Fluids Barriers CNS. 2013 Jan 10;10(1):2. doi: 10.1186/2045-8118-10-2.
Modeling the blood-brain barrier using stem cell sources.
Fluids and barriers of the CNS
Ethan S Lippmann, Abraham Al-Ahmad, Sean P Palecek, Eric V Shusta
Affiliations
Affiliations
- Dept, of Chemical and Biological Engineering, University of Wisconsin-Madison, 1415 Engineering Dr,, Madison, WI, 53706, USA. [email protected].
PMID: 23305164
PMCID: PMC3564868 DOI: 10.1186/2045-8118-10-2
Abstract
The blood-brain barrier (BBB) is a selective endothelial interface that controls trafficking between the bloodstream and brain interstitial space. During development, the BBB arises as a result of complex multicellular interactions between immature endothelial cells and neural progenitors, neurons, radial glia, and pericytes. As the brain develops, astrocytes and pericytes further contribute to BBB induction and maintenance of the BBB phenotype. Because BBB development, maintenance, and disease states are difficult and time-consuming to study in vivo, researchers often utilize in vitro models for simplified analyses and higher throughput. The in vitro format also provides a platform for screening brain-penetrating therapeutics. However, BBB models derived from adult tissue, especially human sources, have been hampered by limited cell availability and model fidelity. Furthermore, BBB endothelium is very difficult if not impossible to isolate from embryonic animal or human brain, restricting capabilities to model BBB development in vitro. In an effort to address some of these shortcomings, advances in stem cell research have recently been leveraged for improving our understanding of BBB development and function. Stem cells, which are defined by their capacity to expand by self-renewal, can be coaxed to form various somatic cell types and could in principle be very attractive for BBB modeling applications. In this review, we will describe how neural progenitor cells (NPCs), the in vitro precursors to neurons, astrocytes, and oligodendrocytes, can be used to study BBB induction. Next, we will detail how these same NPCs can be differentiated to more mature populations of neurons and astrocytes and profile their use in co-culture modeling of the adult BBB. Finally, we will describe our recent efforts in differentiating human pluripotent stem cells (hPSCs) to endothelial cells with robust BBB characteristics and detail how these cells could ultimately be used to study BBB development and maintenance, to model neurological disease, and to screen neuropharmaceuticals.
References
- J Neurosci. 1987 Oct;7(10):3293-9 - PubMed
- Cell. 1998 Nov 13;95(4):507-19 - PubMed
- Nat Biotechnol. 2010 Feb;28(2):161-6 - PubMed
- J Cell Biol. 2008 Nov 3;183(3):409-17 - PubMed
- Biochem Biophys Res Commun. 1995 Jun 26;211(3):719-26 - PubMed
- Genes Cells. 2005 Jun;10(6):595-604 - PubMed
- Proc Natl Acad Sci U S A. 2011 May 10;108(19):7838-43 - PubMed
- Brain Res Dev Brain Res. 1995 Jun 27;87(1):69-76 - PubMed
- Brain Res Dev Brain Res. 1996 Oct 23;96(1-2):229-40 - PubMed
- J Cereb Blood Flow Metab. 2009 Sep;29(9):1491-502 - PubMed
- Nature. 2009 Jan 15;457(7227):277-80 - PubMed
- Nat Protoc. 2011 Oct 13;6(11):1710-7 - PubMed
