scholarly journals Human pluripotent stem cell-derived brain pericyte-like cells induce blood-brain barrier properties

2018 ◽  
Author(s):  
Matthew J. Stebbins ◽  
Benjamin D. Gastfriend ◽  
Scott G. Canfield ◽  
Ming-Song Lee ◽  
Drew Richards ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Pluripotent Stem Cells ◽  
Neurovascular Unit ◽  
Human Pluripotent Stem Cells ◽  
Brain Barrier ◽  
Blood Brain ◽  
Brain Pericytes ◽  
The Brain

ABSTRACTBrain pericytes play an important role in the formation and maintenance of the neurovascular unit (NVU), and their dysfunction has been implicated in central nervous system (CNS) disorders. While human pluripotent stem cells (hPSCs) have been used to model other components of the NVU including brain microvascular endothelial cells (BMECs), astrocytes, and neurons, cells having brain pericyte-like phenotypes have not been described. In this study, we generated neural crest stem cells (NCSCs), the embryonic precursor to forebrain pericytes, from human pluripotent stem cells (hPSCs) and subsequently differentiated NCSCs to brain pericyte-like cells. The brain pericyte-like cells expressed marker profiles that closely resembled primary human brain pericytes, and they self-assembled with endothelial cells to support vascular tube formation. Importantly, the brain pericyte-like cells induced blood-brain barrier (BBB) properties in BMECs, including barrier enhancement and reduction of transcytosis. Finally, brain pericyte-like cells were incorporated with iPSC-derived BMECs, astrocytes, and neurons to form an isogenic human NVU model that should prove useful for the study of the BBB in CNS health, disease, and therapy.

scholarly journals Human pluripotent stem cell–derived brain pericyte–like cells induce blood-brain barrier properties

2019 ◽  
Vol 5 (3) ◽  
pp. eaau7375 ◽  
Author(s):  
Matthew J. Stebbins ◽  
Benjamin D. Gastfriend ◽  
Scott G. Canfield ◽  
Ming-Song Lee ◽  
Drew Richards ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Neurovascular Unit ◽  
Barrier Properties ◽  
Cell Types ◽  
Brain Barrier ◽  
Human Model ◽  
Blood Brain ◽  
Brain Pericytes

Brain pericytes play important roles in the formation and maintenance of the neurovascular unit (NVU), and their dysfunction has been implicated in central nervous system disorders. While human pluripotent stem cells (hPSCs) have been used to model other NVU cell types, including brain microvascular endothelial cells (BMECs), astrocytes, and neurons, hPSC-derived brain pericyte–like cells have not been integrated into these models. In this study, we generated neural crest stem cells (NCSCs), the embryonic precursor to forebrain pericytes, from hPSCs and subsequently differentiated NCSCs to brain pericyte–like cells. These cells closely resembled primary human brain pericytes and self-assembled with endothelial cells. The brain pericyte–like cells induced blood-brain barrier properties in BMECs, including barrier enhancement and reduced transcytosis. Last, brain pericyte–like cells were incorporated with iPSC-derived BMECs, astrocytes, and neurons to form an isogenic human model that should prove useful for the study of the NVU.

scholarly journals Directed differentiation of human pluripotent stem cells to blood-brain barrier endothelial cells

2017 ◽  
Vol 3 (11) ◽  
pp. e1701679 ◽  
Author(s):  
Tongcheng Qian ◽  
Shaenah E. Maguire ◽  
Scott G. Canfield ◽  
Xiaoping Bao ◽  
William R. Olson ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Pluripotent Stem Cells ◽  
Human Pluripotent Stem Cells ◽  
Brain Barrier ◽  
Directed Differentiation ◽  
Blood Brain

scholarly journals Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells

2012 ◽  
Vol 30 (8) ◽  
pp. 783-791 ◽  
Author(s):  
Ethan S Lippmann ◽  
Samira M Azarin ◽  
Jennifer E Kay ◽  
Randy A Nessler ◽  
Hannah K Wilson ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Pluripotent Stem Cells ◽  
Human Pluripotent Stem Cells ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals Wnt signaling mediates acquisition of blood-brain barrier properties in naïve endothelium derived from human pluripotent stem cells

