A human brain microphysiological system derived from induced pluripotent stem cells to study neurological diseases and toxicity

Abstract

Human in vitro models of brain neurophysiology are needed to investigate molecular and cellular mechanisms associated with neurological disorders and neurotoxicity. We have developed a reproducible iPSC-derived human 3D brain microphysiological system (BMPS), comprised of differentiated mature neurons and glial cells (astrocytes and oligodendrocytes) that reproduce neuronal-glial interactions and connectivity. BMPS mature over eight weeks and show the critical elements of neuronal function: synaptogenesis and neuron-to-neuron (e.g., spontaneous electric field potentials) and neuronal-glial interactions (e.g., myelination), which mimic the microenvironment of the central nervous system, rarely seen in vitro before. The BMPS shows 40% overall myelination after 8 weeks of differentiation. Myelin was observed by immunohistochemistry and confirmed by confocal microscopy 3D reconstruction and electron microscopy. These findings are of particular relevance since myelin is crucial for proper neuronal function and development. The ability to assess oligodendroglial function and mechanisms associated with myelination in this BMPS model provide an excellent tool for future studies of neurological disorders such as multiple sclerosis and other demyelinating diseases. The BMPS provides a suitable and reliable model to investigate neuron-neuroglia function as well as pathogenic mechanisms in neurotoxicology.

References 58

1. 1.

   Agrawal HC, Sprinkle TJ and Agrawal D (1994 ). In vivo phosphorylation of 2’,3’-cyclic nucleotide 3’-phosphohy- drolase (CNP): CNP in brain myelin is phosphorylated by forskolin- and phorbol ester-sensitive protein kinases. Neuro- chem Res 19, 721–728

   Not in our library10.1007/bf00967712

2. 2.

   Aguirre-Rueda D, Guerra-Ojeda S, Aldasoro M (2015 ). Astrocytes protect neurons from Abeta1–42 peptide-induced neurotoxicity increasing TFAM and PGC-1 and decreasing PPAR-gamma and SIRT-1. Int J Med Sci 12, 48–56

   Not in our library10.7150/ijms.10035

3. 3.

   Alépée N, Bahinski A, Daneshian M (2014 ). State- of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology. ALTEX 31, 441–477

   Not in our library10.14573/altex1406111

4. 4.

   Andersen ME, Betts K, Dragan Y (2014 ). Developing microphysiological systems for use as regulatory tools - challenges and opportunities. ALTEX 31, 364–367

   Not in our library10.14573/altex.1405151

5. 5.

   Bourre JM, Honegger P, Daudu O and Matthiue JM (1979 ). The lipid composition of rat brain aggregating cell cultures during development. Neurosci Lett 11, 275–278

   Not in our library10.1016/0304-3940(79)90007-7

6. 6.

   Brubaker CJ, Schmithorst VJ, Haynes EN (2009 ). Altered myelination and axonal integrity in adults with childhood lead exposure: A diffusion tensor imaging study. Neurotoxicology 30, 867–875

   Not in our library10.1016/j.neuro.2009.07.007

7. 7.

   Chomczynski P and Sacchi N (1987 ). Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162, 156–159

   Not in our library10.1006/abio.1987.9999

8. 8.

   Creeley CE, Dikranian KT, Johnson SA (2013 ). Alcohol-induced apoptosis of oligodendrocytes in the fetal macaque brain. Acta Neuropathol Commun 1, 23

   Not in our library10.1186/2051-5960-1-23

9. 9.

   DeAzevedo LC, Fallet C, Moura-Neto V (2003 ). Cortical radial glial cells in human fetuses: Depth-correlated transformation into astrocytes. J Neurobiol 55, 288–298

   Not in our library10.1002/neu.10205

10. 10.

    Deng W and Poretz RD (2003 ). Oligodendroglia in developmental neurotoxicity. Neurotoxicology 24, 161–178

    Not in our library10.1016/s0161-813x(02)00196-1

11. 11.

    Dingle YL, Boutin ME, Chirila AM (2015 ). Three-dimensional neural spheroid culture: An in vitro model for cortical studies. Tissue Eng Part C Methods 21, 1274–1283

    Not in our library10.1089/ten.tec.2015.0135

12. 12.

    Dolle JP, Morrison B 3rd, Schloss RS and Yarmush ML (2014 ). Brain-on-a-chip microsystem for investigating traumatic brain injury: Axon diameter and mitochondrial membrane changes play a significant role in axonal response to strain injuries. Technology (Singap World Sci) 2, 106

    Not in our library10.1142/s2339547814500095

13. 13.

    Fancy SP, Chan JR, Baranzini SE (2011 ). Myelin regeneration: A recapitulation of development? Annu Rev Neu- rosci 34, 21-43

    Not in our library10.1146/annurev-neuro-061010-113629

14. 14.

    Fumagalli M, Lecca D and Abbracchio MP (2016 ). CNS remyelination as a novel reparative approach to neurodegenerative diseases: The roles of purinergic signaling and the P2Y-like receptor GPR17. Neuropharmacology 104, 82–93

    Not in our library10.1016/j.neuropharm.2015.10.005

15. 15.

    Garcia SJ, Seidler FJ and Slotkin TA (2005 ). Developmental neurotoxicity of chlorpyrifos: Targeting glial cells. Environ Toxicol Pharmacol 19, 455-461

    Not in our library10.1016/j.etap.2004.12.007

16. 16.