- Cell Mol Neurobiol. 2005 Feb;25(1):41-58 - PubMed
- Cell Stem Cell. 2012 Jun 14;10(6):771-785 - PubMed
- Endocrinology. 2008 Dec;149(12):6251-61 - PubMed
- J Neurochem. 2011 Nov;119(3):507-20 - PubMed
- Nature. 1987 Jan 15-21;325(6101):253-7 - PubMed
- FASEB J. 2005 Nov;19(13):1872-4 - PubMed
- Cell. 2006 Aug 25;126(4):663-76 - PubMed
- J Neurochem. 2004 Apr;89(2):503-13 - PubMed
- Epilepsia. 2007 Mar;48(3):505-16 - PubMed
- Nature. 2010 Nov 25;468(7323):557-61 - PubMed
- J Cell Physiol. 1996 Jun;167(3):451-60 - PubMed
- Biotechnol Prog. 2007 Jan-Feb;23(1):18-23 - PubMed
- Science. 1998 Nov 6;282(5391):1145-7 - PubMed
- Brain Res Dev Brain Res. 2004 Aug 18;152(1):25-38 - PubMed
- Neuroreport. 2000 Apr 7;11(5):1081-4 - PubMed
- Brain Res. 1997 Sep 12;768(1-2):10-8 - PubMed
- J Cell Biol. 1991 Dec;115(6):1725-35 - PubMed
- Brain Res. 2007 Jul 23;1159:67-76 - PubMed
- Int J Dev Biol. 2011;55(4-5):467-76 - PubMed
- Biochem Pharmacol. 2009 Mar 1;77(5):897-909 - PubMed
- Nat Rev Drug Discov. 2004 Aug;3(8):711-5 - PubMed
- Nature. 1981 Jul 9;292(5819):154-6 - PubMed
- Int J Cell Biol. 2012;2012:508294 - PubMed
- BMC Neurosci. 2011 May 11;12:40 - PubMed
- Nat Med. 2003 Jul;9(7):900-6 - PubMed
- Circulation. 2012 Jan 3;125(1):87-99 - PubMed
- J Neurochem. 2006 May;97(4):922-33 - PubMed
- J Neurochem. 1986 Jun;46(6):1732-42 - PubMed
- Neurochem Int. 2009 Mar-Apr;54(3-4):253-63 - PubMed
- Rev Diabet Stud. 2010 Summer;7(2):93-104 - PubMed
- Nat Neurosci. 2008 Apr;11(4):429-39 - PubMed
- Mol Pharm. 2010 Aug 2;7(4):1057-68 - PubMed
- Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):2807-12 - PubMed
- Nat Biotechnol. 2009 Sep;27(9):851-7 - PubMed
- J Cell Physiol. 1994 Apr;159(1):101-13 - PubMed
- Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):2074-7 - PubMed
- Science. 1996 Jul 12;273(5272):242-5 - PubMed
- Nature. 1989 Aug 10;340(6233):471-3 - PubMed
- Brain Res. 1987 Nov;433(1):155-9 - PubMed
- Lab Chip. 2012 Apr 24;12(10):1784-92 - PubMed
- Science. 2010 Nov 12;330(6006):985-9 - PubMed
- Nat Biotechnol. 2011 May 22;29(6):528-34 - PubMed
- J Cell Mol Med. 2003 Apr-Jun;7(2):165-70 - PubMed
- Toxicol Appl Pharmacol. 2011 Nov 15;257(1):74-83 - PubMed
- Nature. 2009 Sep 17;461(7262):402-6 - PubMed
- Curr Pharm Des. 2011;17(26):2755-61 - PubMed
- J Neurosci Res. 2006 Jun;83(8):1515-24 - PubMed
- Nat Rev Neurosci. 2011 Mar;12(3):169-82 - PubMed
- J Control Release. 2001 Sep 11;76(1-2):139-47 - PubMed
- Methods Mol Med. 2003;89:375-82 - PubMed
- Nat Methods. 2011 May;8(5):424-9 - PubMed
- Proc Natl Acad Sci U S A. 2009 Sep 29;106(39):16698-703 - PubMed
- Mol Ther. 2013 Jan;21(1):240-50 - PubMed
- Nat Biotechnol. 2001 Dec;19(12):1129-33 - PubMed
- Science. 2008 Nov 21;322(5905):1247-50 - PubMed
- Science. 2012 Jul 20;337(6092):358-62 - PubMed
- Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4335-40 - PubMed
- J Cereb Blood Flow Metab. 2008 Jan;28(1):135-48 - PubMed
- J Comp Neurol. 1997 Nov 3;387(4):537-46 - PubMed
- Biochem Biophys Res Commun. 1999 Jul 22;261(1):108-12 - PubMed
- J Neurochem. 2011 Apr;117(2):333-45 - PubMed
- Toxicol Sci. 2011 Sep;123(1):281-9 - PubMed
- J Neurochem. 2008 Dec;107(5):1358-68 - PubMed
- J Cell Physiol. 2009 Mar;218(3):612-22 - PubMed
