Reconstruction of the human blood–brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes

Blanchard, Joel; Bula, Michael; Dávila-Velderrain, José; Akay, Leyla Anne; Zhu, Lena; Frank, Albert R.; Victor, Matheus B.; Bonner, Julia Maeve; Mathys, Hansruedi; Lin, Yong; Ko, Tak; Bennett, David A.; Cam, Hugh P.; Kellis, M; Tsai, Li‐Huei

doi:10.1038/s41591-020-0886-4

Cited by 194 publications

(247 citation statements)

References 58 publications

(54 reference statements)

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“…Intriguingly, we found that hPSC-CNC PCs also expressed PDGFRA, which was also recognized as an oligodendrocyte and fibroblast marker. This data was similar with that of previous studies as revealed by their transcriptome analysis 17,38 . Meanwhile, our RNA-Seq data indicates that the CNC PCs and HBVPs did not express other oligodendrocyte lineage markers SOX10 (the TPM value is about 0.3-1) or OLIG2 (the TPM value is about 0-0.1).…”

Section: Discussionsupporting

confidence: 93%

Transplantation of hPSC-derived pericyte-like cells promotes functional recovery in ischemic stroke mice

et al. 2020

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Pericytes play essential roles in blood–brain barrier (BBB) integrity and dysfunction or degeneration of pericytes is implicated in a set of neurological disorders although the underlying mechanism remains largely unknown. However, the scarcity of material sources hinders the application of BBB models in vitro for pathophysiological studies. Additionally, whether pericytes can be used to treat neurological disorders remains to be elucidated. Here, we generate pericyte-like cells (PCs) from human pluripotent stem cells (hPSCs) through the intermediate stage of the cranial neural crest (CNC) and reveal that the cranial neural crest-derived pericyte-like cells (hPSC-CNC PCs) express typical pericyte markers including PDGFRβ, CD146, NG2, CD13, Caldesmon, and Vimentin, and display distinct contractile properties, vasculogenic potential and endothelial barrier function. More importantly, when transplanted into a murine model of transient middle cerebral artery occlusion (tMCAO) with BBB disruption, hPSC-CNC PCs efficiently promote neurological functional recovery in tMCAO mice by reconstructing the BBB integrity and preventing of neuronal apoptosis. Our results indicate that hPSC-CNC PCs may represent an ideal cell source for the treatment of BBB dysfunction-related disorders and help to model the human BBB in vitro for the study of the pathogenesis of such neurological diseases.

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Section: Discussionsupporting

confidence: 93%

Transplantation of hPSC-derived pericyte-like cells promotes functional recovery in ischemic stroke mice

et al. 2020

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“…In the case of human genetic disease, hPSC-derived BMEC-like cells could play a unique role in modeling human disease when animal models are lacking. For instance, hiPSC-derived BMEC-like cells can be an invaluable tool to examine molecular transport at the human BBB using patient-sourced, diseased hiPSC lines [9,13], and to examine the impact of genetic risk factors on disease modifying processes such as neurovascular amyloid deposition [10]. In addition, hPSCderived BMEC-like cells respond to cues originating from co-cultured neurovascular unit cells such as astrocytes, pericytes, and neurons [1][2][3][4][5][6][7][8][9].…”

Section: Main Textmentioning

confidence: 99%

“…Most relevant to this commentary, induction and maintenance of endothelial character with a corresponding reduction of epithelial character continues to be a goal. Factors such as hypoxia [19], shear stress [9,19], and three dimensional architecture [10,28,29] have been suggested to increase vascular character, and other models based on induction of BBB character in generic hiPSC-derived ECs are beginning to emerge [32]. Despite these advances, we believe it is prudent to exercise caution when utilizing hPSC-derived BMEC-like cells for studies where the endothelial phenotype is crucial.…”

Section: Main Textmentioning

confidence: 99%

“…As mentioned earlier, it is important to complement such studies with in vivo models and human tissue to provide confidence in the accuracy of outcomes. As one example, the workflow employed by Tsai and colleagues to study neurovascular cell-specific deficiencies imparted by APOE status combined hPSC-derived BMEC-like cells and human data [10]. In another example, antibodies that bind hPSC-derived BMEC-like cells were validated by assessing vascular targeting in human brain tissue sections [31].…”

Section: Main Textmentioning

confidence: 99%

“…We defined this cell type as hPSC-derived BMECs. The resultant cells have proven useful for examining interactions between cells of the neurovascular unit [1][2][3][4][5][6][7][8][9][10], evaluating experimental drug permeability at the BBB [1,[11][12][13][14][15][16], and modeling human genetic disease using hiPSCs derived from patient sources [9,10,13], among other applications.…”

Section: Introductionmentioning

confidence: 99%

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

Lippmann

Azarin

Palecek

et al. 2020

Fluids Barriers CNS

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In 2012, we provided the first published evidence that human pluripotent stem cells could be differentiated to cells exhibiting markers and phenotypes characteristic of the blood–brain barrier (BBB). In the ensuing years, the initial protocols have been refined, and the research community has identified both positive and negative attributes of this stem cell-based BBB model system. Here, we give our perspective on the current status of these models and their use in the BBB community, as well as highlight key attributes that would benefit from improvement moving forward.

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Engineering the Human Blood–Brain Barrier at the Capillary Scale using a Double‐Templating Technique

Zhao

Guo

Kulkarni

et al. 2022

Adv Funct Materials

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In vitro blood-brain barrier (BBB) models have played an important role in studying processes such as immune cell trafficking and drug delivery, as well as contributing to the understanding of mechanisms of disease progression. Many biological and pathological processes in the cerebrovasculature occur in capillaries and hence the lack of robust hierarchical models at the capillary scale is a major roadblock in BBB research. Here, a double-templating technique for engineering hierarchical BBB models with physiological barrier function at the capillary scale is reported. First, the formation of hierarchical vascular networks using human umbilical vein endothelial cells is demonstrated. Then, barrier function is characterized in a BBB model using brain microvascular endothelial-like cells differentiated from induced pluripotent stem cells. Finally, immune cell adhesion and transmigration are characterized in response to perfusion with the inflammatory cytokine tumor necrosis factor-alpha, and it is shown that capillary-scale effects, such as leukocyte plugging, observed in mouse models, can be recapitulated. The double-templated hierarchical model enables the study of a wide range of biological and pathological processes related to the human BBB.

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Reconstruction of the human blood–brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes

Cited by 194 publications

References 58 publications

Transplantation of hPSC-derived pericyte-like cells promotes functional recovery in ischemic stroke mice

Transplantation of hPSC-derived pericyte-like cells promotes functional recovery in ischemic stroke mice

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

Engineering the Human Blood–Brain Barrier at the Capillary Scale using a Double‐Templating Technique

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