2021 ◽  
Author(s):  
Benjamin D Gastfriend ◽  
Hideaki Nishihara ◽  
Scott G Canfield ◽  
Koji L Foreman ◽  
Britta Engelhardt ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wnt Signaling ◽  
Blood Brain Barrier ◽  
Pluripotent Stem Cells ◽  
Barrier Properties ◽  
Human Pluripotent Stem Cells ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Central Nervous System

Endothelial cells (ECs) in the central nervous system (CNS) acquire their specialized blood-brain barrier (BBB) properties in response to extrinsic signals, with Wnt/β-catenin signaling coordinating multiple aspects of this process. Our knowledge of CNS EC development has been advanced largely by animal models, and human pluripotent stem cells (hPSCs) offer the opportunity to examine BBB development in an in vitro human system. Here we show that activation of Wnt signaling in hPSC-derived naïve endothelial progenitors, but not in matured ECs, leads to robust acquisition of canonical BBB phenotypes including expression of GLUT-1, increased claudin-5, and decreased PLVAP. RNA-seq revealed a transcriptome profile resembling ECs with CNS-like characteristics, including Wnt-upregulated expression of LEF1, APCDD1, and ZIC3. Together, our work defines effects of Wnt activation in naïve ECs and establishes an improved hPSC-based model for interrogation of CNS barriergenesis.

scholarly journals Single-Cell Analysis of Blood-Brain Barrier Response to Pericyte Loss

2020 ◽  
Author(s):  
Maarja Andaloussi Mäe ◽  
Liqun He ◽  
Sofia Nordling ◽  
Elisa Vazquez-Liebanas ◽  
Khayrun Nahar ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Single Cell ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Specific Gene ◽  
Brain Endothelial Cells ◽  
Blood Brain ◽  
Brain Pericytes ◽  
Endothelial Response ◽  
The Brain

Rationale: Pericytes are capillary mural cells playing a role in stabilizing newly formed blood vessels during development and tissue repair. Loss of pericytes has been described in several brain disorders, and genetically induced pericyte deficiency in the brain leads to increased macromolecular leakage across the blood-brain barrier (BBB). However, the molecular details of the endothelial response to pericyte deficiency remain elusive. Objective: To map the transcriptional changes in brain endothelial cells resulting from lack of pericyte contact at single-cell level, and to correlate them with regional heterogeneities in BBB function and vascular phenotype. Methods and Results: We reveal transcriptional, morphological and functional consequences of pericyte absence for brain endothelial cells using a combination of methodologies, including single-cell RNA sequencing, tracer analyses and immunofluorescent detection of protein expression in pericyte-deficient adult Pdgfbret/ret mice. We find that endothelial cells without pericyte contact retain a general BBB-specific gene expression profile, however, they acquire a venous-shifted molecular pattern and become transformed regarding the expression of numerous growth factors and regulatory proteins. Adult Pdgfbret/ret brains display ongoing angiogenic sprouting without concomitant cell proliferation providing unique insights into the endothelial tip cell transcriptome. We also reveal heterogeneous modes of pericyte-deficient BBB impairment, where hotspot leakage sites display arteriolar-shifted identity and pinpoint putative BBB regulators. By testing the causal involvement of some of these using reverse genetics, we uncover a reinforcing role for angiopoietin 2 at the BBB. Conclusions: By elucidating the complexity of endothelial response to pericyte deficiency at cellular resolution, our study provides insight into the importance of brain pericytes for endothelial arterio-venous zonation, angiogenic quiescence and a limited set of BBB functions. The BBB-reinforcing role of ANGPT2 is paradoxical given its wider role as TIE2 receptor antagonist and may suggest a unique and context-dependent function of ANGPT2 in the brain.

scholarly journals Accelerated differentiation of human induced pluripotent stem cells to blood–brain barrier endothelial cells

2017 ◽  
Vol 14 (1) ◽  
Author(s):  
Emma K. Hollmann ◽  
Amanda K. Bailey ◽  
Archit V. Potharazu ◽  
M. Diana Neely ◽  
Aaron B. Bowman ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Induced Pluripotent Stem Cells ◽  
Blood Brain Barrier ◽  
Pluripotent Stem Cells ◽  
Brain Barrier ◽  
Blood Brain ◽  
Induced Pluripotent
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