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Induction of myelinating oligodendrocytes in human cortical spheroids

Nature Methods volume 15, pages 700–706 (2018)Cite this article

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Abstract

Cerebral organoids provide an accessible system for investigations of cellular composition, interactions, and organization but have lacked oligodendrocytes, the myelinating glia of the central nervous system. Here we reproducibly generated oligodendrocytes and myelin in ‘oligocortical spheroids’ derived from human pluripotent stem cells. Molecular features consistent with those of maturing oligodendrocytes and early myelin appeared by week 20 in culture, with further maturation and myelin compaction evident by week 30. Promyelinating drugs enhanced the rate and extent of oligodendrocyte generation and myelination, and spheroids generated from human subjects with a genetic myelin disorder recapitulated human disease phenotypes. Oligocortical spheroids provide a versatile platform for studies of myelination of the developing central nervous system and offer new opportunities for disease modeling and therapeutic development.

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Fig. 1: Generation of oligodendrocytes in human cortical spheroids.
Fig. 2: Maturation of oligodendrocytes in oligocortical spheroids.
Fig. 3: Cortical patterning and organization in oligocortical spheroids.
Fig. 4: Promyelination drugs promote the generation of oligodendrocytes in oligocortical spheroids.
Fig. 5: Oligocortical spheroids recapitulate a human myelin disease phenotype.

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Acknowledgements

This research was supported by the NIH (R01NS093357 to P.J.T.; R01NS095280 to P.J.T. and R.H.M.; T32GM007250 and F30HD084167 to Z.S.N.), the Pelizaeus-Merzbacher Disease Foundation (P.J.T.), the New York Stem Cell Foundation (P.J.T.), the Connor B. Judge Foundation (P.J.T.), the New York Stem Cell Foundation Research Institute (V.F.), the National Stem Cell Foundation (T.J. and V.F.), and philanthropic support from the Peterson, Fakhouri, Long, Goodman, Geller, Galbut/Heil, and Weidenthal families. Additional support was provided by the CWRU SOM Light Microscopy Core Facility (S10-OD016164) and the Genomics core facility of the Case Comprehensive Cancer Center (P30CA043703). We are grateful to B. Nawash, C. Blake, M. Cartwright, M. Cameron, R. Lee, A. Miron, S. Edelheit, M. Hitomi, F. Pirozzi, and A. Wynshaw-Boris for technical assistance and discussion. Rat anti-PLP1 was a gift from W. Macklin (University of Colorado Anschutz Medical Campus, Aurora, CO, USA); rabbit anti-MYRF was provided by M. Wegner (Institut für Biochemie, Emil-Fischer-Zentrum, Universität Erlangen-Nürnberg, Erlangen, Germany).

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  1. These authors contributed equally: Mayur Madhavan, Zachary S. Nevin.

Authors and Affiliations

  1. Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Mayur Madhavan, Zachary S. Nevin, H. Elizabeth Shick, Benjamin L. L. Clayton, Daniel C. Factor, Kevin C. Allan, Lilianne Barbar & Paul J. Tesar

  2. Department of Anatomy and Regenerative Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Eric Garrison, Molly Karl & Robert H. Miller

  3. Nanofabrication and Imaging Center, George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Cheryl Clarkson-Paredes

  4. The New York Stem Cell Foundation Research Institute, New York, NY, USA

    Tanya Jain, Panagiotis Douvaras & Valentina Fossati

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Contributions

M.M., Z.S.N., and P.J.T. conceived and initiated the project. M.M. and Z.S.N. developed the oligocortical spheroid protocol and generated spheroids for all experiments. M.M., H.E.S., B.L.L.C., K.C.A., and L.B. performed immunohistochemistry and quantification and generated associated figures. D.C.F. and B.L.L.C. analyzed RNA-seq data and generated associated figures. E.G., C.C.-P., M.K., and R.H.M. designed and performed electron microscopy experiments and analysis and generated associated figures. H.E.S. maintained hPSC lines. T.J., P.D., and V.F. independently replicated the oligocortical spheroid protocol. Z.S.N., M.M., and P.J.T. wrote the manuscript with input from all other authors.

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Correspondence to Paul J. Tesar.

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Competing interests

P.J.T. and R.H.M. are consultants for Convelo Therapeutics, which has licensed patents from Case Western Reserve University. P.J.T., R.H.M., and Case Western Reserve University hold equity in Convelo Therapeutics. D.C.F. became an employee of Convelo Therapeutics subsequent to the completion of these studies. P.J.T. is a consultant and on the Scientific Advisory Board of Cell Line Genetics. P.J.T. is chair of the Scientific Advisory Board (volunteer position) for the Pelizaeus-Merzbacher Disease Foundation.

