCMSCsWnt10b in vitro. Conditioned media from HUCMSCsEmp and HUCMSCsWnt10b were collected and used to treat human umbilical cord vein endothelial cells in Matrigel to access vessel formation capacity by tube formation assay. Results:Alizarin red staining, oil red staining and RT-PCR results showed robust osteogenic differentiation but poor adipogenic differentiation ability of HUCMSCsWnt10b. Furthermore, HUCMSCsWnt10b could accelerate bone defect healing, which was likely due to enhanced angiogenesis after the HUCMSCsWnt10b treatment, because more CD31+ vessels and increased vascular endothelial growth factor-A (VEGF-A) expression were observed, compared with the HUCMSCsEmp treatment. Conditioned media from HUCMSCsWnt10b also induced endothelial cells to form vessel tubes in a tube formation assay, which could be abolished by SU5416, an angiogenesis inhibitor. Conclusion:To our knowledge, this is the first study providing empirical evidence that HUCMSCsWnt10b can enhance their ability to heal calvarial bone defects via VEGF-mediated angiogenesis. The translational potential of this article:HUCMSCsWnt10b can accelerate critical size calvaria and are a new promising therapeutic cell source for fracture nonunion healing.

Project description:BackgroundThe therapeutic potential of mesenchymal stem cells (MSCs) may be attributed partly to humoral factors such as growth factors, cytokines, and chemokines. Human term placental tissue-derived MSCs (PlaMSCs), or conditioned medium left over from cultures of these cells, have been reported to enhance angiogenesis. Recently, the exosome, which can transport a diverse suite of macromolecules, has gained attention as a novel intercellular communication tool. However, the potential role of the exosome in PlaMSC therapeutic action is not well understood. The purpose of this study was to evaluate PlaMSC-derived exosome angiogenesis promotion in vitro and in vivo.MethodsMSCs were isolated from human term placental tissue by enzymatic digestion. Conditioned medium was collected after 48-h incubation in serum-free medium (PlaMSC-CM). Angiogenic factors present in PlaMSC-CM were screened by a growth factor array. Exosomes were prepared by ultracentrifugation of PlaMSC-CM, and confirmed by transmission electron microscopy, dynamic light scattering, and western blot analyses. The proangiogenic activity of PlaMSC-derived exosomes (PlaMSC-exo) was assessed using an endothelial tube formation assay, a cell migration assay, and reverse transcription-PCR analysis. The in-vivo angiogenic activity of PlaMSC-exo was evaluated using a murine auricle ischemic injury model.ResultsPlaMSC-CM contained both angiogenic and angiostatic factors, which enhanced endothelial tube formation. PlaMSC-exo were incorporated into endothelial cells; these exosomes stimulated both endothelial tube formation and migration, and enhanced angiogenesis-related gene expression. Laser Doppler blood flow analysis showed that PlaMSC-exo infusion also enhanced angiogenesis in an in-vivo murine auricle ischemic injury model.ConclusionsPlaMSC-exo enhanced angiogenesis in vitro and in vivo, suggesting that exosomes play a role in the proangiogenic activity of PlaMSCs. PlaMSC-exo may be a novel therapeutic approach for treating ischemic diseases.

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VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma.

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VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma.

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