Commentary on human pluripotent stem cell-based blood–brain barrier models

Lippmann, Ethan S.; Azarin, Samira M.; Palecek, Sean P.; Shusta, Eric V.

doi:10.1186/s12987-020-00222-3

Cited by 82 publications

(97 citation statements)

References 34 publications

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“…The standard additives to EC medium (RA, B27 supplement, bFGF) were unchanged from our previous protocol (Neal et al 2019). In cells differentiated from the H9 CDH5-2A-eGFP hESC line, expression of eGFP was similar at day 6 regardless of basal media, and colonies of cells harboring green fluorescence signal at cell-cell borders could be identified in each condition ( Figure 1B); these results agree with previous observations (Lippmann et al 2020). For further validation, we differentiated CC3 and CD10 iPSCs in either DMEM or NB, followed by subculture and immunostaining.…”

Section: Marker Expression In Different Basal Mediasupporting

confidence: 90%

“…They have also gained traction for use in preclinical drug screening applications (Di Marco et al 2020;Ohshima et al 2019;Roux et al 2019). Yet, like animal BBB models, the use of hPSC-derived BMEClike cells is not standardized, and differences in cellular function and phenotype have been noted across the literature, which could reflect a combination of cell sourcing, technique, and culture conditions (Lippmann et al 2020). Therefore, further efforts are warranted to improve understanding of how various external factors influence hPSC-derived BBB performance in vitro, and lessons learned from these studies could be potentially translated to other in vitro model platforms.…”

Section: Introductionmentioning

confidence: 99%

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Influence of basal media composition on barrier fidelity within human pluripotent stem cell-derived blood-brain barrier models

Neal

Katdare

Shi

et al. 2021

Preprint

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It is increasingly recognized that brain microvascular endothelial cells (BMECs), the principle component of the blood-brain barrier (BBB), are highly sensitive to soluble cues from both the bloodstream and the brain. This concept extends in vitro, where the extracellular milieu can also influence BBB properties in cultured cells. However, the extent to which baseline culture conditions can affect BBB properties in vitro remains unclear, which has implications for model variability and reproducibility, as well as downstream assessments of molecular transport and disease phenotypes. Here, we explore this concept by examining BBB properties within human induced pluripotent stem cell (iPSC)-derived BMEC-like cells cultured under serum-free conditions in different basal media with fully defined compositions. We demonstrate notable differences in both passive and active BBB properties as a function of basal media composition. Further, RNA sequencing and phosphoproteome analyses revealed alterations to various signaling pathways in response to basal media differences. Overall, our results demonstrate that baseline culture conditions can have a profound influence on the performance of in vitro BBB models, and these effects should be considered when designing experiments that utilize such models for basic research and preclinical assays.

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Section: Marker Expression In Different Basal Mediasupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Influence of basal media composition on barrier fidelity within human pluripotent stem cell-derived blood-brain barrier models

Neal

Katdare

Shi

et al. 2021

Preprint

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“…In the chronic phase of IS, some stem cells can indirectly improve neovascularization, neurogenesis, and restoration of BBB, thus exerting anti-inflammatory effects. The recent increase in interest in human pluripotent stem cells (hPSC) is due to the fact that they have the potential to differentiate into cells with BBB markers and characteristics ( Lippmann et al, 2020 ); thus, their protective effect could be partly due to their ability to restore the BBB. In light of all these discoveries, stem cell therapy represents a potential treatment to protect the CNS through neuroinflammation activity ( De Feo et al, 2012 ; Figure 2 ).…”

Section: Protective Mechanisms Regulating Stem Cell Therapy After Ismentioning

confidence: 99%

Potential Mechanisms and Perspectives in Ischemic Stroke Treatment Using Stem Cell Therapies

Zhou

Wang

Gao

et al. 2021

Front. Cell Dev. Biol.

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Ischemic stroke (IS) remains one of the major causes of death and disability due to the limited ability of central nervous system cells to regenerate and differentiate. Although several advances have been made in stroke therapies in the last decades, there are only a few approaches available to improve IS outcome. In the acute phase of IS, mechanical thrombectomy and the administration of tissue plasminogen activator have been widely used, while aspirin or clopidogrel represents the main therapy used in the subacute or chronic phase. However, in most cases, stroke patients fail to achieve satisfactory functional recovery under the treatments mentioned above. Recently, cell therapy, especially stem cell therapy, has been considered as a novel and potential therapeutic strategy to improve stroke outcome through mechanisms, including cell differentiation, cell replacement, immunomodulation, neural circuit reconstruction, and protective factor release. Different stem cell types, such as mesenchymal stem cells, marrow mononuclear cells, and neural stem cells, have also been considered for stroke therapy. In recent years, many clinical and preclinical studies on cell therapy have been carried out, and numerous results have shown that cell therapy has bright prospects in the treatment of stroke. However, some cell therapy issues are not yet fully understood, such as its optimal parameters including cell type choice, cell doses, and injection routes; therefore, a closer relationship between basic and clinical research is needed. In this review, the role of cell therapy in stroke treatment and its mechanisms was summarized, as well as the function of different stem cell types in stroke treatment and the clinical trials using stem cell therapy to cure stroke, to reveal future insights on stroke-related cell therapy, and to guide further studies.

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“…While TEER values within the physiological range has been achieved by some of these differentiation protocols, a recent paper by Lu et al demonstrates that the resulting cells from all protocols lack some key characteristics of endothelial cells and appear to be more closely related to epithelial cells [ 92 ]. Yet, these cells remain the only BMECs in culture that have both a strong barrier and functional BBB transporters [ 93 ] and will likely continue to be the gold standard until a better protocol is validated. Maximum barrier maturity with these cell types has taken up to 11 days in culture following differentiation [ 94 ], which will influence the experimental timeline and design considerations for the BoC model.…”

Section: Decision Workflow: Factors To Consider When Selecting a Modementioning

confidence: 99%

Review of Design Considerations for Brain-on-a-Chip Models

et al. 2021

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In recent years, the need for sophisticated human in vitro models for integrative biology has motivated the development of organ-on-a-chip platforms. Organ-on-a-chip devices are engineered to mimic the mechanical, biochemical and physiological properties of human organs; however, there are many important considerations when selecting or designing an appropriate device for investigating a specific scientific question. Building microfluidic Brain-on-a-Chip (BoC) models from the ground-up will allow for research questions to be answered more thoroughly in the brain research field, but the design of these devices requires several choices to be made throughout the design development phase. These considerations include the cell types, extracellular matrix (ECM) material(s), and perfusion/flow considerations. Choices made early in the design cycle will dictate the limitations of the device and influence the end-point results such as the permeability of the endothelial cell monolayer, and the expression of cell type-specific markers. To better understand why the engineering aspects of a microfluidic BoC need to be influenced by the desired biological environment, recent progress in microfluidic BoC technology is compared. This review focuses on perfusable blood–brain barrier (BBB) and neurovascular unit (NVU) models with discussions about the chip architecture, the ECM used, and how they relate to the in vivo human brain. With increased knowledge on how to make informed choices when selecting or designing BoC models, the scientific community will benefit from shorter development phases and platforms curated for their application.

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Commentary on human pluripotent stem cell-based blood–brain barrier models

Cited by 82 publications

References 34 publications

Influence of basal media composition on barrier fidelity within human pluripotent stem cell-derived blood-brain barrier models

Influence of basal media composition on barrier fidelity within human pluripotent stem cell-derived blood-brain barrier models

Potential Mechanisms and Perspectives in Ischemic Stroke Treatment Using Stem Cell Therapies

Review of Design Considerations for Brain-on-a-Chip Models

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