Stem cell research permits insight into early brain development disorders in Zika virus infections


Jay Gopalakrishnan, Olaf Utermöhlen and Martin Krönke from the CMMC, the Inst. of Med. Microbiology, Immunology & Hygiene and the DZIF reprogrammed human skin cells into neural stem cells and used these to develop a 3D experimental model that depicts early brain development.

Since autumn 2015, the Zika virus epidemic has been causing marked increases in the birth of babies with much too small heads, or so-called “microcephaly”, especially in South and Central America.

The link between Zika infections and the microcephaly, which is accompanied by mental and other neurological disorders, has been widely recognised. However, there has been a lack of scientific evidence for the damaging effect Zika has on early brain development. In a joint research project, Cologne scientists have now discovered a new mechanism with which the Zika virus contributes to the development of malformations in the newborns of Zika-infected mothers.

The research teams of Jay Gopalakrishnan, Olaf Utermöhlen and Martin Krönke from the Center for Molecular Medicine Cologne, the Institute of Medical Microbiology, Immunology and Hygiene and the German Center for Infection Research (DZIF) reprogrammed human skin cells into neural stem cells and used these to develop a 3D experimental model that depicts early brain development. With this model, the damaging effect of Zika can be precisely investigated. The findings from this joint project have now been published in the renowned scientific journal “Cell Stem Cell”.

Zika infections are usually harmless. They become dangerous when pregnant women are affected, in which case they can result in the birth of children with severe craniocerebral malformations, or so-called “microcephaly”. Globally, researchers have been searching for the causal relationships responsible for these malformations. This research is particularly challenging due to ethical problems that seem almost insurmountable - as it involves mothers that become infected during pregnancy as well as their unborn children.

A method established by Jay Gopalakrishnan and his team - who is heading a Junior Research Group at the CMMC - now provides a way out of this predicament: in test tubes, with the help of molecular biological methods, human skin cells from healthy donors were reprogrammed into so-called “induced pluripotent stem cells” (ipSC).

In turn, these ipSC were programmed into “neuronal progenitors” under suitable culturing conditions. These neuronal progenitors constitute the original line of cells for the entire further brain development.

Aggregating many neuronal progenitors in defined culturing conditions leads to the development of three-dimensional brain organoids that are a few millimetres in size and which reflect the early embryonic brain development. As model systems in test tubes, these “3D brain organoids” enable investigations on the effect of neurotropic virus infections on human embryonic brain growth.

In this experimental system, the Cologne researchers observed that Zika virus infections in human brain organoids lead to a premature differentiation of neuronal progenitors into mature nerve cells. Although, at a first glance, this early maturation seems harmless, it has a major impact on the further brain development.

This premature, massive differentiation of neuronal progenitors results in a shortage of these important progenitor cells for the developing brain organoids to grow in size. Evidently, Zika virus infections cause lesions in centrosomes, which are small cell organelles that enable rapid and precise cell division and play an important role in the expansion of neuronal progenitors.

For the first time, the experiments with the infection were conducted with a Zika virus strain that had been isolated directly from an affected foetus with microcephaly. This is an important factor for the transferability of the observations to the Zika-associated microcephaly epidemic in South America. With this, convincing scientific evidence of how Zika causes microcephaly has been attained.

This research work was funded by the Fritz Thyssen Foundation, the CMMC and the SFB CRC 670.

Original publication:
Gabriel, E., Ramani, A., Karow, U., Gottardo, M., Natarajan, K., Gooi, L.M., Goranci-Buzhala, G., Krut, O., Peters, F., Nikolic, M., Kuivanen, S., Korhonen, E., Smura, T., Vapalahti, O., Papantonis, A., Schmidt-Chanasit, J., Riparbelli, M., Callaini, G., Krönke, M., Utermöhlen, O., and Gopalakrishnan, J. (2017). Recent Zika Virus Isolates Induce Premature Differentiation of Neural Progenitors in Human Brain Organoids. Cell stem cell.

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