Tumor Vessels Fuel the Fire in Glioblastoma

Glioblastoma, a subset of aggressive brain tumors, deploy several means to increase blood vessel supply dedicated to the tumor mass. This includes typical program borrowed from embryonic development, such as vasculogenesis and sprouting angiogenesis, as well as unconventional processes, including co-option, vascular mimicry, and transdifferentiation, in which tumor cells are pro-actively engaged. However, these neo-generated vascular networks are morphologically and functionally abnormal, suggesting that the vascularization processes are rather inefficient in the tumor ecosystem. In this review, we reiterate the specificities of each neovascularization modality in glioblastoma, and, how they can be hampered mechanistically in the perspective of anti-cancer therapies.     

Association between erythrocyte dynamics and vessel remodelling in developmental vascular networks

Sprouting angiogenesis is an essential vascularization mechanism consisting of sprouting and remodelling. The remodelling phase is driven by rearrangements of endothelial cells (ECs) within the post-sprouting vascular plexus. Prior work has uncovered how ECs polarize and migrate in response to flow-induced wall shear stress (WSS). However, the question of how the presence of erythrocytes (widely known as red blood cells (RBCs)) and their impact on haemodynamics affect vascular remodelling remains unanswered. Here, we devise a computational framework to model cellular blood flow in developmental mouse retina. We demonstrate a previously unreported highly heterogeneous distribution of RBCs in primitive vasculature. Furthermore, we report a strong association between vessel regression and RBC hypoperfusion, and identify plasma skimming as the driving mechanism. Live imaging in a developmental zebrafish model confirms this association. Taken together, our results indicate that RBC dynamics are fundamental to establishing the regional WSS differences driving vascular remodelling via their ability to modulate effective viscosity.     

Mechanotransduction and blood fluid dynamics in developing blood vessels

The vascular endothelium is the interface in the cardiovascular system between the blood vessel wall and the flowing blood. As such, these cells are exposed to both shear stress and circumferential stretch. Though a lot is known about the regulation of gene expression by flow in mature vascular networks, very little is known in developing vessels. Most vascular networks in the adult are homeostatic, exhibiting very low rates of endothelial cell replication and turnover. In disease states such as cancer or macular degeneration, the vascular system is able to recapitulate embryonic growth and reinduce blood vessel growth. The vasculature that develops is similar to the embryonic vasculature, and so many have used knowledge of embryonic development to interpret pathological blood vessel growth. It was believed until recently that the embryonic vasculature was not sensitive to flow. We recently showed that shear stress is necessary for proper vascular development. We therefore review the role of blood flow and mechanical forces in vascular development. We examine the pattern and magnitude of flow present in primitive vascular networks as well as exploring gene regulation by shear stress in both in vitro and in vivo embryonic systems.     

Hierarchically Assembled Mesenchymal Stem Cell Spheroids Using Biomimicking Nanofilaments and Microstructured Scaffolds for Vascularized Adipose Tissue Engineering

Composite multicellular spheroids composed of mesenchymal stem cells (MSCs) and synthetic biodegradable nanofilaments are fabricated. Extracellular‐matrix‐mimicking nanofilaments, prepared from transverse fragmentation of semicrystalline poly(L ‐lactic acid) nanofibers and subsequent surface modification with cell adhesive peptides, are used to form composite multicellular spheroids with MSCs by cellular self‐assembly. The size of the composite spheroids could be readily controlled with the integrated amount of the nanofilaments. The composite spheroids show enhanced adipogenic potential compared to homotypic spheroids. The resultant spheroids are used as building blocks for 3D biohybrid construction with the assistance of a microstructured scaffold fabricated by a direct polymer melt deposition process. An angiogenic growth factor, basic fibroblast growth factor, is also locally delivered in a sustained fashion from the heparinized scaffold surface for facile neovascularization of adipogenic tissue. The produced multiscaled and multifunctional hybrid MSC construct enable the successful formation of vascularized adipose tissue in vivo.     

