Magnesium Deprivation Potentiates Human Mesenchymal Stem Cell Transcriptional Remodeling.

Azzurra Sargenti,Emil Malucelli,Francesca Bianchi,Giovanna Farruggia,Stefano Iotti,Lucia Merolle,Alessandra Cazzaniga,Sara Castiglioni,Carlo Ventura,Concettina Cappadone,Elena Olivi,Jeanette Maier

doi:10.3390/ijms19051410

Abstract

Magnesium plays a pivotal role in energy metabolism and in the control of cell growth. While magnesium deprivation clearly shapes the behavior of normal and neoplastic cells, little is known on the role of this element in cell differentiation. Here we show that magnesium deficiency increases the transcription of multipotency markers and tissue-specific transcription factors in human adipose-derived mesenchymal stem cells exposed to a mixture of natural molecules, i.e., hyaluronic, butyric and retinoid acids, which tunes differentiation. We also demonstrate that magnesium deficiency accelerates the osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. We argue that magnesium deprivation generates a stressful condition that modulates stem cell plasticity and differentiation potential. These studies indicate that it is possible to remodel transcription in mesenchymal stem cells by lowering extracellular magnesium without the need for genetic manipulation, thus offering new hints for regenerative medicine applications.

Highlights

Magnesium (Mg) is essential for life and health, since it is implicated in all metabolic and biochemical processes in the cell, including energy metabolism, DNA duplication, RNA transcription, protein synthesis and redox reactions [1]
We examined the impact of Mg deprivation on the osteogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs) treated with vitamin D and glycerolphosphate [31]
It is reported that Nanog Homeobox (NANOG) is expressed in cultured mesenchymal stem cells, while SOX2 and OCT4, Mg deficiency potentiates the commitment of adipose-derived mesenchymal stem cells (AD-MSCs) with a mixture of hyaluronic, butyric and retinoic acids toward multiple lineage, including neuronal, cardiac and vascular fates

Summary

Introduction

Magnesium (Mg) is essential for life and health, since it is implicated in all metabolic and biochemical processes in the cell, including energy metabolism, DNA duplication, RNA transcription, protein synthesis and redox reactions [1]. Since (i) Mg deprivation is associated with energetic and oxidative stress in several cell types and tissues [6,17,18], and (ii) redox regulation is implicated in various differentiation and de-differentiation processes [14], we reasoned that Mg withdrawal might reprogram and modulate the differentiation of mesenchymal stem cells. The rationale was to investigate the effects of the stress generated by Mg deprivation both on cell reprogramming and terminal cell differentiation These are distinct and complementary processes, which require the use of different experimental models and different protocols. We evaluated the expression of transcription factors required for osteogenesis, as well as the deposition of extracellular calcium, since the formation of a mineralized extracellular matrix is a hallmark of osteogenic differentiation

22.. Results

Isolation and Culture of Human Mesenchymal Stem Cells

Gene Expression Analysis

Cell Cycle Analysis

Reactive Oxygen Species Evaluation