Study of the translational regulation of mitochondrial remodeling in a model of human Bone Marrow Mesenchymal Stem Cell hepatogenic differentiation

A better comprehension of the mechanisms regulating the self-renewal,
pluripotency and differentiation of stem cells is required to further develop
their potential to treat multiple diseases. Mitochondrial reprograming
occurring during stem cells differentiation is precisely one of these
mechanism. Recently, our team characterized this mitochondrial remodeling
as well as its transcriptomic reprogramming in a model of human Bone
Marrow Mesenchymal Stem Cell (hBM-MSC) hepatogenic differentiation.
This transcriptomic analysis pointed out several elements regarding a
potential translational regulation of mitochondrial biogenesis both in the
cytosol and mitochondria. Among others, these elements are: a strong
repression of 4E-BP1 (eukaryotic initiation factor 4E-binding protein 1, a
protein regulating the translation of nuclear-encoded mitochondrial mRNAs)
and a significant induction of 15 out of 36 mRNAs specifically encoding
mitochondrial ribosomal proteins. This project aims to investigate the
translational control participating in mitochondrial biogenesis occurring
during hepatogenic differentiation of hBM-MSC. First, we will characterize
this translational regulation by polysome profiling in order to monitor the
reprograming of differential translation of mRNAs during differentiation.
Then, we will investigate the underlying regulation mechanisms through the
study of ribosomal protein heterogeneity (by a riboproteomic approach) and
the impact of 4E-BP1. Finally, we will also investigate a potential
mitochondrial translation regulation by studying several candidates
differentially expressed in differentiating cells, as revealed by our
transcriptomic analysis. Altogether, this research project should shed light
on the translational regulation that participates to the interplay between
mitochondria, stem cells and differentiation.