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Scientists at the Proteomics Core Unit of the Spanish National Cancer Research Centre (CNIO), headed by Javier Muñoz, have clarified the mechanisms, unknown to date, included in maintaining embryonic stem cells in the best possible condition for their use in regenerative medicine.
The results, published in Nature Communications, helps to find novel stem-cell therapies for brain stroke, heart disease or neurodegenerative conditions like Alzheimer’s or Parkinson’s disease.
Naïve pluripotent stem cells, perfect for doing research Embryonic stem cells (ESCs) are pluripotent cells that can grow into all somatic cell types – a characteristic that is extremely useful for researchers and regenerative medicine. There are two types of pluripotency: naïve and primed. Naïve ESCs have the potential to differentiate into any cell types.
Thus, they are more relevant in research. However, the naïve condition is unstable, because naïve ESCs are continuously receiving signals that regulate the transition to the primed state and their self-renewal. Understanding the mechanisms that regulate the pluripotent states is important because they might help attain long-term maintenance of stable naïve pluripotent stem cells in ESC cultures.
Traditionally, maintenance of naïve ESC cultures is based on the inhibition of 2 of the signaling pathways that regulate cell differentiation – aka as the 2i culture procedure. Recently, naïve ESCs are maintained adopting a totally different approach, namely, the inhibition of Cdk8/19, a protein that modulates the expression of numerous genes, including the genes that help preserve the naïve state.
While the two approaches are used to culture naïve cells, little is known about the mechanisms involved.”
Javier Muñoz, Study Lead, Spanish National Cancer Research Centre (CNIO)
Currently, using proteomics, the large-scale characterization of proteins coded in a genome, CNIO scientists have described a large number of the molecular events which help stabilize these precious ESC. “This is the first time proteomics has been used in this context,” says Ana Martínez del Val, from the Proteomics Core Unit in CNIO, first author of the article.
“We analyzed the mechanics at a number of levels. First, we ran phosphoproteomic analyses, studying phosphorylated proteins. Phosphorylation modulates protein functions (by activating or inhibiting them). Second, we analyzed the expression of these proteins. With our integrated strategy, we have an accurate picture of the causes of the high degree of plasticity of ESC,” Martínez del Val explains.
The results of the study might have implications for research on some types of cancer. We know that”the inhibition of Cdk8 leads to reduced cell proliferation in acute myeloid leukemia by enhancing tumor suppressors”, and that”Cdk8 is a colorectal cancer oncogene.”
“Cdk8 activity is enigmatic, because its functions vary considerably with the mobile environment,” says Muñoz. “We’ve identified a number of Cdk8 targets which were unknown until now. This can help understand the role this protein regulates in other biological contexts.”
Going beyond genomics with proteomics The analysis by the CNIO team shows the need for a greater focus on proteomics in cancer research strategies.
Two of the most frequently used techniques are genomics, the analysis of the DNA sequence – the molecule that carries all our genetic information – and transcriptomics, the study of these sets of RNA transcripts – the molecules that translate into proteins.
Proteins are macromolecules that are directly involved in chemical processes essential for life. The proteomic approach was adopted relatively recently by biomedical researchers. Proteomics has gained momentum over the past 15 years, yet it is now essential for genomics and transcriptomics to come full circle.
Genomics and proteomics study processes that take place before proteins are created. “We use proteomics to study a number of properties of proteins that cannot be analyzed by studying DNA or RNA,” says Martínez del Val. This is extremely important, since”proteins are responsible for a complete range of basic life functions that take place within cells,” Muñoz adds.
Spanish National Cancer Research Centre
Martinez-Val, A., et al. (2021) Dissection of two routes to naïve pluripotency using different kinase inhibitors. Nature Communications. doi.org/10.1038/s41467-021-22181-5.