- Pharm Res. 1998 Jul;15(7):993-1000 - PubMed
- Sci Transl Med. 2010 Nov 17;2(58):58ps53 - PubMed
- Neuron. 1993 Jul;11(1):173-89 - PubMed
- Brain Res. 2009 Oct 6;1292:14-24 - PubMed
- Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):641-6 - PubMed
- Br J Pharmacol. 2003 May;139(2):329-36 - PubMed
- Cell Mol Life Sci. 2010 Nov;67(22):3837-47 - PubMed
- Angiogenesis. 2007;10(1):35-45 - PubMed
- J Neurosci Res. 2006 Dec;84(8):1656-68 - PubMed
- Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6537-42 - PubMed
- Cell. 1990 Aug 10;62(3):435-45 - PubMed
- Science. 2004 May 28;304(5675):1338-40 - PubMed
- Nature. 2012 Jan 25;482(7384):216-20 - PubMed
- Brain Res. 2005 Mar 21;1038(2):208-15 - PubMed
- Nature. 2012 May 16;485(7399):512-6 - PubMed
- Stem Cells. 2009 Mar;27(3):559-67 - PubMed
- J Pharm Sci. 2012 Apr;101(4):1337-54 - PubMed
- Dev Biol. 1981 May;84(1):183-92 - PubMed
- Anat Rec. 1988 Jun;221(2):663-77 - PubMed
- Adv Drug Deliv Rev. 1999 Apr 5;36(2-3):165-178 - PubMed
- Cell Stem Cell. 2011 Jul 8;9(1):17-23 - PubMed
- J Cereb Blood Flow Metab. 2011 Feb;31(2):693-705 - PubMed
- Proc Natl Acad Sci U S A. 1981 Dec;78(12):7634-8 - PubMed
- Cell Mol Neurobiol. 2010 Apr;30(3):483-91 - PubMed
- J Angiogenes Res. 2010 Jan 14;2:1 - PubMed
- Nat Biotechnol. 2012 Aug;30(8):783-91 - PubMed
- Cell. 2007 Nov 30;131(5):861-72 - PubMed
- J Neurochem. 2003 Jul;86(1):179-95 - PubMed
- Brain Res. 1982 Jun 3;241(1):49-55 - PubMed
- Circulation. 2010 Mar 9;121(9):1113-23 - PubMed
- Int J Biochem Cell Biol. 2011 Sep;43(9):1284-93 - PubMed
- Cell Stem Cell. 2012 Apr 6;10(4):465-72 - PubMed
- Nat Biotechnol. 2008 Mar;26(3):313-5 - PubMed
- Brain Res. 2013 Jul 12;1521:1-15 - PubMed
- J Neurochem. 1990 May;54(5):1798-801 - PubMed
- Nat Biotechnol. 2001 May;19(5):475-9 - PubMed
- Neurosci Lett. 1986 May 6;66(1):39-42 - PubMed
- Cell Stem Cell. 2012 Jul 6;11(1):100-9 - PubMed
- J Physiol. 1990 Oct;429:47-62 - PubMed
- Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5567-72 - PubMed
- Science. 2007 Jul 20;317(5836):381-4 - PubMed
- Biochem Biophys Res Commun. 2008 Jul 18;372(1):243-8 - PubMed
- Nature. 2010 Sep 16;467(7313):285-90 - PubMed
- Cell. 2010 Nov 12;143(4):527-39 - PubMed
- Nat Med. 2000 Mar;6(3):271-7 - PubMed
- Nat Rev Drug Discov. 2011 Nov 11;10(12):915-29 - PubMed
- J Physiol. 1995 Oct 15;488 ( Pt 2):439-48 - PubMed
- Nature. 2010 Nov 25;468(7323):562-6 - PubMed
- J Cell Physiol. 1997 Nov;173(2):206-10 - PubMed
- Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4391-6 - PubMed
- Science. 2011 Dec 23;334(6063):1727-31 - PubMed
- Toxicol In Vitro. 2008 Apr;22(3):799-811 - PubMed
- J Cell Mol Med. 2005 Apr-Jun;9(2):373-9 - PubMed
- Cell. 2008 May 2;133(3):510-22 - PubMed
- Cell Mol Neurobiol. 2000 Feb;20(1):57-76 - PubMed
- J Neurosci. 2001 Mar 1;21(5):1538-47 - PubMed
- J Cereb Blood Flow Metab. 2012 Jan;32(1):81-92 - PubMed
- Nat Biotechnol. 2010 Aug;28(8):848-55 - PubMed
- Nat Biotechnol. 2011 Jul 07;29(8):731-4 - PubMed
- Cell Stem Cell. 2008 Sep 11;3(3):279-88 - PubMed
- Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5759-64 - PubMed
- Science. 2007 Dec 21;318(5858):1917-20 - PubMed
- J Neurochem. 2007 Apr;101(2):555-65 - PubMed
Publication Types