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Biologists Figure Out How Stem Cells Turn Into Other Types of Cells at Molecular Level

Biologists Figure Out How Stem Cells Turn Into Other Types of Cells at Molecular Level

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An international team of researchers including biologists from HSE University has developed a method that helps obtain information on changes in protein expression and properties during cells’ transition from one state to another. One of the most interesting transitions is the transformation of cells from undifferentiated stem cells to differentiated cells of various organs and tissues. ProteoTracker, a newly developed method and web tool that visualizes the detected changes, helps researchers discover the molecular mechanism of parsimonious translation (low protein synthesis rate) in stem cells, as well as suggest a method to maintain pluripotency of cells during cultivation in vitro (out of body). The paper was published in Nature Communications.

Stem cells’ ability to differentiate—transform into other types of cells—is the foundation of regenerative medicine and tissue engineering. Stem cells turn into other kinds of cells thanks to deep changes in their protein composition. That’s why molecular biologists are particularly interested in the chemical foundations of the differentiation process: the changes that happen to proteins as part of stem cells and the conditions of this process.

To understand what happens to proteins during stem cell transition, it is necessary to study the differences between protein composition of undifferentiated stem cells and the resulting differentiated cells.

The researchers received cell cultures of different types to carry out the experiments and reprogrammed human connective tissue cells (fibroblasts) into induced pluripotent stem cells, the cells that are able to transform into cells of almost any tissue. These cells were then turned into so-called ‘embryoid bodies’ to use them as a model of early developmental specification during embryogenesis. The authors also used cell lines of human cancer and embryonic stem cells for comparison.

To investigate the changes happening in cells, the researchers proposed a method that combines protein expression (number of proteins that synthesize in a cell) measurement and ‘proteome-wide integral solubility alteration’ (PISA) assay.

The PISA method involves treating the protein with the method called ‘thermal proteome profiling’ (TPP or CETSA-MS). It is based on the property that when the protein structure changes, its thermal stability (protein’s resistance to temperature fluctuation) also changes.

The researchers heated the cells of the types listed above over a narrow range of temperatures, then lysed the cells and, using mass spectrometric analysis, obtained information about the proteins remaining in solution for each temperature. As a result of this analysis, thermal stability curves were obtained for more than 9000 proteins in each type of studied cells. Simultaneously with thermostability, protein expression in each cell type was also assessed.

To analyse the data they obtained, the authors used a multidimensional visualization tool they had created, ProteoTracker, which is based on Sankey diagrams that reflected the changes in each protein’s properties during differentiation.

The researchers demonstrated that thermal stability and expression of proteins change as stem cells turn into somatic ones, which reflects fundamental differences in cell physiology and morphology of these types of cells.

They found that over 75% of the analysed proteins had considerable differences in expression and thermal stability in pluripotent and differentiated cells. In particular, the expression and stability of proteins responsible for the density of chromatin (substance of which chromosomes consist) change during the process of stem cells’ transition into somatic cells.

As a stem cell becomes a somatic one, the type of glucose metabolism (energy production in a cell) changes in it: in a stem cell, glucose undergoes glycolysis (enzymatic transformations not requiring oxygen), while in a somatic cell, glucose is metabolized mostly via oxidative phosphorylation in mitochondria, which requires sufficient oxygen supplement. When the researchers analysed the moment at which expression of the relevant proteins starts in cells, they found out that the glucose metabolism changes at early stages of pluripotent stem cells’ differentiation, before the chromatin structure changes. This means that the change of metabolism type may trigger subsequent changes in chromatin structure during differentiation.

Previously, researchers observed that somatic stem cells are characterized with a low rate of protein synthesis in cells and growing speed during differentiation. That is why they assumed that the decreasing protein synthesis rate is important for maintaining the stem cell properties. But the mechanism of such regulation had been unclear. In their study, the researchers demonstrated that pluripotent stem cells have a lower proportion of functional ribosomes than differentiated cells. This is due to a low level of SBDS protein expression, which is responsible for maturation of ribosomes.

Diana Maltseva

Diana Maltseva, Head of the HSE International Laboratory of Microphysiological Systems

‘The low level of SBDS protein expression allows the cells to maintain pluripotency, while an increase of its expression promotes differentiation—transformation into other types of cells. In addition, SBDS expression inhibition may be a universal approach to maintaining stem cells in vitro.’

The data obtained during the study can also help develop a better understanding of the nature of developmental defects related to Shwachman-Diamond syndrome—a genetic disease caused by SBDS protein mutation.

The proposed method may be widely used in cell biology, and in particular, in regenerative medicine research. It has the potential to be useful for the search of optimal conditions of various cells’ cultivation and development of stem cell differentiation protocols, as well as for in-depth studies of specific proteins’ functions.

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