“Mini brains” help researchers identify cellular targets for gestational iron deficiency

07 Mar 2023 --- University of Rochester Medical Center (US) researchers have identified a new embryonic neuronal progenitor cell target for gestational iron deficiency (gID), representing significant progress in finding the condition’s cellular origin.

Having identified cellular targets in a mouse model of gID, the researchers are in the process of establishing a human model of iron deficiency using brain organoids – a mass of cells that represents a brain. 

These “mini-brains” can be instructed to form specific regions of the ganglionic eminences of the embryonic human brain to help researchers mimic the development of the neuronal progenitor cells targeted by gID in the mouse.

“This model will not only allow us to determine the relevance of our finding in the mouse model for the human system but will also enable us to find new cellular targets for gID that are not even present in mouse models,” says Margot Mayer-Proschel, Ph.D. and professor of Biomedical Genetics and Neuroscience at the University of Rochester Medical Center.

Iron deficiency limits brain development
According to the researchers, numerous studies have found that mothers with low iron levels during pregnancy have a higher risk of giving birth to a child that develops cognitive impairments. 

“Understanding such cellular targets of this prevalent nutritional deficiency will be imperative to take the steps necessary to make changes to how we think of maternal health. Iron is an important part of that and the limited impact of iron supplementation after birth makes it necessary to identify alternative approaches,” explains Mayer-Proschel.

The cells that make up the human brain begin developing long before the physical shape of the brain has formed. This early organizing of a network of cells plays a major role in brain health throughout a lifetime. 

The study, “Gestational iron deficiency affects the ratio between interneuron subtypes in the postnatal cerebral cortex in mice,” and its findings were published in Development.

Targets for future therapiesExpectant mothers with low iron levels are at higher risk of having a child with cognitive disorders.
The mechanisms by which gID contributes to cognitive impairment are not fully understood. The researchers first demonstrated that the brains of animals born to iron-deficient mice react abnormally to excitatory brain stimuli and that iron supplements given at birth do not restore functional impairment that appears later in life. 

The lab was awarded a US$2 million grant from the National Institute of Child Health & Human Development in 2018 to carry out the work. 

“This could connect gestational iron deficiency to these very complex disorders. Understanding that connection could lead to changes to healthcare recommendations and potential targets for future therapies,” says Mayer-Proschel.

The scientists worked backward to make the connection. They looked at the brains of adults and young mice born with gID and found a disruption of interneurons – cells that control the balance of excitation and inhibition and ensure that the mature brain can respond appropriately to incoming signals. 

“As we looked back, we could identify when the progenitor cells started acting differently in the iron-deficient animals compared to iron normal controls,” Mayer-Proschel explains. 

“This confirms that the correlation between the cellular change and gID happens in early utero. Translating the timeline to humans would put it in the first three months of gestation before many women know they are pregnant.”

The specific progenitor cell pool was disrupted in embryonic brains exposed to gID. These findings provide evidence that gID affects the behavior of embryonic progenitor cells causing the creation of a suboptimal network of specialized neurons later in life.

Another study published in Nutrients revealed a significant link between greatly exceeding the recommended amounts of the trace minerals copper and iron and cognitive decline. The researchers hold that further studies must be conducted to confirm their initial findings. 

Edited by Inga de Jong