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Single Cell Analyses Suggest Stressed out Organoids Do Not Match Up

Review of “Cell stress in cortical organoids impairs molecular subtype specification” from Nature by Stuart P. Atkinson

Our relative lack of knowledge regarding the cellular-makeup of the developing brain has limited our ability to evaluate the utility of cerebral organoids for disease modeling, drug screening, and regenerative medicine. While studies have suggested the preservation of cell types in organoid models [1, 2] and the emergence of spatial gradients [3-5], others have underscored the dissimilarity of organoids and primary cells [6-8]. In the hope of providing support for research based on cerebral organoids, a team led by Arnold R. Kriegstein (University of California, San Francisco, USA) recently compared the transcriptome of developing human cortex and cortical organoids at the single-cell level [9].

Bhaduri et al. describe their comparison of ~250,000 single cells derived from 37 forebrain organoids with cells derived from samples representative of normal human cortical development during the period that encompasses neurogenesis. Overall, organoids failed to display the same distinct cellular subtype identities, appropriate progenitor maturation, or spatial segregation; furthermore, the authors also discovered the ectopic activation of cell stress pathways in cortical organoids, as evidenced by expression of the glycolysis gene phosphoglycerate kinase 1 (PK1) and the endoplasmic reticulum stress genes Archain 1 (ARCN1) and Golgi reassembly stacking protein 2 (GORASP2), which causes the subsequent impairment to cell-type specification. 

Interestingly, primary progenitors transplanted into organoids also displayed elevated levels of stress-related genes, suggesting that the organoid environment itself activates stress; furthermore, transplantation of dissociated organoids into the mouse cortex alleviated organoid stress and subtype defects, suggesting that metabolic stress contributes to specification deficiencies in organoid cells.

The authors underscore that the lack of specificity in organoids must be considered when studying areas such as development, cell-type-specific disease phenotypes, or cellular connectivity, and also suggest that metabolic stress in utero could foster unwanted changes to molecular identity that may promote altered human brain development.

For more on the past, present, and future of organoids, do not stress! Head over to the Stem Cells Portal to find out more!

References

  1. Camp JG, Badsha F, Florio M, et al., Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. PNAS 2015;112:15672.
  2. Sloan SA, Darmanis S, Huber N, et al., Human Astrocyte Maturation Captured in 3D Cerebral Cortical Spheroids Derived from Pluripotent Stem Cells. Neuron 2017;95:779-790.e6.
  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. PNAS 2013;110:20284.
  4. Lancaster MA, Renner M, Martin C-A, et al., Cerebral organoids model human brain development and microcephaly. Nature 2013;501:373-379.
  5. Eiraku M, Watanabe K, Matsuo-Takasaki M, et al., Self-Organized Formation of Polarized Cortical Tissues from ESCs and Its Active Manipulation by Extrinsic Signals. Cell Stem Cell 2008;3:519-532.
  6. Pollen AA, Bhaduri A, Andrews MG, et al., Establishing Cerebral Organoids as Models of Human-Specific Brain Evolution. Cell 2019;176:743-756 e17.
  7. Amiri A, Coppola G, Scuderi S, et al., Transcriptome and epigenome landscape of human cortical development modeled in organoids. Science 2018;362.
  8. Mansour AA, Goncalves JT, Bloyd CW, et al., An in vivo model of functional and vascularized human brain organoids. Nature Biotechnology 2018;36:432-441.
  9. Bhaduri A, Andrews MG, Mancia Leon W, et al., Cell stress in cortical organoids impairs molecular subtype specification. Nature 2020;578:142-148.