Mtu1 defects are correlated with reduced osteogenic differentiation

Qiufen He,Xiongfeng Li,Qiong Zhao,Ye Chen,Ruolang Pan,Qianqian Li

doi:10.1038/s41419-020-03345-5

Abstract

Accumulating evidence has revealed that mitochondria dynamics and function regulation is essential for the successful mesenchymal stem cell (MSC) differentiation. In the present study, the researchers reported for the first time that Mtu1 defects are correlated with reduced osteogenic differentiation. Using in vitro cultured bone marrow MSCs and stromal cell line MS5, we demonstrated that depressed Mtu1 expression was associated with reduced 2-thiouridine modification of the U34 of mitochondrial tRNAGln, tRNAGlu, and tRNALys, which led to respiratory deficiencies and reduced mitochondrial ATP production, and finally suppressed osteogenic differentiation. As expected, these Mtu1-deficient mice exhibited obvious osteopenia. Therefore, our findings in this study provide new insights into the pathophysiology of osteopenia.

Highlights

Mesenchymal stem cells (MSCs), which are multipotent cells readily accessible from various tissues and give rise to mesoderm cell lineages such as osteoblasts and adipocytes, have been widely studied over the past two decades
Osteopenia induced in Mtu1-deficient mice Researchers generated a 35-bp insertion, which caused a frameshift from codon 10 and terminated early at codon 11, in the exon 1 of Mtu[1] knockout mice through CRISPR/Cas[9] technology to test the role of Mtu[1] in MSC differentiation (Fig. 1A)
The results showed decreased bone volume per tissue volume (BV/TV; Fig. 1F), trabecular thickness (Tb.Th; Fig. 1G), as well as significant increased specific bond surface (BS/BV; Fig. 1H) and trabecular separation (Tb.Sp; Fig. 1I), indicating significant poor bone quality in Mtu1+/− mice compared with wild type mice

Summary

Introduction

Mesenchymal stem cells (MSCs), which are multipotent cells readily accessible from various tissues and give rise to mesoderm cell lineages such as osteoblasts and adipocytes, have been widely studied over the past two decades. MSCs own a DNA (mtDNA) copy number, protein levels of respiratory enzymes, oxygen consumption rates (OCRs), mRNA levels of mitochondrial biogenesis-associated genes, and intracellular ATP content were observed upon differentiation induction[11,12,13,14]. These studies indicate that mitochondria play an important regulatory role in differentiation capacity of MSCs15. Understanding the roles of mitochondrial dynamics during MSC differentiation will facilitate the optimization of differentiation protocols, and benefit the development of new pharmacologic strategies in regenerative medicine

Methods

Results

Conclusion