Blood-brain barrier-on-a-chip: Microphysiological systems that capture the complexity of the blood-central nervous system interface.

The blood-brain barrier is a dynamic and highly organized structure that strictly regulates the molecules allowed to cross the brain vasculature into the central nervous system. The blood-brain barrier pathology has been associated with a number of central nervous system diseases, including vascular malformations, stroke/vascular dementia, Alzheimer's disease, multiple sclerosis, and various neurological tumors including glioblastoma multiforme. There is a compelling need for representative models of this critical interface.

Multiscale Modeling of Glioblastoma Suggests that the Partial Disruption of Vessel/Cancer Stem Cell Crosstalk Can Promote Tumor Regression Without Increasing Invasiveness.

Objective: In glioblastoma, the crosstalk between vascular endothelial cells (VECs) and glioma stem cells (GSCs) has been shown to enhance tumor growth. We propose a multiscale mathematical model to study this mechanism, explore tumor growth under various initial and microenvironmental conditions, and investigate the effects of blocking this crosstalk.

Methods: We develop a hybrid continuum-discrete model of highly organized vascularized tumors.

3D microtumors in vitro supported by perfused vascular networks.

There is a growing interest in developing microphysiological systems that can be used to model both normal and pathological human organs in vitro. This "organs-on-chips" approach aims to capture key structural and physiological characteristics of the target tissue. Here we describe in vitro vascularized microtumors (VMTs).

Three-Dimensional Adult Cardiac Extracellular Matrix Promotes Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Pluripotent stem cell-derived cardiomyocytes (CMs) have great potential in the development of new therapies for cardiovascular disease. In particular, human induced pluripotent stem cells (iPSCs) may prove especially advantageous due to their pluripotency, their self-renewal potential, and their ability to create patient-specific cell lines. Unfortunately, pluripotent stem cell-derived CMs are immature, with characteristics more closely resembling fetal CMs than adult CMs, and this immaturity has limited their use in drug screening and cell-based therapies.

Engineering anastomosis between living capillary networks and endothelial cell-lined microfluidic channels.

This paper reports a method for generating an intact and perfusable microvascular network that connects to microfluidic channels without appreciable leakage. This platform incorporates different stages of vascular development including vasculogenesis, endothelial cell (EC) lining, sprouting angiogenesis, and anastomosis in sequential order. After formation of a capillary network inside the tissue chamber via vasculogenesis, the adjacent microfluidic channels are lined with a monolayer of ECs, which then serve as the high-pressure input ("artery") and low pressure output ("vein") conduits.

Executive summary of the 11th HHT international scientific conference.

Hereditary hemorrhagic telangiectasia (HHT) is a hereditary condition that results in vascular malformations throughout the body, which have a proclivity to rupture and bleed. HHT has a worldwide incidence of about 1:5000 and approximately 80 % of cases are due to mutations in ENG, ALK1 (aka activin receptor-like kinase 1 or ACVRL1) and SMAD4. Over 200 international clinicians and scientists met at Captiva Island, Florida from June 11-June 14, 2015 to present and discuss the latest research on HHT.

A role for partial endothelial-mesenchymal transitions in angiogenesis?

The contribution of epithelial-to-mesenchymal transitions (EMT) in both developmental and pathological conditions has been widely recognized and studied. In a parallel process, governed by a similar set of signaling and transcription factors, endothelial-to-mesenchymal transitions (EndoMT) contribute to heart valve formation and the generation of cancer-associated fibroblasts. During angiogenic sprouting, endothelial cells express many of the same genes and break down basement membrane; however, they retain intercellular junctions and migrate as a connected train of cells rather than as individual cells.

A three-dimensional in vitro model of tumor cell intravasation.

Metastasis is the cause of over 90% of all human cancer deaths. Early steps in the metastatic process include: the formation of new blood vessels, the initiation of epithelial-mesenchymal transition (EMT), and the mobilization of tumor cells into the circulation. There are ongoing efforts to replicate the physiological landscape of human tumor tissue using three-dimensional in vitro culture models; however, few systems are able to capture the full range of authentic, complex in vivo events such as neovascularization and intravasation.

A strategy for integrating essential three-dimensional microphysiological systems of human organs for realistic anticancer drug screening.

Cancer is one of the leading causes of morbidity and mortality around the world. Despite some success, traditional anticancer drugs developed to reduce tumor growth face important limitations primarily due to undesirable bone marrow and cardiovascular toxicity. Many drugs fail in clinical development after showing promise in preclinical trials, suggesting that the available in vitro and animal models are poor predictors of drug efficacy and toxicity in humans.

Interferon-induced transmembrane protein 1 regulates endothelial lumen formation during angiogenesis.

Objective: It is well established that angiogenesis is a complex and coordinated multistep process. However, there remains a lack of information about the genes that regulate individual stages of vessel formation. Here, we aimed to define the role of human interferon-induced transmembrane protein 1 (IFITM1) during blood vessel formation.

Implanted cell-dense prevascularized tissues develop functional vasculature that supports reoxygenation after thrombosis.

