Induction of Mesoderm and Neural Crest-Derived Pericytes from Human Pluripotent Stem Cells to Study Blood-Brain Barrier Interactions

Overview

Journal Stem Cell Reports

Publisher Cell Press

Specialty Cell Biology

Date 2019 Feb 13

PMID 30745035

Citations 56

Authors

Tannaz Faal

Duc T T Phan

Hayk Davtyan

Vanessa M Scarfone

Erika Varady

Mathew Blurton-Jones

Christopher C W Hughes

Matthew A Inlay

Affiliations

Soon will be listed here.

Abstract

In the CNS, perivascular cells ("pericytes") associate with endothelial cells to mediate the formation of tight junctions essential to the function of the blood-brain barrier (BBB). The BBB protects the CNS by regulating the flow of nutrients and toxins into and out of the brain. BBB dysfunction has been implicated in the progression of Alzheimer's disease (AD), but the role of pericytes in BBB dysfunction in AD is not well understood. In the developing embryo, CNS pericytes originate from two sources: mesoderm and neural crest. In this study, we report two protocols using mesoderm or neural crest intermediates, to generate brain-specific pericyte-like cells from induced pluripotent stem cell (iPSC) lines created from healthy and AD patients. iPSC-derived pericytes display stable expression of pericyte surface markers and brain-specific genes and are functionally capable of increasing vascular tube formation and endothelial barrier properties.

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References

Winkler E, Bell R, Zlokovic B . Central nervous system pericytes in health and disease. Nat Neurosci. 2011; 14(11):1398-1405. PMC: 4020628. DOI: 10.1038/nn.2946. View

Zhao Z, Nelson A, Betsholtz C, Zlokovic B . Establishment and Dysfunction of the Blood-Brain Barrier. Cell. 2015; 163(5):1064-1078. PMC: 4655822. DOI: 10.1016/j.cell.2015.10.067. View

Winkler E, Sengillo J, Bell R, Wang J, Zlokovic B . Blood-spinal cord barrier pericyte reductions contribute to increased capillary permeability. J Cereb Blood Flow Metab. 2012; 32(10):1841-52. PMC: 3463878. DOI: 10.1038/jcbfm.2012.113. View

Nikolakopoulou A, Zhao Z, Montagne A, Zlokovic B . Regional early and progressive loss of brain pericytes but not vascular smooth muscle cells in adult mice with disrupted platelet-derived growth factor receptor-β signaling. PLoS One. 2017; 12(4):e0176225. PMC: 5404855. DOI: 10.1371/journal.pone.0176225. View

He L, Vanlandewijck M, Raschperger E, Mae M, Jung B, Lebouvier T . Analysis of the brain mural cell transcriptome. Sci Rep. 2016; 6:35108. PMC: 5057134. DOI: 10.1038/srep35108. View

Stratman A, Schwindt A, Malotte K, Davis G . Endothelial-derived PDGF-BB and HB-EGF coordinately regulate pericyte recruitment during vasculogenic tube assembly and stabilization. Blood. 2010; 116(22):4720-30. PMC: 2996127. DOI: 10.1182/blood-2010-05-286872. View

Srinivasan B, Kolli A, Esch M, Abaci H, Shuler M, Hickman J . TEER measurement techniques for in vitro barrier model systems. J Lab Autom. 2015; 20(2):107-26. PMC: 4652793. DOI: 10.1177/2211068214561025. View

Etchevers H, Vincent C, Le Douarin N, Couly G . The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain. Development. 2001; 128(7):1059-68. DOI: 10.1242/dev.128.7.1059. View

Daneman R, Zhou L, Kebede A, Barres B . Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature. 2010; 468(7323):562-6. PMC: 3241506. DOI: 10.1038/nature09513. View

10.

Wang X, Phan D, Sobrino A, George S, Hughes C, Lee A . Engineering anastomosis between living capillary networks and endothelial cell-lined microfluidic channels. Lab Chip. 2015; 16(2):282-90. PMC: 4869859. DOI: 10.1039/c5lc01050k. View

11.

Tai L, Thomas R, Marottoli F, Koster K, Kanekiyo T, Morris A . The role of APOE in cerebrovascular dysfunction. Acta Neuropathol. 2016; 131(5):709-23. PMC: 4837016. DOI: 10.1007/s00401-016-1547-z. View

12.

Kumar A, DSouza S, Moskvin O, Toh H, Wang B, Zhang J . Specification and Diversification of Pericytes and Smooth Muscle Cells from Mesenchymoangioblasts. Cell Rep. 2017; 19(9):1902-1916. PMC: 6428685. DOI: 10.1016/j.celrep.2017.05.019. View

13.

Halliday M, Rege S, Ma Q, Zhao Z, Miller C, Winkler E . Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease. J Cereb Blood Flow Metab. 2015; 36(1):216-27. PMC: 4758554. DOI: 10.1038/jcbfm.2015.44. View

14.

Winkler E, Sagare A, Zlokovic B . The pericyte: a forgotten cell type with important implications for Alzheimer's disease?. Brain Pathol. 2014; 24(4):371-86. PMC: 4423607. DOI: 10.1111/bpa.12152. View

15.

Ormestad M, Astorga J, Carlsson P . Differences in the embryonic expression patterns of mouse Foxf1 and -2 match their distinct mutant phenotypes. Dev Dyn. 2004; 229(2):328-33. DOI: 10.1002/dvdy.10426. View

16.

Appelt-Menzel A, Cubukova A, Gunther K, Edenhofer F, Piontek J, Krause G . Establishment of a Human Blood-Brain Barrier Co-culture Model Mimicking the Neurovascular Unit Using Induced Pluri- and Multipotent Stem Cells. Stem Cell Reports. 2017; 8(4):894-906. PMC: 5390136. DOI: 10.1016/j.stemcr.2017.02.021. View

17.

Lippmann E, Al-Ahmad A, Azarin S, Palecek S, Shusta E . A retinoic acid-enhanced, multicellular human blood-brain barrier model derived from stem cell sources. Sci Rep. 2014; 4:4160. PMC: 3932448. DOI: 10.1038/srep04160. View

18.

Cattoretti G, Schiro R, Orazi A, Soligo D, Colombo M . Bone marrow stroma in humans: anti-nerve growth factor receptor antibodies selectively stain reticular cells in vivo and in vitro. Blood. 1993; 81(7):1726-38. View

19.

Siegenthaler J, Choe Y, Patterson K, Hsieh I, Li D, Jaminet S . Foxc1 is required by pericytes during fetal brain angiogenesis. Biol Open. 2013; 2(7):647-59. PMC: 3711032. DOI: 10.1242/bio.20135009. View

20.

Armulik A, Genove G, Mae M, Nisancioglu M, Wallgard E, Niaudet C . Pericytes regulate the blood-brain barrier. Nature. 2010; 468(7323):557-61. DOI: 10.1038/nature09522. View