Abstract
Citrate, generated in the mitochondria, is a key metabolite that might link metabolism with signaling, chromatin structure and transcription to orchestrate mesenchymal stem cells (MSCs) fate determination. Based on a detailed morphological analysis of 3D reconstruction of mitochondria and nuclei in single cells, we identified contact sites between these organelles that drastically increase in volume and number during the early stage of mesenchymal stem cell differentiation. These contact sites create a microdomain that facilitates exchange of signals from mitochondria to the nucleus. Interestingly, we found that the citrate derived from mitochondria is necessary for osteogenic lineage determination. Indeed, inhibition of the citrate transporter system dramatically affected osteogenesis, reduced citrate levels that could be converted in α-ketoglutarate, and consequently affected epigenetic marker H3K9me3 associated with the osteogenesis differentiation process. These findings highlight that mitochondrial metabolites play key regulatory roles in the MSCs differentiation process. Further in-depth investigation is needed to provide novel therapeutic strategies in the field of regenerative medicine.
Highlights
IntroductionMesenchymal stem cells (MSCs) are multipotent cells that give rise to osteoblasts, adipocytes, and chondrocytes [1,2,3], whereby the studying of their differentiation processes is of great interest for their promising application in tissue engineering of mesenchymal tissues.mesenchymal stem cells (MSCs) nuclear reprogramming during differentiation processes has been widely characterized [4], but several recent studies have focused on the novel mechanisms involving mitochondrial activities in stem cell biology.Variations in the abundances, morphology, and functions of mitochondria in different stem cell types have been described [3,5,6,7,8,9], and it has been established that upregulation of mitochondrial biogenesis and metabolic shifts toward oxidative phosphorylation are hallmarks of differentiation inCells 2020, 9, 1034; doi:10.3390/cells9041034 www.mdpi.com/journal/cellsMSCs [10,11]
mesenchymal stem cells (MSCs) differentiation has largely been investigated from a transcription factor point of view, whereas little is known concerning how metabolism might regulate this complex process
We showed that during the early phase of adipogenic and osteogenic differentiation, mitochondria volume and number increased dramatically in agreement with the enhanced mitochondrial respiration (Figures 1 and 2), confirming previous evidence detected by the classical immunofluorescence technique [6,36]
Summary
Mesenchymal stem cells (MSCs) are multipotent cells that give rise to osteoblasts, adipocytes, and chondrocytes [1,2,3], whereby the studying of their differentiation processes is of great interest for their promising application in tissue engineering of mesenchymal tissues.MSC nuclear reprogramming during differentiation processes has been widely characterized [4], but several recent studies have focused on the novel mechanisms involving mitochondrial activities in stem cell biology.Variations in the abundances, morphology, and functions of mitochondria in different stem cell types have been described [3,5,6,7,8,9], and it has been established that upregulation of mitochondrial biogenesis and metabolic shifts toward oxidative phosphorylation are hallmarks of differentiation inCells 2020, 9, 1034; doi:10.3390/cells9041034 www.mdpi.com/journal/cellsMSCs [10,11]. MSC nuclear reprogramming during differentiation processes has been widely characterized [4], but several recent studies have focused on the novel mechanisms involving mitochondrial activities in stem cell biology. Variations in the abundances, morphology, and functions of mitochondria in different stem cell types have been described [3,5,6,7,8,9], and it has been established that upregulation of mitochondrial biogenesis and metabolic shifts toward oxidative phosphorylation are hallmarks of differentiation in. In addition to a well-established role in cellular energy metabolism, mitochondria are critical mediators of cell signaling [13]; little is known regarding the direct effect of metabolic pathway activity on chromatin dynamics and MSC differentiation. Recent evidence suggests that metabolic intermediates of cellular metabolism are required as cofactors for epigenetic modulators, providing a direct link between mitochondrial metabolism and gene expression [14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
