TY - JOUR TI - Heterogeneous Glioma Cell Invasion Under Interstitial Flow Depending on Their Differentiation Status AU - Namba, Naoko AU - Chonan, Yuta AU - Nunokawa, Takehito AU - Sampetrean, Oltea AU - Saya, Hideyuki AU - Sudo, Ryo T2 - Tissue Engineering Part A AB - Glioblastoma (GBM) is the most common and lethal type of malignant brain tumor. A deeper mechanistic understanding of the invasion of heterogeneous GBM cell populations is crucial to develop therapeutic strategies. A key regulator of GBM cell invasion is interstitial flow. However, the effect of an interstitial flow on the invasion of heterogeneous GBM cell populations composed of glioma initiating cells (GICs) and relatively differentiated progeny cells remains unclear. In the present study, we investigated how GICs invade three-dimensional (3D) hydrogels in response to an interstitial flow with respect to their differentiation status. Microfluidic culture systems were used to apply an interstitial flow to the cells migrating from the cell aggregates into the 3D hydrogel. Phase-contrast microscopy revealed that the invasion and protrusion formation of the GICs in differentiated cell conditions were significantly enhanced by a forward interstitial flow, whose direction was the same as that of the cell invasion, whereas those in stem cell conditions were not enhanced by the interstitial flow. The mechanism of flow-induced invasion was further investigated by focusing on differentiated cell conditions. Immunofluorescence images revealed that the expression of cell–extracellular matrix adhesion-associated molecules, such as integrin β1, focal adhesion kinase, and phosphorylated Src, was upregulated in forward interstitial flow conditions. We then confirmed that cell invasion and protrusion formation were significantly inhibited by PP2, a Src inhibitor. Finally, we observed that the flow-induced cell invasion was preceded by nestin-positive immature GICs at the invasion front and followed by tubulin β3-positive differentiated cells. Our findings provide insights into the development of novel therapeutic strategies to inhibit flow-induced glioma invasion. DA - 2021/01/06/ PY - 2021 DO - 10.1089/ten.tea.2020.0280 DP - liebertpub.com (Atypon) SN - 1937-3341 UR - https://www.liebertpub.com/doi/10.1089/ten.tea.2020.0280 Y2 - 2021/02/24/18:54:17 ER -