Two cutting edge stem cell techniques have joined forces this week to produce a breakthrough in our understanding of the causes of Autism Spectrum Disorders (ASD). Years of study have gone into assessing if specific mutations in autism-associated genes contribute to the abnormal brain development observed in ASD with little or no luck.
Seeing this problem, a group of enterprising researchers led by Flora M. Vaccarino (Yale University, USA) chose to try something new – combining the generation of induced pluripotent stem cells (iPSCs) from ASD patients and three-dimensional (3D) brain “organoid” culture techniques.
So how did they apply this new strategy and what did they discover?
- The group generated iPSCs from ASD patients presenting with an abnormally large head/brain (macrocephaly)
- This is a common trait linked to the clinical severity of ASD.
- They then differentiated these cells into well ordered “mini-brains” a few millimeters in diameter in a free-floating 3D culture.
- No common mutations existed in these cells, but the study found a common pattern of gene dysregulation: the upregulation of cell proliferation, neuronal differentiation, and synaptic assembly genes.
- In-depth organoid analysis then found that GABAergic neural progenitor cells proliferated at a higher rate than normally observed, leading to the overproduction of GABAergic neurons.
- This creates an overabundance of cells and an imbalance in the ratio of the inhibitory GABAergic and the excitatory glutamatergic neurons which make up most neural circuits.
- Transcriptional analysis linked high progenitor proliferation, overproduction of neurons, and disease severity to the overexpression of a single gene – the transcription factor FOXG1.
- FOXG1 silencing via small interfering (si)RNA limited cell proliferation and the excessive GABAergic differentiation seen in ASD organoids.
The combination of these techniques has brought great success, with FOXG1 now representing not only a molecular signature of ASD, but also a potential drug target.
But let´s think big; iPSC-derived organoid production may improve the understanding of multiple diseases and disorders of unknown origin involving any human organ and could lead to new effective therapies.
You can read this amazing new study at Cell, July 2015.