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Cerebral organoids model human brain development and microcephaly.
Literature Information
| DOI | 10.1038/nature12517 |
|---|---|
| PMID | 23995685 |
| Journal | Nature |
| Impact Factor | 48.5 |
| JCR Quartile | Q1 |
| Publication Year | 2013 |
| Times Cited | 2507 |
| Keywords | cerebral organoids, human brain development, microcephaly |
| Literature Type | Journal Article, Research Support, Non-U.S. Gov't |
| ISSN | 0028-0836 |
| Pages | 373-9 |
| Issue | 501(7467) |
| Authors | Madeline A Lancaster, Magdalena Renner, Carol-Anne Martin, Daniel Wenzel, Louise S Bicknell, Matthew E Hurles, Tessa Homfray, Josef M Penninger, Andrew P Jackson, Juergen A Knoblich |
TL;DR
This study presents a novel three-dimensional organoid culture system derived from human pluripotent stem cells, which successfully replicates various brain regions and their development, including the cerebral cortex with its distinct progenitor populations. By modeling microcephaly using patient-specific induced pluripotent stem cells, the research reveals premature neuronal differentiation in organoids, providing insights into the underlying mechanisms of this challenging brain disorder and demonstrating the potential of organoids for studying human brain development and diseases.
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cerebral organoids · human brain development · microcephaly
Abstract
The complexity of the human brain has made it difficult to study many brain disorders in model organisms, highlighting the need for an in vitro model of human brain development. Here we have developed a human pluripotent stem cell-derived three-dimensional organoid culture system, termed cerebral organoids, that develop various discrete, although interdependent, brain regions. These include a cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids are shown to recapitulate features of human cortical development, namely characteristic progenitor zone organization with abundant outer radial glial stem cells. Finally, we use RNA interference and patient-specific induced pluripotent stem cells to model microcephaly, a disorder that has been difficult to recapitulate in mice. We demonstrate premature neuronal differentiation in patient organoids, a defect that could help to explain the disease phenotype. Together, these data show that three-dimensional organoids can recapitulate development and disease even in this most complex human tissue.
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Primary Questions Addressed
- How do cerebral organoids compare to traditional animal models in studying brain disorders?
- What specific features of microcephaly can be further explored using cerebral organoids?
- In what ways can the findings from cerebral organoid studies influence therapeutic approaches for brain development disorders?
- What are the limitations of using cerebral organoids for modeling complex brain functions and diseases?
- How can the organization of progenitor zones in cerebral organoids inform our understanding of cortical development in humans?
Key Findings
Research Background and Purpose
The human brain's complexity poses significant challenges for studying brain disorders in traditional model organisms. This study aims to develop an in vitro model that accurately reflects human brain development and can be used to study neurodevelopmental disorders, specifically focusing on microcephaly.
Main Methods/Materials/Experimental Design
The researchers developed a 3D culture system to generate cerebral organoids from human pluripotent stem cells (PSCs). This system allows the formation of distinct brain regions and mimics various aspects of human brain development.
Technical Workflow
- Cell Culture: Human embryonic stem cells (H9) or induced pluripotent stem cells (iPSCs) were cultured and dissociated.
- Neuroectoderm Formation: EBs were formed and induced to develop into neuroectoderm.
- 3D Culture: Tissues were embedded in Matrigel droplets and transferred to a spinning bioreactor to enhance nutrient absorption.
- Cerebral Organoid Development: Organoids were allowed to develop for 20-30 days, leading to the formation of defined brain regions.
- Modeling Microcephaly: Patient-derived iPSCs were used to study microcephaly, examining premature neuronal differentiation.
Key Results and Findings
- Cerebral Organoid Characteristics: The organoids displayed features resembling human brain regions, including distinct cortical structures and the presence of outer radial glial (oRG) cells.
- Microcephaly Modeling: Organoids derived from a patient with CDK5RAP2 mutations exhibited reduced size and premature differentiation of neurons, consistent with microcephaly phenotypes.
- Neuronal Behavior: Organoids demonstrated spontaneous calcium oscillations, indicating functional neuronal activity.
Main Conclusions/Significance/Innovation
The study successfully established a novel in vitro model of human brain development using cerebral organoids, which can replicate aspects of human neurodevelopment and model disorders like microcephaly. This model presents a significant advancement in understanding human brain development and associated diseases, potentially offering insights into pathogenesis that cannot be obtained from traditional animal models.
Research Limitations and Future Directions
- Limitations: The model may not fully replicate the complexity of the human brain, including the lack of a circulatory system and potential artifacts of in vitro culture.
- Future Directions: Further refinement of the organoid model is needed to enhance its maturity and functionality. Additionally, exploring other neurodevelopmental disorders and their mechanisms using this model could provide valuable insights.
| Section | Summary |
|---|---|
| Research Background | Need for in vitro human brain models to study complex disorders. |
| Methods | 3D culture of cerebral organoids from human PSCs, modeling microcephaly. |
| Key Results | Organoids replicate human brain features; microcephaly model shows premature differentiation. |
| Conclusions | A novel model for studying human neurodevelopment and diseases. |
| Limitations | Complexity of human brain not fully replicated; need for further refinement. |
| Future Directions | Enhance model maturity; study additional neurodevelopmental disorders. |
References
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Literatures Citing This Work
- Developmental neuroscience: Miniature human brains. - Oliver Brüstle - Nature (2013)
- Stem cells: Small but beautiful. - Leonie Welberg - Nature reviews. Neuroscience (2013)
- Cerebral organoids in a dish: progress and prospects. - Marina Bershteyn;Arnold R Kriegstein - Cell (2013)
- Artificial three-dimensional niches deconstruct pancreas development in vitro. - Chiara Greggio;Filippo De Franceschi;Manuel Figueiredo-Larsen;Samy Gobaa;Adrian Ranga;Henrik Semb;Matthias Lutolf;Anne Grapin-Botton - Development (Cambridge, England) (2013)
- Stem cells: The developing human brain--modeled in a dish. - Erika Pastrana - Nature methods (2013)
- Engineering approaches to illuminating brain structure and dynamics. - Karl Deisseroth;Mark J Schnitzer - Neuron (2013)
- Progress in the genetics of polygenic brain disorders: significant new challenges for neurobiology. - Steven A McCarroll;Steven E Hyman - Neuron (2013)
- Evolving concepts of gliogenesis: a look way back and ahead to the next 25 years. - Marc R Freeman;David H Rowitch - Neuron (2013)
- Cortical evolution: judge the brain by its cover. - Daniel H Geschwind;Pasko Rakic - Neuron (2013)
- Precocious acquisition of neuroepithelial character in the eye field underlies the onset of eye morphogenesis. - Kenzo Ivanovitch;Florencia Cavodeassi;Stephen W Wilson - Developmental cell (2013)
... (2497 more literatures)
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