The rise of totipotency - Manipulating the metabolic state causes emergence of totipotent-like cell in culture

Embryonic cells are the cells which have the largest potential in our bodies, and therefore understanding how these so-called ‘totipotent’ cells function can enable major findings to manipulate cellular plasticity. Rodriguez-Terrones et al. have analyzed the metabolic state of totipotent-like cells, which can be cultured, and identified three metabolic compounds that can induce their emergence, opening up the possibility to induce cellular reprogramming by manipulating cellular metabolism.

@Helmholtz Zentrum München

Generating cells for repair is a key endeavor towards cell replacement. Cells with enhanced cell potential can therefore provide unique paradigms to generate multiple cell types. So far, it has remained unclear, whether cells with different potential display different metabolic needs and activities. Therefore, the group of researchers of the Institute of Epigenetics and Stem Cells (IES) investigated the metabolic features of totipotent-like or 2-cell-like cells, which arise spontaneously in a culture of pluripotent embryonic stem cells (ESCs). Comparison of gene expression in 2-cell-like cells and ESCs discovered changes in metabolic enzymes and regulators involved in glycolysis, TCA-cycle, electron transport or glutamine metabolism.

In collaboration with Dr. G. Hartleben from the Institute of Diabetes and Cancer (IDC), D. Rodriguez-Terrones newly established the procedure to measure the oxygen consumption rate for living 2-cell-like cells and for the use of low-number cells. These analyses hinted at the possibility that 2-cell-like cells display very different features to the normal ‘pluripotent’ stem cells. Indeed, the researchers discovered morphological differences in their mitochondria and reactive oxygen species (ROS) levels. Based on this, the researchers tested the hypothesis that 2-cell-like cells can be reprogrammed by the addition of specific metabolites. After analyzing 20 different metabolites in culture for their potential to induce 2-cell like cells, the group identified 3 metabolites which are shown for the first time to reprogram totipotent-like cells in culture.

Altogether, Rodriguez-Terrones et al. observed that the reprogramming of pluripotent ESCs to potentially totipotent 2-cell like cells was accompanied by a metabolic shift, particularly by changes in mitochondria morphology, reduction of reactive oxygen species (ROS) and increase in glucose uptake identified three metabolites that are capable of inducing 2-cell-like cells in a dose-dependent manner. Joining the forces and expertise of the IES and IDC made it possible to analyze the emergence of 2-cell-like cells in vitro from another perspective opening up the possibility to study and recreate the molecular features of totipotency in vitro.

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