A neurovascular-unit-on-a-chip for the evaluation of the restorative potential of stem cell therapies for ischaemic stroke

Lyu, Zhonglin; Park, Jon; Kim, Kwangmin; Jin, Hye-jin; Wu, Haodi; Rajadas, Jayakumar; Kim, Deok Ho; Steinberg, Gary K.; Lee, Wonjae

doi:10.1038/s41551-021-00744-7

Cited by 74 publications

(71 citation statements)

References 109 publications

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“…hCMEC/D3 cells (human microvascular endothelial cells) were seeded on the upper surface of the porous membrane, and astrocytes (HA cells) and microglial cells (HMC3 cells) were seeded on the opposite surface of the membrane ( Figure 2 C). The BBB chip was cultured with 100 μL/h (equivalent to 0.0325 dyn/cm 2 ) of continuous medium flow in both channels, as accumulated evidence indicated the expressions of tight junction proteins and some endothelial markers are flow-dependent, and a physiological shear stress promotes BBB maturation and function [ 29 , 38 ]. A total of 3 days later, confocal microscopic images revealed expressions of adherens junction VE-cadherin and tight junction proteins ZO-1 and Claudin-5 in brain endothelial cells ( Figure 2 D).…”

Section: Resultsmentioning

confidence: 99%

Malignant Melanoma-Derived Exosomes Induce Endothelial Damage and Glial Activation on a Human BBB Chip Model

Wang

Chen

et al. 2022

Biosensors

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Malignant melanoma is a type of highly aggressive tumor, which has a strong ability to metastasize to brain, and 60–70% of patients die from the spread of the tumor into the central nervous system. Exosomes are a type of nano-sized vesicle secreted by most living cells, and accumulated studies have reported that they play crucial roles in brain tumor metastasis, such as breast cancer and lung cancer. However, it is unclear whether exosomes also participate in the brain metastasis of malignant melanoma. Here, we established a human blood–brain barrier (BBB) model by co-culturing human brain microvascular endothelial cells, astrocytes and microglial cells under a biomimetic condition, and used this model to explore the potential roles of exosomes derived from malignant melanoma in modulating BBB integrity. Our findings showed that malignant melanoma-derived exosomes disrupted BBB integrity and induced glial activation on the BBB chip. Transcriptome analyses revealed dys-regulation of autophagy and immune responses following tumor exosome treatment. These studies indicated malignant melanoma cells might modulate BBB integrity via exosomes, and verified the feasibility of a BBB chip as an ideal platform for studies of brain metastasis of tumors in vitro.

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Section: Resultsmentioning

confidence: 99%

Malignant Melanoma-Derived Exosomes Induce Endothelial Damage and Glial Activation on a Human BBB Chip Model

Wang

Chen

et al. 2022

Biosensors

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“…A multitude of stem cells has been tested in animal models of stroke, including fetal-derived neural stem cells, embryonic stem cells, bone marrow stem cells, umbilical cord stem cells, adipose stem cells, and induced pluripotent stem cells. [91][92][93][94][95][96] An increasing number of these cells have reached clinical trials. [97][98][99] The logistics in generating an ample supply of stem cells and the ethics associated with harvesting these cells remain as critical factors of consideration when contemplating translation of stem cells products from the laboratory to the clinic.…”

Section: Stem Cell Therapy For Strokementioning

confidence: 99%

Neuroinflammation, Stem Cells, and Stroke

Anthony

Cabantan

Monsour

et al. 2022

Stroke

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Stroke remains a significant unmet clinical need with few treatment options that have a very narrow therapeutic window, thereby causing massive mortality and morbidity in the United States and around the world. Accordingly, finding safe and effective novel treatments with a wider therapeutic window stands as an urgent need in stroke. The progressive inflammation that occurs centrally and peripherally after stroke serves as a unique therapeutic target to retard and even halt the secondary cell death. Stem cell therapy represents a potent approach that can diminish inflammation in both the stroke brain and periphery (eg, spleen), advancing a paradigm shift from a traditionally brain-focused therapy to treating stroke as a neurological disorder with a significant peripheral pathology. The purpose of this review article is to highlight the inflammation-mediated secondary cell death that plagues both brain and spleen in stroke and to evaluate the therapeutic potential of stem cell therapy in dampening these inflammatory responses.

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“…These types of physiological investigations are more difficult using in vivo models in which the tumor cannot be easily separated into certain components (such as only investigating the tumor cell interaction with the surrounding microvasculature) ( 72 ). Existing models are limited by only incorporating 1-2 cell types, thereby failing to include the complex interactions between multiple cell types such as tumor, stromal, and immune cells in RCC ( 85 , 86 ). Thus, existing RCC research using these devices has typically focused on a single physiologic process within the tumor environment, but there is great potential for more complex RCC modeling using microfluidics ( 72 , 87 ).…”

Section: Microfluidic (Microphysiological) Modelsmentioning

confidence: 99%

Models of Renal Cell Carcinoma Used to Investigate Molecular Mechanisms and Develop New Therapeutics

et al. 2022

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Modeling renal cell carcinoma is critical to investigating tumor biology and therapeutic mechanisms. Multiple systems have been developed to represent critical components of the tumor and its surrounding microenvironment. Prominent in vitro models include traditional cell cultures, 3D organoid models, and microphysiological devices. In vivo models consist of murine patient derived xenografts or genetically engineered mice. Each system has unique advantages as well as limitations and researchers must thoroughly understand each model to properly investigate research questions. This review addresses common model systems for renal cell carcinoma and critically evaluates their performance and ability to measure tumor characteristics.

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A neurovascular-unit-on-a-chip for the evaluation of the restorative potential of stem cell therapies for ischaemic stroke

Cited by 74 publications

References 109 publications

Malignant Melanoma-Derived Exosomes Induce Endothelial Damage and Glial Activation on a Human BBB Chip Model

Malignant Melanoma-Derived Exosomes Induce Endothelial Damage and Glial Activation on a Human BBB Chip Model

Neuroinflammation, Stem Cells, and Stroke

Models of Renal Cell Carcinoma Used to Investigate Molecular Mechanisms and Develop New Therapeutics

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