Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier

Vatine, Gad D.; Al‐Ahmad, Abraham; Barriga, Bianca K.; Svendsen, Soshana; Salim, A.; Garcia, Leslie; Garcia, Veronica J.; Ho, Ritchie; Yucer, Nur; Qian, Tongcheng; Lim, Ryan G.; Wu, Jie; Thompson, Leslie M.; Spivia, Weston R.; Chen, Zhaohui; Eyk, Jennifer E. Van; Palecek, Sean P.; Refetoff, Samuel; Shusta, Eric V.; Svendsen, Clive N.

doi:10.1016/j.stem.2017.04.002

Cited by 194 publications

(224 citation statements)

References 55 publications

(86 reference statements)

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“…Within the CNS environment, the choroid plexus contains epithelial cells that form tight junctions and prevent transcytosis of unwanted substances from the blood into the cerebrospinal fluid (CSF), to form the blood-CSF barrier 20,46–48 . We investigated whether iBMECs resemble these neuroectodermal epithelial cells (NE-EpiCs).…”

Section: Resultsmentioning

confidence: 99%

Human induced pluripotent stem cell-derived neuroectodermal epithelial cells mistaken for blood-brain barrier-forming endothelial cells

Redmond

Magdeldin

et al. 2019

Preprint

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33Brain microvascular endothelial cells (BMECs) possess unique properties 34underlying the blood-brain-barrier (BBB), that are crucial for homeostatic brain functions 35 and interactions with the immune system. Modulation of BBB function is essential for 36 treatment of neurological diseases and effective tumor targeting. Studies to-date have 37 been hampered by the lack of physiological models using cultivated human BMECs that 38 sustain BBB properties. Recently, differentiation of induced pluripotent stem cells (iPSCs) 39into cells with BBB-like properties has been reported, providing a robust in vitro model for 40 drug screening and mechanistic understanding of neurological diseases. However, the 41 precise identity of these iBMECs remains unclear. Employing single-cell RNA 42 sequencing, bioinformatic analysis and immunofluorescence for several pathways, 43 transcription factors (TFs), and surface markers, we examined the molecular and 44 functional properties of iBMECs differentiated either in the absence or presence of 45 retinoic acid. We found that iBMECs lack both endothelial-lineage genes and ETS TFs 46 that are essential for the establishment and maintenance of EC identity. Moreover, 47 iBMECs fail to respond to angiogenic stimuli and form lumenized vessels in vivo. We 48 demonstrate that human iBMECs are not barrier-forming ECs but rather EpCAM + 49 neuroectodermal epithelial cells (NE-EpiCs) that form tight junctions resembling those 50 present in BBB-forming BMECs. Finally, overexpression of ETS TFs (ETV2, FLI1, and 51 ERG) reprograms NE-EpiCs to become more like the BBB-forming ECs. Thus, although 52 directed differentiation of human iBMECs primarily gives rise to epithelial cells, 53 overexpression of several ETS TFs can divert them toward a vascular BBB in vitro. 54 55 56 57 Introduction 58Brain microvascular endothelial cells (BMECs) which line the vascular network of 59 the central nervous system (CNS) form a specialized barrier termed the blood-brain 60 barrier (BBB) that regulates the dynamic transfer of select molecules into and out of the 61 CNS. The BBB also restricts the entry of immune cell and is essential for healthy brain 62 activity. These properties are achieved through the presence of specialized tight junctions 63 exhibiting a high transendothelial electrical resistance (TEER) in vivo, reduced caveolar-64 mediated transport and the presence of selective transporters 1-3 . Loss of BBB integrity is 65 a hallmark of many neurological diseases such as ischemic stroke and multiple sclerosis 66 and contributes to tumor metastasis and pathogenesis of glioblastoma multiforme 67 (GBM) 1,4 . The presence of a neurovascular barrier, on the other hand, impedes 68 successful delivery of therapeutics into the CNS in many neurological and psychiatric 69 diseases. The development of in vitro models has accelerated mechanical studies on the 70 BBB as well as large scale screening of drugs with potential to penetrate the brain, with 71 some limitations 5-9 . Human primary BMECs are difficult to pro...

