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Sartore RC, Cardoso SC, Lages YV, Paraguassu JM, Madeiro da Costa RF, Guimarães MZ, Pérez CA, Rehen SK. (2016) Trace elements during primordial plexiform network formation in human cerebral organoids. PeerJ Preprints4:e2126v1https://doi.org/10.7287/peerj.preprints.2126v1
Systematic studies of micronutrients during brain formation are hindered by restrictions to animal models and adult post-mortem tissues. Recently, advances in stem cell biology have enabled recapitulation of the early stages of human telencephalon development. In the present work, we exposed cerebral organoids derived from human pluripotent stem cells to synchrotron radiation in order to measure how biologically valuable micronutrients are incorporated and distributed in the exogenously developing brain. Our findings indicate that elemental inclusion in organoids is consistent with human brain tissue and involves calcium, iron, phosphorus, potassium, sulfur, and zinc. Local trends in concentrations suggest a switch from passive to actively mediated transport across cell membranes. Finally, correlational analysis for pairs of elements shows spatially conserved patterns, suggesting they may physically associate, be stored in similar compartments or used in related biological processes. These findings might reflect which trace elements are important during human brain development and will support studies aimed to unravel the consequences of disrupted metal homeostasis for neurodevelopmental diseases, including those manifested in adulthood.
The levels of trace elements in normal and pathological conditions are central to establishing cause and effect relationships between nutritional deficiencies or metal transporters inabilities and disorders. In fact, disturbances in early brain development have been deemed in increasing risk of later developing Parkinson’s disease and schizophrenia. We developed a cerebral organoid, slightly different from Lancaster et al (2013), in which two distinct developmental stages could be distinguished: one with high proliferation and low differentiation and the other low proliferation and high differentiation. Then we employed Synchrotron Radiation based micro X-Ray Fluorescence with these organoids to provide a first glimpse into how and where elements may play active roles in early brain formation and development, comparing these two stages. Results of this study are of interest to investigators in several different fields, including neurobiology and developmental biology, and may pave a new model for the analysis of the consequences of imbalanced trace elements in human brain organogenesis and neurological diseases. In addition, it further explores the cerebral organoid as an innovative model for understanding human brain development per se and in pathologies.
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