Abstract
The limited access to functional human brain tissue has led to the development of stem cell-based alternative models. The differentiation of human pluripotent stem cells into cerebral organoids with self-organized architecture has created novel opportunities to study the early stages of the human cerebral formation. Here we applied state-of-the-art label-free shotgun proteomics to compare the proteome of stem cell-derived cerebral organoids to the human fetal brain. We identified 3,073 proteins associated with different developmental stages, from neural progenitors to neurons, astrocytes, or oligodendrocytes. The major protein groups are associated with neurogenesis, axon guidance, synaptogenesis, and cortical brain development. Glial cell proteins related to cell growth and maintenance, energy metabolism, cell communication, and signaling were also described. Our data support the variety of cells and neural network functional pathways observed within cell-derived cerebral organoids, confirming their usefulness as an alternative model. The characterization of brain organoid proteome is key to explore, in a dish, atypical and disrupted processes during brain development or neurodevelopmental, neurodegenerative, and neuropsychiatric diseases.
Highlights
Understanding the molecular basis of human diseases is currently one of the main challenges faced in contemporary medicine
We present findings on large-scale proteome profiling of human cerebral organoids, using systems level analysis showing initial development of varied cell types leading to a complex neural network
To resolve the complex proteome of whole, 45-day cerebral organoids, we used state-of-the-art label-free shotgun proteomics to provide broader coverage of cerebral organoids cultured for 45 days (Figure 1A), in which early neuronal network formation already takes place, as previously reported by our group (Sartore et al, 2017)
Summary
Understanding the molecular basis of human diseases is currently one of the main challenges faced in contemporary medicine. Some recent studies have shown potential for modeling several human disorders using cerebral organoids, such as microcephaly (Lancaster et al, 2013), lissencephaly (Bershteyn et al, 2017), Zika virus infection microcephaly (Cugola et al, 2016; Garcez et al, 2016; Qian et al, 2016), Alzheimer’s disease (Raja et al, 2016), and autism spectrum disorders (Mariani et al, 2015) Those modeling applications may lead to new insight into drug discovery and interactions, cell therapy, and basic research (Brennand et al, 2014; Quadrato and Arlotta, 2017)
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