“Evolutionary origins of stemness”
Dr Zoran Ivanovic, MD, PhD University of Bordeaux, France
Time and location: February 4th at 13.30, MV Lecture Hall (Hörsalen), coffee and cake at 14.30
Dr Ivanovic has pioneered work on the induction of stem cell self-renewal at low oxygen concentrations. More than one decade of work allowed him to develop his concept “Oxygen Stem Cell Paradigm” considering “anaerobic”, low-energy proliferation to be a key of self-renewal: Low availability of energy preventing cells from differentiating, which requires much more energy than simple cell division not coupled with differentiation. This feature of stem cells seems to reflect the ancestral, primitive unicellular organisms existing at the time when atmosphere oxygen concentration was still very low. This concept, applied to cell engineering, enabled Dr Ivanovic and his group to develop clinical-scale ex-vivo expansion procedures. One such procedure combines an anti-oxidant-supplied medium with cytokines, that mimics the effects of low oxygen concentrations in order to neutralize the negative effects of hyper-oxygenation (20-21% O2). The team has also designed novel approach of stem and progenitor cell conservation in hypothermia.
Multicellular organisms characterize a plethora of cells – from highly specialized for concrete functions to undifferentiated ones with a potential rather than function. These undifferentiated and primitive “stem cells” determine the regenerative capacities and longevity of the animal organisms. In the last two decades, a link between the anaerobic metabolic profile and cell stemness was established. Furthermore, the O2 availability induces, by default, commitment and differentiation of stem cells unless protective mechanisms mimic low O2 availability. This is, for example, the reason for the exhaustion of hematopoietic stem cells cultivated ex vivo in cultures exposed to 20% O2 atmosphere. This exhaustion of stem cells was limited by using the molecules stabilizing the HIFs, antioxidants and agents inhibiting the oxidative phosphorylation.
In situ, most cells forming a tissue are exposed to a low O2 concentration, standard established in Paleozoic era, where animals evolved. The stem cells, however, were placed in extremely low O2 areas, rather corresponding to the O2 concentrations present in Earths deep time (Proterozoic). The low O2 concentration is helping, in combination with the “hypoxia mimicking” mechanisms, in the maintenance of stem cell potential.
A stem cell is, in fact, a cell entity able to undergo the self-renewing division, i.e. division without commitment to differentiation, which represents the way of reproduction of the first single-cell eukaryotes. During the evolution of eukaryotes, they adapted to the environment (especially to the highly oxygenated environment later) expressing the different features i.e. functions, which are “stored” in the genome of each animal cell. Some of these functions are activated spontaneously if O2 is sufficiently high and if the cell is not under another “hypoxia mimicking” protection mechanism. To enable the self-renewal, activation of these function should be stopped or inhibited and this is the purpose of “pluripotency factors”.
Thus, we consider the simple, low energy cell division of the first eukaryotes as a prototype of the self-renewal of modern somatic stem cells. Even if mitochondria are present, their aerobic energetic contribution is not essential for primitive cells oriented, either to glycolysis or, in absence of glucose, to anaerobic mitochondrial respiration. To realize such a division the inhibition of the functional mechanisms of adaptation (perceived as “differentiation”) should be done. This could be the role of the “factors of stemness”, which are regulated via HIF system.
Emma Hammarlund, TCR, firstname.lastname@example.org