Improved survival of mesenchymal stem cells by macrophage migration inhibitory factor.

Wenzheng Xia,Miaomiao Jiang,Congying Xie,Meng Hou

doi:10.1007/s11010-015-2361-y

Abstract

Macrophage migration inhibitory factor (MIF) is a critical inflammatory cytokine that was recently associated with progenitor cell survival and potently inhibits apoptosis. We examined the protective effect of MIF on hypoxia/serum deprivation (SD)-induced apoptosis of mesenchymal stem cells (MSCs), as well as the possible mechanisms. MSCs were obtained from rat bone marrow and cultured in vitro. Apoptosis was induced by culturing MSCs under hypoxia/SD conditions for up to 24 h and assessed by flow cytometry. Expression levels of c-Met, Akt, and FOXO3a were detected by Western blotting. CD74 expression was detected by qRT-PCR, Western blot, and immunofluorescence. Oxidative stress under hypoxia/SD was examined by detection of reactive oxygen species (ROS) and activity of superoxide dismutase (SOD) and malondialdehyde (MDA). Hypoxia/SD-induced apoptosis was significantly attenuated by recombinant rat MIF in a concentration-dependent manner. MIF induced CD74-asssociated c-Met activation, which was blocked by knocking down CD74 expression using siRNA. MIF also induced Akt and associated FOXO3a phosphorylation, and this effect was abolished by knocking down either CD74 or Akt. In addition, MIF decreased oxidative stress in MSCs, as shown by decreased ROS and MDA, and increased the activity of SOD. Knockdown of CD74, Akt, or FOXO3a largely attenuated the anti-apoptotic effect of MIF and its ability to protect against oxidative stress. MIF protected MSCs from hypoxia/SD-induced apoptosis by interacting with CD74 to stimulate c-Met, leading to downstream PI3K/Akt-FOXO3a signaling and decreased oxidative stress.

Highlights

In the absence of effective endogenous repair mechanisms after cardiac injury, cell-based therapies have rapidly emerged as a potential novel therapeutic approach in ischemic heart disease [1]
The ratio of surviving cells following mesenchymal stem cells (MSCs) engraftment is extremely low despite the large number of implanted cells, probably due to a high rate of cell death induced by the ischemic environment [5, 32], where transplanted MSCs encounter nutrient and oxygen deprivation and oxidative stress
In such a stressful environment, it is likely that many transplanted cells undergo apoptosis, so enhancing the survival of MSCs is a significant challenge for stem cell-based therapy [24]

Summary

Introduction

In the absence of effective endogenous repair mechanisms after cardiac injury, cell-based therapies have rapidly emerged as a potential novel therapeutic approach in ischemic heart disease [1]. Many problems, including massive cell death after transplantation, have limited the efficacy of this cell therapy [3]. At this stage, further optimization of MSC-based therapy is urgently needed, and growth factors and cytokines, preconditioning, and genetic modification, have all been manipulated in an attempt to enhance MSC survival [4,5,6]. Devising a more effective and accessible pro-survival strategy may make this therapeutic approach more attractive to the specialist.

Methods

Results

Conclusion