    Hartung T (2007 ). Food for thought... on cell culture. ALTEX 24, 143-152. http://www.altex.ch/resources/ altex_2007_3_143_147_FFT_HartungE.PDF

    Not in our library10.14573/altex.2007.3.143

17. 17.

    Hartung T (2008 ). Thoughts on limitations of animal models. Parkinsonism Relat Disord 14, Suppl 2, S81-S83

    Not in our library10.1016/j.parkreldis.2008.04.003

18. 18.

    Hartung T (2013 ). Look back in anger - what clinical studies tell us about preclinical work. ALTEX 30, 275–291

    Not in our library10.14573/altex.2013.3.275

19. 19.

    Hartung T (2014 ). 3D - a new dimension of in vitro research. Adv Drug Deliv Rev 69–70, vi

    Not in our library10.1016/j.addr.2014.04.003

20. 20.

    Hedlund E, Belnoue L, Theofilopoulos S (2016 ). Dopamine receptor antagonists enhance proliferation and neurogenesis of midbrain Lmx1a-expressing progenitors. Sci Rep 6, 26448

    Not in our library10.1038/srep26448

21. 21.

    Jiang P, Chen C, Liu XB (2016 ). Human iPSC-derived immature astroglia promote oligodendrogenesis by increasing TIMP-1 secretion. Cell Rep 15, 1303–1315

    Not in our library10.1016/j.celrep.2016.04.011

22. 22.

    Juraver-Geslin HA and Durand BC (2015 ). Early development of the neural plate: New roles for apoptosis and for one of its main effectors caspase-3. Genesis 53, 203–224

    Not in our library10.1002/dvg.22844

23. 23.

    Kadoshima T, Sakaguchi H, Nakano T (2013 ). Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc Natl Acad Sci U S A 110, 20284–20289

    Not in our library10.1073/pnas.1315710110

24. 24.
    Dishing out mini-brains: Current progress and future prospects in brain organoid research · 2016

    No notice
25. 25.

    Kerman BE, Kim HJ, Padmanabhan K (2015 ). In vitro myelin formation using embryonic stem cells. Development 142, 2213–2225

    Not in our library10.1242/dev.116517

26. 26.

    Krug AK, Gutbier S, Zhao L (2014 ). Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP(+). Cell Death Dis 5, e1222

    Not in our library10.1038/cddis.2014.166

27. 27.

    Lancaster MA, Renner M, Martin CA (2013 ). Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379

    Not in our library10.1038/nature12517

28. 28.

    Lariosa-Willingham KD, Rosler ES, Tung JS (2016 ). Development of a central nervous system axonal my- elination assay for high throughput screening. BMC Neurosci 17, 16

    Not in our library10.1186/s12868-016-0250-2

29. 29.

    Li H and Richardson WD (2008 ). The evolution of Olig genes and their roles in myelination. Neuron Glia Biol 4, 129–135

    Not in our library10.1017/s1740925x09990251

30. 30.

    Li X and Jin P (2010 ). Roles of small regulatory RNAs in determining neuronal identity. Nat Rev Neurosci 11, 329–338

    Not in our library10.1038/nrn2739

31. 31.

    Livak KJ and Schmittgen TD (2001 ). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25, 402–408

    Not in our library10.1006/meth.2001.1262

32. 32.

    Lyck L, Dalmau I, Chemnitz J (2008 ). Immunohistochemical markers for quantitative studies of neurons and glia in human neocortex. J Histochem Cytochem 56, 201–221

    Not in our library10.1369/jhc.7a7187.2007

33. 33.

    Marx U, Andersson TB, Bahinski A (2016 ). Biology-inspired microphysiological system approaches to solve the prediction dilemma of substance testing. ALTEX 33, 272–321

    Not in our library10.14573/altex.1603161

34. 34.

    Meijer DH, Kane MF, Mehta S (2012 ). Separated at birth? The functional and molecular divergence of OLIG1 and OLIG2. Nat Rev Neurosci 13, 819–831

    Not in our library10.1038/nrn3386

35. 35.

    Monyer H, Sprengel R, Schoepfer R (1992 ). Heteromeric NMDA receptors: Molecular and functional distinction of subtypes. Science 256, 1217–1221

    Not in our library10.1126/science.256.5060.1217

36. 36.

    Nakano T, Ando S, Takata N (2012 ). Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 10, 771–785

    Not in our library10.1016/j.stem.2012.05.009

37. 37.

    Nave KA (2010 ). Myelination and support of axonal integrity by glia. Nature 468, 244–252

    Not in our library10.1038/nature09614

38. 38.

    Nieweg K, Andreyeva A, van Stegen B (2015 ). Alzheimer’s disease-related amyloid-beta induces synaptotoxicity in human iPS cell-derived neurons. Cell Death Dis 6, e1709

    Not in our library10.1038/cddis.2015.72

39. 39.

    Park J, Lee BK, Jeong GS (2015 ). Three-dimensional brain-on-a-chip with an interstitial level of flow and its application as an in vitro model of Alzheimer’s disease. Lab Chip 15, 141–150

    Not in our library10.1039/c4lc00962b

40. 40.

    Pasca AM, Sloan SA, Clarke LE (2015 ). Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods 12, 671–678

    Not in our library10.1038/nmeth.3415

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