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Wang Su's team at Southeast University found that microenvironmental glial cells regulate stem cell self-renewal and differentiation by delivering iron to neural stem cells through ferritin

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The study of neural stem cells is of great significance for the treatment of neural development and nervous system diseases. However, the regulation mechanism of neural stem cells has not been fully elucidated, especially the regulation of neural stem cells by microenvironment is relatively less known.

On September 10, 2024, the team of Professor Wang Su of Southeast University published the title "eLife" in the internationally renowned academic journal" Glial ferritin maintain neural stem cells via transporting iron need for self-renewal inDrosophila"The research paper reported that microenvironmental glial cells regulate stem cell self-renewal and differentiation by delivering iron to neural stem cells through ferritin. The paper is featured as eLife Digest (https://elifesciences.org/digests/93604/ironing-out-the-developing-brain).

This study used Drosophila as a model and found that ferritin in microenvironmental glial cells transported iron to neural stem cells through cooperation with Zip13, ensuring normal ATP production and maintaining stem cell self-renewal and proliferation. In addition, knockdown of ferritin or chelated iron in glial cells inhibited tumor growth in tumor models, suggesting that ferritin is a potential target for tumor suppression. Finally, this study proposes a new type of iron homeostasis model-binary cell iron homeostasis, that is, the iron homeostasis formed between stem cells and microenvironment cells: microenvironment cells produce sufficient ferritin (iron-containing), while stem cells that hardly produce ferritin need iron to maintain their normal functions, which will transmit signals to glial cells to transport iron into stem cells through ferritin, thus ensuring the progress of normal biological processes. This study provides a new perspective for the regulation of neural stem cells and their microenvironment, and reveals that ferritin or iron metabolism in the microenvironment can be used as potential tumor suppression targets.

Iron is an important micronutrient required by almost all living organisms. According to the World Health Organization, iron deficiency is the most common nutritional deficiency, affecting 33% of non-pregnant women, 40% of pregnant women and 42% of children. Although anemia is the most obvious clinical manifestation of iron deficiency, impaired neurodevelopment is also a serious problem because the problem persists long after the iron deficiency is treated and the anemia is resolved. However, it is not clear how iron affects the development of the nervous system.

When there is a lack of iron in the food, the brain development of the fruit fly is obviously defective and the volume becomes smaller. After further observation, iron deficiency will lead to a decrease in the number of neural stem cells, decreased proliferation. In addition, the team found that knocking down the ferritin-encoding gene that stores iron in glial cells can also lead to brain development defects, a decrease in the number of stem cells, and a significant decline in proliferation. Next to explore the mechanism, the authors found that ferritin in glial cells will be transported to stem cells, providing them with iron, so as to maintain the energy production of stem cells, so that they can carry out normal self-renewal and proliferation. Combined with the data of Shengxin, the NAD of stem cells after knocking down ferritin was further determined.⁺Defects in generation, energy generation, biosynthesis, etc. More importantly, energy production can be partially restored by overexpressing NADH dehydrogenase Ndi1 in stem cells, rescuing the stem cell loss phenotype. After a series of analysis, it was finally proved that the loss of stem cells caused by ferritin knockdown was caused by the lack of energy and the early differentiation of stem cells, rather than due to the origin defect or apoptosis.

In addition, ferritin/iron metabolism is critical not only for normal neural stem cell function, but also for tumor growth. In the Drosophila tumor model, knockdown of ferritin in its microenvironment or restriction of iron in the microenvironment by chelating agents can effectively inhibit tumor growth. Similarly, intraperitoneal injection of iron chelator can effectively inhibit the growth of glioma in mice and prolong the survival time of mice. In the future, targeting ferritin in the mammalian tumor microenvironment to inhibit tumor growth is a promising direction.

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