Generation of a Human iPSC-Based Blood-Brain Barrier Chip

Jagadeesan, Srikanth; Workman, Michael J.; Herland, Anna; Svendsen, Clive N.; Vatine, Gad D.

doi:10.3791/60925-v

Cited by 2 publications

(23 citation statements)

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“…34 This strategy, which was subsequently improved [35][36][37][38][39][40] and adapted by many different groups, [41][42][43][44][45][46][47][48][49] is based on an undirected/spontaneous differentiation process assumed to promote neural and endothelial codifferentiation. These cells have also been used in complex microfluidic systems [50][51][52][53][54][55][56] and combined with other NVU cells derived from the same hiPSC lines to produce human BBB models. [57][58][59] The generation of patient-derived cells using this undirected method to study BBB dysfunction in neurological disorders has also been reported.…”

Section: Introductionmentioning

confidence: 99%

High and low permeability of human pluripotent stem cell–derived blood–brain barrier models depend on epithelial or endothelial features

Girard

Julien-Gau²,

Molino³

et al. 2023

The FASEB Journal

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The search for reliable human blood–brain barrier (BBB) models represents a challenge for the development/testing of strategies aiming to enhance brain delivery of drugs. Human‐induced pluripotent stem cells (hiPSCs) have raised hopes in the development of predictive BBB models. Differentiating strategies are thus required to generate endothelial cells (ECs), a major component of the BBB. Several hiPSC‐based protocols have reported the generation of in vitro models with significant differences in barrier properties. We studied in depth the properties of iPSCs byproducts from two protocols that have been established to yield these in vitro barrier models. Our analysis/study reveals that iPSCs derivatives endowed with EC features yield high permeability models while the cells that exhibit outstanding barrier properties show principally epithelial cell‐like (EpC) features. We found that models containing EpC‐like cells express tight junction proteins, transporters/efflux pumps and display a high functional tightness with very low permeability, which are features commonly shared between BBB and epithelial barriers. Our study demonstrates that hiPSC‐based BBB models need extensive characterization beforehand and that a reliable human BBB model containing EC‐like cells and displaying low permeability is still needed.

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Section: Introductionmentioning

confidence: 99%

High and low permeability of human pluripotent stem cell–derived blood–brain barrier models depend on epithelial or endothelial features

Girard

Julien-Gau²,

Molino³

et al. 2023

The FASEB Journal

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“…Half of the articles evaluated displayed membrane-free microfluidic chips[ 18 - 20 , 24 , 25 , 29 , 31 ], as shown in Table 1 . The remaining studies reported the presence of a membrane dividing the channels within the chip: Three (21%) made of PDMS[ 21 , 26 , 27 ], one made of polyethylene terephthalate (PE)[ 28 ], two made of polyester (PETE)[ 22 , 23 ], and one of porous polycarbonate (PC)[ 30 ]. Almost all microfluidic chips with membranes were designed to comprise a top and a bottom channel[ 21 - 23 , 26 - 28 ].…”

Section: Resultsmentioning

confidence: 99%

“…The remaining studies reported the presence of a membrane dividing the channels within the chip: Three (21%) made of PDMS[ 21 , 26 , 27 ], one made of polyethylene terephthalate (PE)[ 28 ], two made of polyester (PETE)[ 22 , 23 ], and one of porous polycarbonate (PC)[ 30 ]. Almost all microfluidic chips with membranes were designed to comprise a top and a bottom channel[ 21 - 23 , 26 - 28 ]. An exception was found in the study by Wang et al [ 30 ], whose chip design was more complex, containing four parts that were stacked to compose the BBB model.…”

Section: Resultsmentioning

confidence: 99%

“…To build the BBB, as shown in Table 2 and Figure 2A , IMR90-C4 from human fetal lung fibroblasts was the main iPSC line used (41.1%)[ 18 , 19 , 21 , 23 , 24 , 28 , 30 ], commonly cultivated in Matrigel-coated flasks. Few studies (17.6%) have reported the use of different iPSC lines[ 20 , 26 , 27 ], one of which used nine different types of iPSCs[ 27 ] that were extracted from skin fibroblasts or the peripheral blood of healthy (5) or unhealthy donors (2). Two of these skin fibroblast lines from unhealthy donors were modified by clustered regularly interspaced short palindromic repeat (CRISPR)[ 27 ].…”

