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Using “Cerebral Organoids” to Trace the Elemental Composition of a Developing Brain

Curator: Marzan Khan, B.Sc

A research focused on the detection of micronutrient accumulation in the developing brain has been conducted recently by a team of scientific researchers in Brazil(1). Their study was comprised of a cutting-edge technology – human cerebral organoids, which are a close equivalent of the embryonic brain, in in-vitro models to identify some of the minerals essential during brain development using synchroton radiation(1). Since the majority of studies done on this matter have relied on samples from animal models, the adult brain or post-mortem tissue, this technique has been dubbed the “closest and most complete study system to date for understanding human neural development and its pathological manifestations”(2).

Cerebral organoids are three-dimensional miniature structures derived from human pluripotent stem cells that further differentiate into structures closely resembling the developing brain(2). Concentrating on two different time points during the developmental progression, the researchers illustrated the micronutrient content during an interval of high cell division marked on day 30 as well as day 40 when the organoids were starting to become mature neurons that secrete neurotransmitters, arranging into layers and forming synapses(2).

Synchrotron radiation X-ray fluorescence (SR-XRF) spectroscopy was used to discern each type of element present(2). After an incident beam of X-ray was directed at the sample, each atom emitted a distinct photon signature(2). Phosphorus (P), Potassium (P), Sulphur (S), Calcium (Ca), Iron (Fe), and Zinc (Zn) were found to be present in the samples in significant concentrations(2). Manganese (Mn), Nickel (Ni) and Copper (Cu) were also detected, but in negligible amounts, and therefore tagged as “ultratrace” elements(2). The distribution of these minerals, their concentration as well as their occurrence in pairs were examined at each interval(2).

Phosphorus was discovered to be the most abundant element in the cerebral organoid samples(3). Between the two time points at 30 days (cell proliferation) and 45 days (neuronal maturation) there was a marked decrease in P content(2). Since phosphorus is a major component of nucleotides and phospholipids, this reduction was clarified as a shift from a stage of cell division that requires the production of DNA and phospholipids, to a migratory and differentiation phase(2). Potassium levels were maintained during both phases, substantiating its role in mitotic cell division as well as cell migration over long distances(2). Sulfur levels were reportedly high at 30 days and 45 days(2). It was hypothesized that this element was responsible for the patterning of the organoids(2). Calcium, known to control transcription factors involved in neuronal differentiation and survival were detected in the micromolar range, along with zinc and iron(2). Zinc commits the differentiation of pluripotent stem cells into neuronal cells and iron is necessary for neuronal tissue expansion(2).

The cells in an embryo start to differentiate very early on- the neural plate is formed on the 16^th day of contraception, which further folds and bulges out to become the nervous system (containing the brain and spinal cord regions)(3). Nutrients obtained from the mother are the primary sources of diet and energy for a developing embryo to fully differentiate and specialize into different organs(2). Lack of proper nutrition in pregnant mothers has been linked to many neurodegenerative diseases occurring in their progeny(2). Spina bifida which is characterized by the incomplete development of the brain and spinal cord, is a classic example of maternal malnutrition(2,4). Paucity of minerals in the diet of pregnant women are known to hamper learning and memory in children(2). Even Schizophrenia, Parkinson’s and Huntington’s disease have been associated to malnourishment(2). By showing the different types of elements present in statistically significant concentrations in cerebral organoids, the results of this study underscore the necessity of a healthy nourishment available to mothers during pregnancy for optimal development of the fetal brain(2).

References:

1.Kenny Walter. 02/10/2017. Study focuses on Microcutrients in Human Minibrains. RandDMagazine.http://www.rdmag.com/article/2017/02/study-focuses-micronutrients-human-minibrains?et_cid=5825577&et_rid=461755519&type=cta&et_cid=5825577&et_rid=461755519&linkid=conten

2.Sartore RC, Cardoso SC, Lages YVM, Paraguassu JM, Stelling MP, Madeiro da Costa RF, Guimaraes MZ, Pérez CA, Rehen SK.(2017)Trace elements during primordial plexiform network formation in human cerebral organoids. PeerJ 5:e2927https://doi.org/10.7717/peerj.292

3.Fetal Development: Baby’s Nervous System and Brain; What to expect; 20/07/201. http://www.whattoexpect.com/pregnancy/fetal-brain-nervous-system/

4. Spina Bifida Fact Sheet; National Institute of Neurological Disorders and Stroke National Institutes of Health, Bethesda, MD 20892

https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Spina-Bifida-Fact-Sheet

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