title: The differentiation of hMSCs counteracts their migration capability and pro-angiogenic effects in vitro.
abstract: Human mesenchymal stem cells (hMSCs) have been applied therapeutically in numerous clinical trials. The pro-angiogenic effects of hMSCs, as well as their strong tumor tropism, have been shown both in vitro and in vivo. Some studies suggest using hMSCs as potential drug-carriers for tumor therapy. In previous investigations by our group, the pro-tumorigenic effects of hMSCs on head and neck squamous cell carcinoma (HNSCC) were shown. However, the influence of hMSCs on tumor vascularization as well as the possibility of its inhibition are yet to be elucidated. The cytokine patterns of the HNSCC cell line FaDu, native hMSCs (hMSCs-nat), hMSCs differentiated into adipocytes (hMSCs-adip) and osteocytes (hMSCs-ost) were evaluated. Human umbilical vein endothelial cells (HUVECs) were co-cultured with FaDu cells, hMSCs-nat, hMSCs-adip and hMSCs-ost. The capillary tube formation assay was applied. Furthermore, the migration capability of hMSCs-nat, hMSCs-adip and hMSCs-ost towards FaDu cells was measured in a Transwell system. Spheroids were cultured from hMSCs-nat, FaDu cells and DiI-labeled HUVECs. FaDu cells, hMSCs-nat, hMSCs-adip and hMSCs-ost released a wide range of cytokines and growth factors, e.g., IL-6, IL-8, IL-10, GRO and MCP. In the capillary tube formation assay, HUVECs generated significantly longer tubes after co-cultivation with hMSCs-nat as compared to HUVECs alone and FaDu. Differentiation into adipocytes and osteocytes counteracted the tube formation. The adipogenic differentiation did not alter hMSC motility, whereas osteogenic differentiation significantly inhibited hMSC migration. Generation of multi-cellular spheroids from hMSCs-nat, FaDu cells and DiI-labeled HUVECs was possible. Florescence microscopy revealed that all HUVECs were present in the spheroid core. Taken together, hMSCs-nat have a pro-angiogenic effect. The effects are counteracted by the differentiation of hMSCs towards osteogenic and adipogenic lineages. The differentiation of stem cells into different lineages may be a promising solution to generating carriers for cancer therapy without pro-tumorigenic properties.
authors.affiliation: Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D‑97080 Wuerzburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Scherzed
authors.affiliation: Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D‑97080 Wuerzburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Hackenberg
authors.affiliation: Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D‑97080 Wuerzburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Froelich
authors.affiliation: Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D‑97080 Wuerzburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Rak
authors.affiliation: Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D‑97080 Wuerzburg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Schendzielorz
authors.affiliation: Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D‑97080 Wuerzburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Gehrke
authors.affiliation: Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D‑97080 Wuerzburg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Hagen
authors.affiliation: Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D‑97080 Wuerzburg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Kleinsasser
mesh_terms: D050156:Adipogenesis; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000276:immunology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000276:immunology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D066298:In Vitro Techniques; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000276:immunology; D018919:Neovascularization, Physiologic; D010012:Osteogenesis; D018874:Spheroids, Cellular / Q000166:cytology / Q000276:immunology; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D016207:Cytokines