Models of the blood-brain barrier using iPSC-derived cells

Delsing, Louise; Herland, Anna; Falk, Anna; Hicks, Ryan; Synnergren, Jane; Zetterberg, Henrik

doi:10.1016/j.mcn.2020.103533

Cited by 44 publications

(38 citation statements)

References 104 publications

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“…However, markers for pericyte lineage are significantly less well-established than those for endothelial cells or astrocytes. [1] Research on this front is rapidly evolving, however, and we expect to utilize a hiAstro-hiPeri mixture for the perivascular compartment in the near future. Another goal is to introduce microglia to such BBB model where onset of neuroinflammation could be biologically rather than chemically induced.…”

Section: Resultsmentioning

confidence: 99%

“…332.3 Da, logP ~ 0). [1,67] With our own Transwell controls, we determined = 0.8 nm s −1 (CI95% [0.4; 1.4];…”

Section: Pre/post-intervention (Tracer Dye)mentioning

confidence: 99%

“…Static in-vitro studies recreating the BBB are more accessible and have been performed with several different cell sources, typically on microporous membranes suspended inside standard tissue culture wells (e.g., Transwells). [1,2] More recently, engineering approaches to create dynamic in-vitro models using microfluidics have emerged (i.e., BBB-on-chip). [3] To date, ~20-30 distinct BBB-on-chip models have been reported, attempting to better mimic biological cues such as ECM or fluid flow.…”

Section: Introductionmentioning

confidence: 99%

“…The healthy BBB consists of a layer of brain microvascular endothelial cells (BMECs) closely interlinked by membrane protein complexes. [1,2] This tight barrier is supported structurally and metabolically by pericytes and astrocytes embedded in an underlying layer of extracellular matrix (ECM), and further interacts with nearby neurons and microglia. With its central role in homeostasis, understanding the BBB is critical to shedding light on disorders and developing new therapeutics.…”

Section: Introductionmentioning

confidence: 99%

“…Only over the past decade, human induced pluripotent stem cells (hiPSC) have emerged as an alternative to avoid inter-species variation and achieve in-vivo biological function in-vitro. [1] Several protocols have been published for hiPSC-derived BMEC-like cells (hiBMEC) that achieve up to 4 kΩ cm 2 as monocultures. As mentioned earlier, in-vivo BBB function is reliant also on BMEC interactions with other cell types, with, e.g., tight junction formation being induced by neural progenitor cells.…”

Section: Introductionmentioning

confidence: 99%

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Continuous monitoring reveals protective effects of N-acetylcysteine amide on an isogenic microphysiological model of the neurovascular unit

Matthiesen

Voulgaris

Nikolakopoulou

et al. 2021

Preprint

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Microphysiological systems mimic the in vivo cellular ensemble and microenvironment with the goal of providing more human-like models for biopharmaceutical research. We report the first such model of the blood-brain barrier (BBB-on-chip) featuring both isogenic human induced pluripotent stem cell (hiPSC)-derived cells and continuous barrier integrity monitoring with <2-minute temporal resolution. We showcase its capabilities in the first microphysiological study of nitrosative stress and antioxidant prophylaxis. Relying on off-stoichiometry thiol-ene epoxy (OSTE+) for fabrication greatly facilitates assembly and sensor integration compared to the prevalent polydimethylsiloxane devices. The integrated cell-substrate endothelial resistance monitoring allows us to capture formation and breakdown of our blood-brain barrier model, consisting of co-cultured hiPSC-derived endothelial-like and astrocyte-like cells. We observe clear cellular disruption when exposing the BBB-on-chip to the nitrosative stressor linsidomine, and report on the barrier permeability and barrier-protective effects of the antioxidant N-acetylcysteine amide. Using metabolomic network analysis, we further find drug-induced changes consistent with prior literature regarding, e.g., cysteine and glutathione involvement. A model like ours opens new possibilities for drug screening studies and personalized medicine, relying solely on isogenic human-derived cells and providing high-resolution temporal readouts that can help in pharmacodynamic studies.

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Section: Resultsmentioning

confidence: 99%

“…332.3 Da, logP ~ 0). [1,67] With our own Transwell controls, we determined = 0.8 nm s −1 (CI95% [0.4; 1.4];…”

Section: Pre/post-intervention (Tracer Dye)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Continuous monitoring reveals protective effects of N-acetylcysteine amide on an isogenic microphysiological model of the neurovascular unit

Matthiesen

Voulgaris

Nikolakopoulou

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Continuous Monitoring Reveals Protective Effects of N‐Acetylcysteine Amide on an Isogenic Microphysiological Model of the Neurovascular Unit

Matthiesen

Voulgaris

Nikolakopoulou

et al. 2021

Small

Self Cite

View full text Add to dashboard Cite

Microphysiological systems mimic the in vivo cellular ensemble and microenvironment with the goal of providing more human‐like models for biopharmaceutical research. In this study, the first such model of the blood‐brain barrier (BBB‐on‐chip) featuring both isogenic human induced pluripotent stem cell (hiPSC)‐derived cells and continuous barrier integrity monitoring with <2 min temporal resolution is reported. Its capabilities are showcased in the first microphysiological study of nitrosative stress and antioxidant prophylaxis. Relying on off‐stoichiometry thiol–ene–epoxy (OSTE+) for fabrication greatly facilitates assembly and sensor integration compared to the prevalent polydimethylsiloxane devices. The integrated cell–substrate endothelial resistance monitoring allows for capturing the formation and breakdown of the BBB model, which consists of cocultured hiPSC‐derived endothelial‐like and astrocyte‐like cells. Clear cellular disruption is observed when exposing the BBB‐on‐chip to the nitrosative stressor linsidomine, and the barrier permeability and barrier‐protective effects of the antioxidant N‐acetylcysteine amide are reported. Using metabolomic network analysis reveals further drug‐induced changes consistent with prior literature regarding, e.g., cysteine and glutathione involvement. A model like this opens new possibilities for drug screening studies and personalized medicine, relying solely on isogenic human‐derived cells and providing high‐resolution temporal readouts that can help in pharmacodynamic studies.

show abstract