Brain organoids (3D) have been reproduced for the first time in the laboratory as a model for studying Fragile X syndrome, an inherited disorder linked to mutations in the FMRP gene located on the X chromosome, which causes cognitive disability, learning and interpersonal problems.

The study, published in the journal Cell Death and Disease, is an all-Italian collaboration between the Istituto Italiano di Tecnologia – IIT (Italian Institute of Technology), and Sapienza University of Rome. In particular between Silvia Di Angelantonio and Alessandro Rosa, professors at the Department of Physiology and Pharmacology "Vittorio Erspamer" and the Department of Biology and Biotechnology "Vittorio Erspamer" respectively, and researchers affiliated with the IIT of Rome 'Center for Life Nano & Neuro-Science' coordinated by Giancarlo Ruocco of Sapienza University and the D3Validation group of the IIT in Genoa. 

3D organoids are artificial three-dimensional cell structures generated from human stem cells that mimic the characteristics of real organs. They are in vitro models that show conditions very similar to human ones from both a physiological and a pathological point of view and mimic the interaction between cells in vitro.

In recent years, the development of human brain organoids derived from induced pluripotent stem cells (iPS cells, Nobel Prize for Medicine 2012) has made it possible to reduce the number of tests carried out on animal models and has opened up new horizons for studying neurodevelopmental diseases such as autism and schizophrenia or the notorious Zika virus infection.

iPS cells are stem cells obtained by 'reprogramming' non-stem cells, e.g. blood or skin cells, taken from an adult individual. 

In this study, classical cell cultures (2D) and brain organoids (3D) developed from iPS cells reproduce in vitro some typical features of Fragile X syndrome, allowing researchers to study the molecular mechanism of the pathology and to demonstrate how the FMRP protein is required to support the proliferation of neuronal and glial cells properly and to set the correct excitation-inhibition ratio in human brain development.

The study of 3D cell models has also revealed an imbalance in the size of Fragile X organoids and healthy control organoids but above all, an impairment in the excitation-inhibition balance of Fragile X cells in favour of hyperexcitability, which could be hypothesised to be at the root of epileptic seizures, typical symptoms of Fragile X patients.

These results expand our knowledge of Fragile X syndrome and lay the groundwork for screening new effective drugs for this condition and repositioning those already in use.

"'To date, this work is the first to demonstrate the possibility of studying Fragile X syndrome in brain organoids and suggests that this experimental platform can be applied to model Fragile X syndrome in vitro," says Silvia Di Angelantonio.

"'Using human organoids to study diseases such as Fragile X syndrome has significant advantages for understanding the underlying molecular mechanisms," adds Alessandro Rosa. 

References:

Novel fragile X syndrome 2D and 3D brain models based on human isogenic FMRP-KO iPSCs - Carlo Brighi, Federico Salaris, Alessandro Soloperto, Federica Cordella, Silvia Ghirga, Valeria de Turris, Maria Rosito, Pier Francesca Porceddu, Chiara D’Antoni, Angelo Reggiani, Alessandro Rosa and Silvia Di Angelantonio - Cell Death & Disease 2021 https://doi.org/10.1038/s41419-021-03776-8

Further Information

Silvia Di Angelantonio
Department of Physiology and Pharmacology "Vittorio Erspamer"
silvia.diangelantonio@uniroma1.it

Alessandro Rosa
Department of Biology and Biotechnology "Charles Darwin"
alessandro.rosa@uniroma1.it