Coaxially Bioprinted Cell-Laden Tubular-Like Structure for Studying Glioma Angiogenesis

Abstract

Glioblastomas are the most frequently diagnosed and one of the most lethal primary brain tumors, and one of their key features is a dysplastic vascular network. However, because the origin of the tumor blood vessels remains controversial, an optimal preclinical tumor model must be established to elucidate the tumor angiogenesis mechanism, especially the role of tumor cells themselves in angiogenesis. Therefore, shell-glioma cell (U118)-red fluorescent protein (RFP)/core-human umbilical vein endothelial cell (HUVEC)-green fluorescent protein (GFP) hydrogel microfibers were coaxially bioprinted. U118–RFP and HUVEC–GFP cells both exhibited good proliferation in a three-dimensional (3D) microenvironment. The secretability of both vascular endothelial growth factor A and basic fibroblast growth factor was remarkably enhanced when both types of cells were cocultured in 3D models. Moreover, U118 cells promoted the vascularization of the surrounding HUVECs by secreting vascular growth factors. More importantly, U118–HUVEC-fused cells were found in U118–RFP/HUVEC–GFP hydrogel microfibers. Most importantly, our results indicated that U118 cells can not only recruit the blood vessels of the surrounding host but also directly transdifferentiate into or fuse with endothelial cells to participate in tumor angiogenesis in vivo. The coaxially bioprinted U118–RFP/HUVEC–GFP hydrogel microfiber is a model suitable for mimicking the glioma microenvironment and for investigating tumor angiogenesis.

Applications of 3D Bioprinting Technology to Brain Cells and Brain Tumor Models: Special Emphasis to Glioblastoma

“…It was found that 22% and 78% of the tumor CD105+ cells were human and mouse origin, respectively, suggesting that cancer cells can recruit host vascular endothelial cells to be involved in tumor angiogenesis as well as directly taking part in the angiogenesis themselves. Tubule-like forms containing endothelial/glial phenotypic cells were also detected in xenograft tumors indicating that U118 cells could transdifferentiate or fuse with endothelial cells to play a role in tumor angiogenesis (Figure E,F) …”

“…Tubule-like forms containing endothelial/glial phenotypic cells were also detected in xenograft tumors indicating that U118 cells could transdifferentiate or fuse with endothelial cells to play a role in tumor angiogenesis (Figure 5E,F). 152 Glioma and GSCs promote glioma angiogenesis by converting into endothelial cells or excreting VEGF. 32 A study examined the role of GSCs in tumor vascularization on the GSC tumor model which was developed using a 3D multinozzle bioprinter.…”

“…A recent study elucidated the influences of bioprinted GBM cells on the vascularization potential of endothelial cells and their involvement in angiogenesis. 152 Coaxial extrusion bioprinting was employed to fabricate core–shell hydrogel microfibers whose inner core consists of HUVECSs in collagen and outer layer includes human GBM (U118) cells in sodium alginate ( Figure 5 A,B). Using these cells together caused a higher proliferation rate than culturing these cells individually.…”

“…Tubule-like forms containing endothelial/glial phenotypic cells were also detected in xenograft tumors indicating that U118 cells could transdifferentiate or fuse with endothelial cells to play a role in tumor angiogenesis ( Figure 5 E,F). 152 …”

“…(E, F) Illustration of tubular structures formed in the microfiber. Reproduced with permission from ref ( 152 ). Open Access.…”