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Developmental biology - Stem Cells|
Predicting How One Cell Can Become Another
"The method has great potential for regenerative medicine when it comes to replacing cell populations that are lost in the course of disease"
In collaboration with Parkinson disease's research at Karolinska Institute in Sweden, Luxembourg scientists tested the feasibility of their method showing stem cells from the brain can be reprogrammed and ultimately converted into neurons. Their results appear in Nature Communications.
Identifying cell types
Skin cells and neurons are not the same, obvious to anyone looking at them. But even cells of the same type can have minute differences in genetic activity with a powerful influence over their function, giving rise to different cell subpopulations or subtypes.
For example, dopaminergic neurons are nerve cells in the brain that produce a dopamine neurotransmitter. Located in the substantia nigra of the midbrain, over the course of Parkinson's disease, dopaminergic neurons die off - but only one specific subtype. "The identity of a particular cell subtype is characterised and maintained by a few interacting regulatory genes", del Sol explains. "Yet the differences between subtypes are subtle and difficult to detect using existing analytic methods."
In order to address this problem, del Sol and his team developed a computational platform "TransSyn," able to predict gene expression based on individual cells within a population. Following a multistep computation, TransSyn searches for subtle differences between cell subtypes.
Researchers know there are multiple, harmonious interactions regulating how genes work together which characterise a subtype. Once these harmonious 'transcriptional cores' are identified in each subtype, there is enough data to convert one cell subtype into another. The scientists treat cell cultures with specific factors that activate certain genes while deactivating others - and alter the gene's expression or function.
Cooperation with Karolinska Institute
Working from predictions made in Luxembourg, researchers at the Swedish Karolinska Institute, converted human neuroepithelial stem cells (hNES cells) from the hindbrain into midbrain dopaminergic neuron progenitor cells, which are capable of developing into dopaminergic neurons. "This could prove to be a strategy for cell therapy in Parkinson's disease," del Sol asserts.
Testing predictions in the lab
Luxembourg researchers continue testing their platform, at present in collaboration with the Gladstone Institute of Cardiovascular Disease, Roddenberry Stem Cell Center in San Francisco, California, USA. American researchers, led by Deepak Srivastava MD, Director, are looking for an efficient way to convert heart cells of the right ventricle into those of the left ventricle and vice versa. The two ventricle subtypes exhibit subtle differences in their gene expression profiles and function.
"We have the predictions all ready. Our colleagues in the US will be starting their experiments in the next few weeks."
Single-cell RNA sequencing allows defining molecularly distinct cell subpopulations. However, the identification of specific sets of transcription factors (TFs) that define the identity of these subpopulations remains a challenge. Here we propose that subpopulation identity emerges from the synergistic activity of multiple TFs. Based on this concept, we develop a computational platform (TransSyn) for identifying synergistic transcriptional cores that determine cell subpopulation identities. TransSyn leverages single-cell RNA-seq data, and performs a dynamic search for an optimal synergistic transcriptional core using an information theoretic measure of synergy. A large-scale TransSyn analysis identifies transcriptional cores for 186 subpopulations, and predicts identity conversion TFs between 3786 pairs of cell subpopulations. Finally, TransSyn predictions enable experimental conversion of human hindbrain neuroepithelial cells into medial floor plate midbrain progenitors, capable of rapidly differentiating into dopaminergic neurons. Thus, TransSyn can facilitate designing strategies for conversion of cell subpopulation identities with potential applications in regenerative medicine.
Authors: Satoshi Okawa, Carmen Saltó, Srikanth Ravichandran, Shanzheng Yang, Enrique M. Toledo, Ernest Arenas and Antonio del Sol.
S.O. is supported by an FNR CORE grant (C15/BM/10397420), S.R. by University of Luxembourg IRP Grant (R-AGR-3227-11), E.M.T. by a fellowship from the Swedish Research Council. This project was supported by the Swedish Research Council (VR 2016-01526), Swedish Foundation for Strategic Research (SRL program and SB16-0065), European Commission (NeuroStemcellRepair), Karolinska Institutet, Cancerfonden (CAN 2016/572), and Hjärnfonden (FO2015:0202). We would also like to thank Gioele La Manno and Peter Lönneberg for help with single cell data; and the Knut and Alice Wallenberg Foundation for support to the CLICK imaging facility at KI.
The authors declare no competing interests.
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A newly developed computation method allows Luxembourg researchers to accurately predict how one subpopulation of stem cells can be converted into another. Image: University of Luxembourg