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Supplementary Figure 1 Generation of oligodendrocyte precursor cells in human cortical spheroids.

a, Schematic of spheroid generation. The protocols to generate neurocortical spheroids (NCS) and oligocortical spheroids (OCS) were the same until week 8. Neurocortical spheroids were grown in basal media, while oligocortical spheroids were treated with PDGF-AA/IGF-1 to generate OPCs from day 50-60. Increase in OPC numbers was assessed at the end of week 9. Colors in the schematic simulate neurons (magenta), astrocytes (red) and OPCs/Oligodendrocytes (green). b-c, Representative fluorescence images of week 8 (b) and week 9 (c) H7 spheroids generated with the neurocortical protocol. These spheroids do not generate OPCs (OLIG2:yellow and SOX10:mageneta). Scale bar, 50μm for b-d. d, Representative fluorescence image of week 9, H7 spheroids generated with the oligocortical protocol up through treatment with PDGF-AA/IGF-1. These spheroids generate OPCs (OLIG2:yellow and SOX10:mageneta). Arrows show OLIG2/SOX10 double-positive cells. e, Quantification of OLIG2-positive and SOX10/OLIG2-double positive OPCs in week 9 spheroids generated with the neurocortical or oligocortical protocol. Cells were counted from three planes each from five individual spheroids (colored points) of lines H7, H9 and CWRU191 and averaged (white boxes). Error bars are standard deviation, n=5 spheroids from the same batch per line.

Supplementary Figure 2 Validation of the oligocortical protocol in three additional human pluripotent cell lines.

a, Representative fluorescence images of PLP1 in week 14 oligocortical spheroids generated from H9, CWRU191, and RUES1. Similar results were obtained from 3 independent batches of spheroids for H9, CWRU191 and CWRU198 and one batch of RUES1. Scale bar, 50μm. b, Representative fluorescence images of MYRF in week 14 oligocortical spheroids generated from H9, CWRU191, and RUES1 Similar results were obtained from 3 independent batches of spheroids for H9, CWRU191 and CWRU198 and one batch of RUES1. Scale bar, 50μm. c, Schematic of MYRF quantification in Figure 1d with representative fluorescence images of MYRF in a single week 14 oligocortical spheroid generated from H7. The four panels (1-4) demonstrate four equally magnified, equally sized, and consistently distributed areas that were imaged and counted per spheroid. The reported %MYRF-positive cells per spheroid is the average of these four images. Scale bar, 50μm.

Supplementary Figure 3 Maturation of oligodendrocytes from additional pluripotent cell lines.

a, Representative fluorescence images of MYRF and PLP1 expression in week 20, H9, CWRU191, and RUES1 oligocortical spheroids. Results are representative of spheroids generated from 2 independent batches of lines H9 and CWRU191 and 1 batch of line RUES1. Scale bar, 50μm. b, Representative EM images of multiple loosely compacted myelin wraps around axons in week 20, H9 and CWRU191 oligocortical spheroids. EM analysis was performed on 3 spheroids from the same batch for each line. EM analysis of RUES1 was not performed. Scale bar, 1μm. c, Representative fluorescence images of Sox10 and MYRF expression in week 14 and 20 H7 oligocortical spheroids. Results are representative of spheroids generated from 2 independent batches. Scale bar, 50μm.

Supplementary Figure 4 BrdU-based fate mapping of oligodendrocytes in oligocortical spheroids.

a, Representative fluorescence images of two additional H7, and two H9, and two CWRU191 spheroids generated with the oligocortical protocol up through PDGF-AA/IGF-1 treatment, then administered two doses of BrdU during week 9 (day 58 and 60) to label dividing cells. After the second BrdU pulse, a majority of BrdU-positive (magenta) cells localize with SOX2-positive (yellow) and Vimentin-positive (blue) cells. By Week 14, some of the BrdU labelled cells are double-positive (arrows in high magnification inset) for the oligodendrocyte marker MYRF (cyan). Pulse chase experiments were performed on a single batch of spheroids from each line, and 4 spheroids per line were analyzed. Scale bar, 50μm.

Supplementary Figure 5 Single-cell analysis of cell populations in week 12 oligocortical spheroids.

a, Clustering of single cell RNA-seq data from Week 12 H7 oligocortical spheroids compared to single cell human fetal brain cells generated by Nowakowski et al. 2017. A continuum of progenitor populations is evident in both data sets through visualization of progenitor markers Vimentin, SOX2, Nestin, and Sox6 while only the oligocortical spheroids show evidence of an emerging oligodendrocyte cluster (PLP1/DM20 and OMG). Single Cell RNA-seq was performed 10 spheroids from a single batch.

Supplementary Figure 6 CRISPR correction of a PLP1 point mutation.

a, Schematic of the correction of a PLP1 point mutation (PLP1c.254T>G) in patient-derived hiPSCs using a guide RNA overlapping the mutation and single strand antisense oligonucleotide donor. b, Sanger sequencing trace and karyotype of the mutant parental (PLP1c.254G) line. c, Sanger sequencing trace and karyotype of the corrected (PLP1c.254T) line.

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Madhavan, M., Nevin, Z.S., Shick, H.E. et al. Induction of myelinating oligodendrocytes in human cortical spheroids. Nat Methods 15, 700–706 (2018). https://doi.org/10.1038/s41592-018-0081-4

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