Human umbilical cord mesenchymal stem cells conditioned medium exerts anti-tumor effects on KGN cells in a cell density-dependent manner through activation of the Hippo pathway

Abstract

Background The conditioned medium from human umbilical cord mesenchymal stem cells (UCMSCs-CM) provides a new cell-free therapy for tumors due to its unique secretome. However, there are many contradictory reports about the effect of UCMSCs-CM on tumor cells. The loss of contact inhibition is a common characteristic of tumor cells. A relationship between the effect of UCMSCs-CM on tumor cells and contact inhibition in tumor cells is rarely concerned. Whether the effect of UCMSCs-CM on tumor cells is affected by cell density? Here, we explored the effect of UCMSCs-CM on granulosa tumor cell line (KGN) cells at low or high density. Methods Growth curve and CCK8 assay were used to assess cell proliferation and viability. Scratch wound and matrigel invasion assay were implicated to detect cell motility of KGN cells. UCMSCs-CM effects on cell cycle, apoptosis and pathway-related proteins were investigated by flow cytometry, TUNEL assay, western blot and immunofluorescence analysis respectively. Results In growth curve analysis, before KGN cells proliferated into confluence, UCMSCs-CM had no effect on cell proliferation. However, once the cells proliferate to contact each other, UCMSCs-CM significantly inhibited proliferation. Meanwhile, when KGN cells were implanted at high density, UCMSCs-CM could induce cell cycle arrest at G1 phase, inhibit cell migration, invasion and promote apoptosis. While it had no similar effect on KGN cells implanted at low density. In mechanism, the UCMSCs-CM treatment activated the Hippo pathway when KGN cells were implanted at high density. Consistently, the MST1/2 inhibitor, XMU-MP-1, inhibited the activation of the Hippo pathway induced by UCMSCs-CM treatment and accordingly declined the anti-tumor effect of UCMSCs-CM on KGN cells. Conclusions The effect of UCMSCs-CM on tumor cells is affected by cell density. UCMSCs-CM exerted anti-tumor effect on KGN cells by activating Hippo pathway to restore contact inhibition. Our results suggest that UCMSCs-CM is a promising therapeutic candidate for GCT treatment.

YAP represses the TEAD–NF-κB complex and inhibits the growth of clear cell renal cell carcinoma

“…Previous studies have shown that the small molecule inhibitor XMU-MP-1 selectively inhibits the activity of Hippo kinases MST1 and MST2 and upstream of LATS1/2 and, subsequently, enables YAP nuclear activity ( 34 , 35 ). We used this drug to investigate the effect of activating endogenous YAP on ccRCC cell phenotype.…”

Effect of umbilical cord mesenchymal stem cells on hypoxia-inducible factor-1 alpha (HIF-1α) production in arteriovenous fistula (AVF) animal model: A preliminary study

“…These newly formed blood vessels may support the delivery of oxygen and nutrients to the surrounding tissues, reducing hypoxia and preventing IH formation [ 20 ]. Another possible mechanism is that UC-MSCs have immunomodulatory properties [ 21 ] which are important factors in IH development by modulating the immune response and can suppress inflammation in the vessel wall [ 22 ]. This anti-inflammatory effect may prevent the activation of smooth muscle cells and the subsequent proliferation of these cells, which is a key process in IH development [ 23 ].…”

Umbilical cord mesenchymal stem cell; a potential therapy on reducing intimal hyperplasia in rabbit arteriovenous fistula (AVF) model, analysis the expression of HIF-1a, eNOS, and MMP-2

“…16 Furthermore, umbilical cord mesenchymal stem cells have been found to possess immunomodulatory properties. These cells can modulate the immune response and reduce inflammation, which are important factors in intimal hyperplasia development, 17 and it may promote vascular repair and inhibit the development of intimal hyperplasia. 18 The combination of umbilical cord mesenchymal stem cells and HIF-1α can enhance these angiogenic properties and improve the outcomes of arteriovenous fistula creation.…”