EPCs与NSCs共移植对MCAO模型大鼠神经功能缺损恢复影响

目的：将体外培养的EPCs与NSCs共移植体移入MCAO模型大鼠脑内,观察缺血区血管新生和神经功能缺损修复情况。方法;选择240只SD大鼠随机分为假手术组、MCAO组、MCAO＋NSCs组、MCAO＋EPCs组、MCAO＋EPCs和NSCs共移值体组,在1d、3d、7d、14d、30d、60d各时间点观察各组脑缺血半暗区微血管密度和大鼠的电生理指标（运动诱发电位）及行为学（mNSS改良神经功能评分）。结果：MCAO＋NSCs组的微血管密度与MCAO组在各时间点无差别;MCAO＋EPCs组、MCAO＋EPCs和NSCs共移值体组的微血管密度除1d外其他各时间点均高于MCAO组。在7d后MCAO＋NSCs组、MCAO＋EPCs组、MCAO＋共移植体组运动诱发电位与缺血对照组有差异,MCAO＋共移植体组差异最大。MCAO＋EPCs组、MCAO＋共移值体组与MCAO照组相比在3d后有差异,MCAO＋共移植体组差异最大。结论：EPCs与NSCs共移植体移入MCAO模型大鼠脑内,可增加其缺血半暗区血管新生,促进神经功能的进一步恢复。     

Mixed‐Ligand Mononuclear Copper(II) Complex: Crystal Structure and Anticancer Activity

A novel copper(II) complex with mixed ligands including β‐[(3‐formyl‐5‐methyl‐2‐hydroxy‐benzylidene)amino]propionic acid anion and 1,10′‐phenanthroline was synthesized, and its crystal structure was thoroughly characterized. It exerted excellent inducing apoptosis, anti‐angiogenesis and antiproliferative properties in vitro. The complex can bind human serum albumin (HSA) at physiological pH conditions. Remarkably, it can induce formation of the mixed parallel/antiparallel G‐quadruplex structures in the G‐rich sequence of the proximal vascular endothelial growth factor (VEGF) promoter, and stabilize these G‐quadruplex structures, which provide an opportunity for anti‐angiogenesis chemotherapeutics. Furthermore, the complex showed a strong uptake, and exhibited multiple anticancer functions by inhibiting the expression of p‐Akt and p‐Erk1/2 proteins and by upregulating the levels of reactive oxygen species (ROS). Because of the reported results, this new copper(II) complex qualifies itself as a potential anticancer drug candidate.     

Capillary Network‐Like Organization of Endothelial Cells in PEGDA Scaffolds Encoded with Angiogenic Signals via Triple Helical Hybridization

Survival of tissue engineered constructs after implantation depends on proper vascularization. The differentiation of endothelial cells into mature microvasculature requires dynamic interactions between cells, scaffold, and growth factors, which are difficult to recapitulate in artificial systems. Previously, photocrosslinked poly(ethylene glycol) diacrylate (PEGDA) hydrogels displaying collagen mimetic peptides (CMPs), dubbed PEGDA‐CMP, that can be further conjugated with bioactive molecules via CMP‐CMP triple helix hybridization were reported. Here, it is shown that a bifunctional peptide featuring pro‐angiogenic domain mimicking vascular endothelial growth factor (VEGF) and a collagen mimetic domain that can fold into a triple helix conformation can hybridize with CMP side chains of the PEGDA‐CMP hydrogel, which results in presentation of insoluble VEGF‐like signals to endothelial cells. Presentation of VEGF‐like signals on the surface of micropatterned scaffolds in this way transforms cells from a quiescent state to elongated and aligned phenotype suggesting that this system could be used to engineer organized microvasculature. It is also shown that the pro‐angiogenic peptide, when applied topically in combination with modified dextran/PEGDA hydrogels, can enhance neovascularization of burn wounds in mice demonstrating the potential clinical use of CMP‐mediated matrix‐bound bioactive molecules for dermal injuries.