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New Stem Cell Strategy for Creates Reliable Blood-Brain Barrier Model

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Review of “Directed differentiation of human pluripotent stem cells to blood-brain barrier endothelial cells” from Science Advances by Stuart P. Atkinson

The construction of a reliable model of the blood-brain barrier (BBB), an important interface between the blood circulation and the central nervous system (CNS), may help us to fully understand barrier development and function and explore related diseases/disorders [1]. Researchers from the laboratory of Sean P. Palecek (University of Wisconsin-Madison, Madison, WI, USA) have endeavored to overcome one of the main difficulties faced by researchers in this area – the efficient and scalable production of brain microvascular endothelial cells (BMECs) [2, 3], the main component of the BBB, from human pluripotent stem cells (hPSCs). Their recent Science Advance study builds on their previously published work [4, 5], culminating in the description of an efficient chemically-defined approach to BMEC production from hPSCs in the hope of significantly accelerating BBB research [6].

Employing expertise garnered from in vivo developmental studies, Qian et al. first exposed human induced pluripotent stem cells (hiPSCs) to small molecule activators of the canonical Wnt signaling pathway to induce the homogenous differentiation of endothelial progenitor cells via primitive streak-like and intermediate mesoderm-like stages. From here, treatment with retinoic acid drove the specification of progenitors to endothelial cells (ECs) expressing BBB-specific markers. Encouragingly, hPSC-derived ECs shared a common transcriptional profile with primary BMECs and displayed many BMEC-specific characteristics, including endothelial properties (tube formation and low-density lipoprotein uptake) and efflux transporter activities. 

Although this strategy appears straightforward, the authors note several important considerations. Firstly, high-efficiency differentiation to BMECs required an optimal hiPSC seeding density as well as the presence of retinoic acid to promote the induction of BMEC phenotypes such as the expression and localization of tight junction proteins that ensure barrier function. Furthermore, the authors highlighted their use of an entirely defined differentiation platform that improved reliability and reproducibility in part due to the absence of lot-to-lot variability in reagents.

All signs suggest that hPSC-derived BMECs display all the required properties for an efficient in vitro BBB model that will accelerate research into the development and treatment of BBB-related diseases and disorders. For more on human pluripotent stem cell-based modeling, stay tuned to the Stem Cells Portal.

References

  1. Naik P and Cucullo L, In vitro blood-brain barrier models: current and perspective technologies. J Pharm Sci 2012;101:1337-54.
  2. Obermeier B, Daneman R, and Ransohoff RM, Development, maintenance and disruption of the blood-brain barrier. Nat Med 2013;19:1584-96.
  3. Weksler BB, Subileau EA, Perriere N, et al., Blood-brain barrier-specific properties of a human adult brain endothelial cell line. FASEB J 2005;19:1872-4.
  4. Lippmann ES, Azarin SM, Kay JE, et al., Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells. Nat Biotechnol 2012;30:783-91.
  5. Lippmann ES, Al-Ahmad A, Azarin SM, et al., A retinoic acid-enhanced, multicellular human blood-brain barrier model derived from stem cell sources. Sci Rep 2014;4:4160.
  6. Qian T, Maguire SE, Canfield SG, et al., Directed differentiation of human pluripotent stem cells to blood-brain barrier endothelial cells. Science Advances 2017;3.