A team of scientists, led by Dr Gabriel Balmus, Fellow at the UK DRI at Cambridge, have successfully developed a seven-week protocol for the derivation of mouse haploid embryonic stem cells, producing a fast, reproducible and versatile means for creating disease models. Moreover, this protocol can be used for the derivation of human haploid embryonic stem cells.
Within mammals, the majority of species maintain their genomes in a diploid (2n) organization for most somatic cells and haploid (n) for gametes. The somatic/diploid and germline/haploid configuration is beneficial and enables genetic variation to be increased through sexual reproduction. However, when utilising cells for experimental investigation and manipulation, the diploid status of most cells makes it difficult to target genes via mutagenesis techniques.
Published today (03 June) in Nature Protocols, Gabriel and the team outline a relatively quick protocol to derive and subsequently maintain mouse haploid embryonic stem cells (hESC). The authors say these are genomically and karyotypically stable, are innately immortal, isogenic and can be derived in an array of differentiated cell types, thus highly amenable for genetic screens and for defining molecular connectivity pathways.
On the novelty and importance of this work, Gabriel said:
‘The capability of deriving haploid embryonic stem cells (ESC) of mouse and human origin represents an important advancement towards creating tools that will be useful for better understanding medical relevant problems. The availability of such pluripotent cell lines brings the power of yeast genetics to mammalian models. It will allow scientists to perform experiments targeted at creating single point mutants in a fast and reliable manner as well as allow for unbiased mutagenesis screens.
Many neurodegenerative diseases are result of specific point mutations within our genome. The generation of such models in diploid cell lines is difficult and takes substantial effort. By using both mouse and human haploid systems we are circumventing these problems for rapid creation of such disease models. These ESC that can be subsequently differentiated into different neuronal types or organoids and used to ask disease relevant questions.’
Commenting on what this could mean for people with dementia, Gabriel added:
‘Research directed towards better understanding dementia has lagged behind as compared to other research fields. One of the reasons for this was lack of cellular systems that could be used to recapitulate neuronal biology in vitro for rapid analyses that could lead to the discovery of novel therapeutic approaches (novel diagnostic markers or novel therapeutics). By developing such cellular systems, we believe we can accelerate discovery towards bringing solutions for the patients and their families.’