Achieving adequate vascularization within implanted engineered tissues is a significant obstacle to maintaining viability and functionality. In vitro prevascularization of engineered tissues has been explored as a potential solution to this challenge. The traditional paradigm of in vitro prevascularization is to implant an engineered tissue with a preformed vascular network that is perfused after anastomosis with the host circulation.

Angiogenic sprouting is regulated by endothelial cell expression of Slug.

The Snail family of zinc-finger transcription factors are evolutionarily conserved proteins that control processes requiring cell movement. Specifically, they regulate epithelial-to-mesenchymal transitions (EMT) where an epithelial cell severs intercellular junctions, degrades basement membrane and becomes a migratory, mesenchymal-like cell. Interestingly, Slug expression has been observed in angiogenic endothelial cells (EC) in vivo, suggesting that angiogenic sprouting may share common attributes with EMT.

A microfluidic platform for generating large-scale nearly identical human microphysiological vascularized tissue arrays.

This paper reports a polydimethylsiloxane microfluidic model system that can develop an array of nearly identical human microtissues with interconnected vascular networks. The microfluidic system design is based on an analogy with an electric circuit, applying resistive circuit concepts to design pressure dividers in serially-connected microtissue chambers. A long microchannel (550, 620 and 775 mm) creates a resistive circuit with a large hydraulic resistance.

In vitro perfused human capillary networks.

Replicating in vitro the complex in vivo tissue microenvironment has the potential to transform our approach to medicine and also our understanding of biology. In order to accurately model the 3D arrangement and interaction of cells and extracellular matrix, new microphysiological systems must include a vascular supply. The vasculature not only provides the necessary convective transport of oxygen, nutrients, and waste in 3D culture, but also couples and integrates the responses of organ systems.

Analysis of stromal cell secretomes reveals a critical role for stromal cell-derived hepatocyte growth factor and fibronectin in angiogenesis.

Objective: Angiogenesis requires tightly coordinated crosstalk between endothelial cells (ECs) and stromal cells, such as fibroblasts and smooth muscle cells. The specific molecular mechanisms moderating this process are still poorly understood.

Methods And Results: Stromal cell-derived factors are essential for EC sprouting and lumen formation.

Full range physiological mass transport control in 3D tissue cultures.

We report the first demonstration of a microfluidic platform that captures the full physiological range of mass transport in 3-D tissue culture. The basis of our method used long microfluidic channels connected to both sides of a central microtissue chamber at different downstream positions to control the mass transport distribution within the chamber. Precise control of the Péclet number (Pe), defined as the ratio of convective to diffusive transport, over nearly five orders of magnitude (0.

Macrophages and angiogenesis: a role for Wnt signaling.

Macrophages regulate many developmental and pathological processes in both embryonic and adult tissues, and recent studies have shown a significant role in angiogenesis. Similarly, Wnt signaling is fundamental to tissue morphogenesis and also has a role in vascular development. In this review, we summarize recent advances in the field of macrophage-regulated angiogenesis, with a focus on the role of macrophage-derived Wnt ligands.

BMP9 induces EphrinB2 expression in endothelial cells through an Alk1-BMPRII/ActRII-ID1/ID3-dependent pathway: implications for hereditary hemorrhagic telangiectasia type II.

ALK1 (ACVRL1) is a member of the TGFβ receptor family and is expressed predominantly by arterial endothelial cells (EC). Mutations in ACVRL1 are responsible for hereditary hemorrhagic telangiectasia type 2 (HHT2), a disease manifesting as fragile vessels, capillary overgrowth, and numerous arterio-venous malformations. Arterial EC also express EphrinB2, which has multiple roles in vascular development and angiogenesis and is known to be reduced in ACVRL1 knockout mice.

Longitudinal in vivo imaging to assess blood flow and oxygenation in implantable engineered tissues.

The functionality of vascular networks within implanted prevascularized tissues is difficult to assess using traditional analysis techniques, such as histology. This is largely due to the inability to visualize hemodynamics in vivo longitudinally. Therefore, we have developed dynamic imaging methods to measure blood flow and hemoglobin oxygen saturation in implanted prevascularized tissues noninvasively and longitudinally.

Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) [corrected] is a vascular dysplasia syndrome caused by mutations in transforming growth factor-β/bone morphogenetic protein pathway genes, ENG and ACVRL1. HHT [corrected] shows considerable variation in clinical manifestations, suggesting environmental and/or genetic modifier effects. Strain-specific penetrance of the vascular phenotypes of Eng(+/-) and Tgfb1(-/-) mice provides further support for genetic modification of transforming growth factor-β pathway deficits.

The requirement for fibroblasts in angiogenesis: fibroblast-derived matrix proteins are essential for endothelial cell lumen formation.

A role for fibroblasts in physiological and pathological angiogenesis is now well recognized; however, the precise mechanisms underlying their action have not been determined. Using an in vitro angiogenesis model in combination with a candidate gene approach, column chromatography, and mass spectrometry, we identify two classes of fibroblast-derived factors--one that supports vessel sprouting but not lumen formation, and one that promotes lumen formation. In the absence of fibroblasts a combination of angiopoietin-1, angiogenin, hepatocyte growth factor, transforming growth factor-α, and tumor necrosis factor drives robust endothelial cell (EC) sprouting; however, lumens fail to form.