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.

Safety and Homing of Human Dental Pulp Stromal Cells in Head and Neck Cancer

“…In addition, the in vitro and in vivo migration capacity of DPSCs towards the FaDu HNSCC cell line was evaluated. As previously demonstrated for BM-MSCs (49,(66)(67)(68), FaDu cells displayed a signi cant chemoattractant effect on DPSCs in an in vitro transwell migration assay. Different administration routes have already been applied to test the in vivo tropism of MSCs towards cancer cells.…”

Hypoxia alleviates dexamethasone-induced inhibition of angiogenesis in cocultures of HUVECs and rBMSCs via HIF-1α

“…The osteogenic environment is associated with differentiated MSCs, HUVECs, and OIM. Studies have shown that many factors have a negative effect on the angiogenesis of HUVECs, including differentiated MSCs and OIM [8][9][10]. However, it is still unknown which components in OIM inhibit the angiogenesis of HUVECs.…”

Osteogenic commitment and differentiation of human mesenchymal stem cells by low‐intensity pulsed ultrasound stimulation

“…To this end, LIPUS with spatially averaged and temporally averaged (SATA) intensity of 30 mW/cm 2 was applied to hMSCs cultured in basal or osteogenic medium at different experimental time points. The MSC differentiation response to shortand long-term LIPUS stimulation was analyzed in terms of (a) changes in the expression of protein markers, through MS-based quantitative proteomic technologies, in order to identify protein networks; and (b) the modulation of different stem cell markers (CD73, CD90, CD105, OCT-3/4, NANOG, SOX2) and osteogenic pathways; both activated by LIPUS (Kuhn & Tuan, 2010;Liu & Lee, 2014;Pricola, Kuhn, Haleem-Smith, Song, & Tuan, 2009;Scherzed et al, 2016;Yoon et al, 2014).…”