Unraveling the interplay between mitochondria and the hepatogenic differentiation of human mesenchymal stem cells

PhD thesis defended by Anaïs WANET (Prof. Patsy RENARD) - 04/09/2015

Prof. Patsy RENARD, UNamur, NARILIS

Dr. Mustapha NAJIMI, UCLouvain, IREC


Patricia Renard (Supervisor), Catherine Verfaillie (Jury), Luc Bertrand (Jury), Etienne Sokal (Jury), Sarah Snyckers (Jury), Thierry Arnould (President) & Mustapha Najimi (Co-Supervisor)


Stem cells offer promising applications in regenerative medecine and cell therapy ; yet, a better understanding of the mechanisms regulating their self-renewal, pluripotency and differentiation, is required to exploit their potential to treat multiple diseases. Mitochondria, often regarded as the powerhouses of cells, recently emerged as critical regulators of the pluripotency and differentiation of stem cells. An increase in the mitochondrial content and activity, as well as a shift from a glycolytic-based, anaerobic metabolism towards an oxidative phosphorylation (OXPHOS)-based, aerobic metabolism, is observed during stem cell differentiation towards multiple lineages. However, the regulators driving the mitochondrial biogenesis during stem cell differentiation remain mostly unknown.

In this research project, we investigated the mitochondrial changes occurring during the hepatogenic differentiation of primary human bone marrow-derived mesenchymal stem cells (BM-MSCs). We evidenced that a mitochondrial biogenesis, accompanied by a metabolic shift towards increased OXPHOS, occurs during the hepatogenic differentiation of BM-MSCs. Using a transcriptomic approach combined with bioinformatics analyses, we identified several regulators possibly involved in the simultaneous regulation of mitochondrial biogenesis and stem cell differentiation. We validated the requirement of one of them for both the increased mitochondrial biogenesis and proper differentiation of stem cells. Furthermore, we identified transcriptional regulators possibly acting as molecular switch allowing mitochondrial biogenesis to proceed when stem cells loose their pluripotency and commit to the hepatic lineage.