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A Quick and Easy Strategy for Cerebral Organoid Production

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Review of “Rapid Induction of Cerebral Organoids from Human Induced Pluripotent Stem Cells Using a Chemically Defined Hydrogel and Defined Cell Culture Medium” from Stem Cells Translational Medicine by Stuart P. Atkinson

The recent flurry of studies into pluripotent stem cell (PSC)-derived “mini” organs, better known as “organoids”, has highlighted the importance of three-dimensional culture growth techniques. Self-assembling differentiating cultures of PSCs can form small immature versions of major human organs [1] and may represent an interesting new platform to study development, screen drugs, model disease, and produce therapeutically relevant cells for transplant [2, 3].

Brainy researchers from the laboratory of Timothy D. O’Brien (University of Minnesota, USA) realized the potential of organoid production and sought to devise a quick and easy strategy to create cerebral organoids! They now report their endeavors in Stem Cells Translational Medicine, where they describe a robust, simple, and defined system to produce organoids with evidence of forebrain, midbrain, and hindbrain specification [4].

The starting point for the process involved the imbedding of large, undisrupted iPSC colonies within a hyaluronic acid/chitosan 3D hydrogel followed by culture in xeno-free/feeder-free PSC medium without additional growth factor addition. After 10 to 14 days of culture, the authors observed 1 mm wide spherical organoids with a neural morphology, including evidence of neural rosette and other neuroepithelial structure formation. Notably, the organoid production process progressed in a similar manner in iPSCs derived from cerebral childhood adrenoleukodystrophy (ccALD) patients, a disorder characterized by demyelination within the cerebral white matter [5].

Analysis of organoid content suggested the presence of various progenitor/stem cell types, and provided evidence for forebrain, midbrain, and hindbrain neural cell development. Further cerebral organoid growth till day 28 permitted the growth of 3 mm spherical structures with increased complexity (See figure) including evidence for corticogenesis. Physiologic assessment of the cerebral organoids also demonstrated responses expected of functioning neurons, such as responses to glutamate and depolarization in many cells.

The simplicity, rapidity, scalability, and use of defined substrates/growth media without additional (expensive) growth factors make this system an especially attractive means to produce cerebral organoids. Quick and easy strategies such as this have the potential to provide a means to model normal development, model disease, to develop and test new drugs and treatment regimens, and also, to apply in cell treatment/replacement therapies.

References

  1. Lancaster MA and Knoblich JA Organogenesis in a dish: modeling development and disease using organoid technologies. Science 2014;345:1247125.
  2. Lancaster MA, Renner M, Martin CA, et al. Cerebral organoids model human brain development and microcephaly. Nature 2013;501:373-379.
  3. Kadoshima T, Sakaguchi H, Nakano T, et al. 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 2013;110:20284-20289.
  4. Lindborg BA, Brekke JH, Vegoe AL, et al. Rapid Induction of Cerebral Organoids From Human Induced Pluripotent Stem Cells Using a Chemically Defined Hydrogel and Defined Cell Culture Medium. Stem Cells Transl Med 2016;5:970-979.
  5. Berger J and Gartner J X-linked adrenoleukodystrophy: clinical, biochemical and pathogenetic aspects. Biochim Biophys Acta 2006;1763:1721-1732.