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Section: Resultsmentioning

confidence: 99%

Human induced pluripotent stem cell-derived neuroectodermal epithelial cells mistaken for blood-brain barrier-forming endothelial cells

Redmond

Magdeldin

et al. 2019

Preprint

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“…2). For instance, dysfunction of GLUT1 glucose transport, LAT1 amino acid transport, and MCT8 thyroid hormone transport across the BBB leads to seizure, autism spectrum, and psychomotor retardation syndromes, respectively (Seidner et al, 1998; Tărlungeanu et al, 2016; Vatine et al, 2017).…”

Section: Bbb Dysfunctionmentioning

confidence: 99%

“…Can subtle changes in different BBB properties cause specific neurological symptoms? Dysfunction in several BBB transporters causes specific developmental disorders (Seidner et al, 1998; Tărlungeanu et al, 2016; Vatine et al, 2017), and there may be more undiscovered instances of this pattern. It is possible that regional heterogeneity at the BBB renders particular brain regions vulnerable to certain disease pathologies.…”

Section: Bbb Dysfunctionmentioning

confidence: 99%

The blood–brain barrier in health and disease: Important unanswered questions

Profaci

Munji

Pulido

et al. 2020

Journal of Experimental Medicine

471

358

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The blood vessels vascularizing the central nervous system exhibit a series of distinct properties that tightly control the movement of ions, molecules, and cells between the blood and the parenchyma. This “blood–brain barrier” is initiated during angiogenesis via signals from the surrounding neural environment, and its integrity remains vital for homeostasis and neural protection throughout life. Blood–brain barrier dysfunction contributes to pathology in a range of neurological conditions including multiple sclerosis, stroke, and epilepsy, and has also been implicated in neurodegenerative diseases such as Alzheimer’s disease. This review will discuss current knowledge and key unanswered questions regarding the blood–brain barrier in health and disease.

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“…10,11 Currently, the basic structure of the BBB in vitro model includes a transwell membrane insert and seeded cells. 10,12 Primary brain ECs isolated from human brain tissue were monocultured or co/tricultured with pericytes on one side of the insert membrane and astrocytes (sometimes with neurons) on the other side.…”

Section: Introductionmentioning

confidence: 99%

Establishment of a Human iPSC- and Nanofiber-Based Microphysiological Blood–Brain Barrier System

Lin

et al. 2018

ACS Appl. Mater. Interfaces

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The blood–brain barrier (BBB) is an active and complex diffusion barrier that separates the circulating blood from the brain and extracellular fluid, regulates nutrient transportation, and provides protection against various toxic compounds and pathogens. Creating an in vitro microphysiological BBB system, particularly with relevant human cell types, will significantly facilitate the research of neuropharmaceutical drug delivery, screening, and transport, as well as improve our understanding of pathologies that are due to BBB damage. Currently, most of the in vitro BBB models are generated by culturing rodent astrocytes and endothelial cells, using commercially available transwell membranes. Those membranes are made of plastic biopolymers that are nonbiodegradable, porous, and stiff. In addition, distinct from rodent astrocytes, human astrocytes possess unique cell complexity and physiology, which are among the few characteristics that differentiate human brains from rodent brains. In this study, we established a novel human BBB microphysiologocal system, consisting of a three-dimensionally printed holder with a electrospun poly(lactic-co-glycolic) acid (PLGA) nanofibrous mesh, a bilayer coculture of human astrocytes, and endothelial cells, derived from human induced pluripotent stem cells (hiPSCs), on the electrospun PLGA mesh. This human BBB model achieved significant barrier integrity with tight junction protein expression, an effective permeability to sodium fluorescein, and higher transendothelial electrical resistance (TEER) comparing to electrospun mesh-based counterparts. Moreover, the coculture of hiPSC-derived astrocytes and endothielial cells promoted the tight junction protein expression and the TEER value. We further verified the barrier functions of our BBB model with antibrain tumor drugs (paclitaxel and bortezomib) and a neurotoxic peptide (amyloid β 1–42). The human microphysiological system generated in this study will potentially provide a new, powerful tool for research on human BBB physiology and pathology.

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Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier

Cited by 194 publications

References 55 publications

Human induced pluripotent stem cell-derived neuroectodermal epithelial cells mistaken for blood-brain barrier-forming endothelial cells

Human induced pluripotent stem cell-derived neuroectodermal epithelial cells mistaken for blood-brain barrier-forming endothelial cells

The blood–brain barrier in health and disease: Important unanswered questions

Establishment of a Human iPSC- and Nanofiber-Based Microphysiological Blood–Brain Barrier System

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