Section: Resultsmentioning

confidence: 99%

“…Other particular iPSC lines, such as Ax0018 (neural stem cells)[ 20 ] and BC1-hiPSC (bone marrow)[ 31 ], were cultured on Matrigel, whereas GM25256 (skin fibroblast)[ 22 ], and ACS-1024 (bone marrow)[ 24 ] were cultured on laminin. The ECM on which EZ-Spheres (neural progenitors) were grown was not defined[ 26 ]. Interestingly, the study by Motallebnejad et al [ 24 ] compared cultivation of the ACS-1024 line on different laminin isoforms (LN511 and LN411), or on collagen IV associated with fibronectin[ 24 ].…”

Section: Resultsmentioning

confidence: 99%

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Current overview of induced pluripotent stem cell-based blood-brain barrier-on-a-chip

Alves¹,

Nucci²,

Valle³

et al. 2023

World J Stem Cells

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BACKGROUND Induced pluripotent stem cells (iPSCs) show great ability to differentiate into any tissue, making them attractive candidates for pathophysiological investigations. The rise of organ-on-a-chip technology in the past century has introduced a novel way to make in vitro cell cultures that more closely resemble their in vivo environments, both structural and functionally. The literature still lacks consensus on the best conditions to mimic the blood-brain barrier (BBB) for drug screening and other personalized therapies. The development of models based on BBB-on-a-chip using iPSCs is promising and is a potential alternative to the use of animals in research. AIM To analyze the literature for BBB models on-a-chip involving iPSCs, describe the microdevices, the BBB in vitro construction, and applications. METHODS We searched for original articles indexed in PubMed and Scopus that used iPSCs to mimic the BBB and its microenvironment in microfluidic devices. Thirty articles were identified, wherein only 14 articles were finally selected according to the inclusion and exclusion criteria. Data compiled from the selected articles were organized into four topics: (1) Microfluidic devices design and fabrication; (2) characteristics of the iPSCs used in the BBB model and their differentiation conditions; (3) BBB-on-a-chip reconstruction process; and (4) applications of BBB microfluidic three-dimensional models using iPSCs. RESULTS This study showed that BBB models with iPSCs in microdevices are quite novel in scientific research. Important technological advances in this area regarding the use of commercial BBB-on-a-chip were identified in the most recent articles by different research groups. Conventional polydimethylsiloxane was the most used material to fabricate in-house chips (57%), whereas few studies (14.3%) adopted polymethylmethacrylate. Half the models were constructed using a porous membrane made of diverse materials to separate the channels. iPSC sources were divergent among the studies, but the main line used was IMR90-C4 from human fetal lung fibroblast (41.2%). The cells were differentiated through diverse and complex processes either to endothelial or neural cells, wherein only one study promoted differentiation inside the chip. The construction process of the BBB-on-a-chip involved previous coating mostly with fibronectin/collagen IV (39.3%), followed by cell seeding in single cultures (36%) or co-cultures (64%) under controlled conditions, aimed at developing an in vitro BBB that mimics the human BBB for future applications. CONCLUSION This review evidenced technological advances in the construction of BBB models using iPSCs. Nonetheless, a definitive BBB-on-a-chip has not yet been achieved, hindering the applicability of the models.

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Generation of a Human iPSC-Based Blood-Brain Barrier Chip

Cited by 2 publications

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High and low permeability of human pluripotent stem cell–derived blood–brain barrier models depend on epithelial or endothelial features

High and low permeability of human pluripotent stem cell–derived blood–brain barrier models depend on epithelial or endothelial features

Current overview of induced pluripotent stem cell-based blood-brain barrier-on-a-chip

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