Experimental Type 2 Diabetes Differently Impacts on the Select Functions of Bone Marrow-Derived Multipotent Stromal Cells.

Jonathan Ribot,Hervé Petite,Rebecca Landon,Cyprien Denoeud,Fani Anagnostou,Morad Bensidhoum,Guilhem Frescaline,Graciela Pavon-Djavid

doi:10.3390/cells10020268

Abstract

Bone marrow-derived multipotent stromal cells (BMMSCs) represent an attractive therapeutic modality for cell therapy in type 2 diabetes mellitus (T2DM)-associated complications. T2DM changes the bone marrow environment; however, its effects on BMMSC properties remain unclear. The present study aimed at investigating select functions and differentiation of BMMSCs harvested from the T2DM microenvironment as potential candidates for regenerative medicine. BMMSCs were obtained from Zucker diabetic fatty (ZDF; an obese-T2DM model) rats and their lean littermates (ZL; controls), and cultured under normoglycemic conditions. The BMMSCs derived from ZDF animals were fewer in number, with limited clonogenicity (by 2-fold), adhesion (by 2.9-fold), proliferation (by 50%), migration capability (by 25%), and increased apoptosis rate (by 2.5-fold) compared to their ZL counterparts. Compared to the cultured ZL-BMMSCs, the ZDF-BMMSCs exhibited (i) enhanced adipogenic differentiation (increased number of lipid droplets by 2-fold; upregulation of the Pparg, AdipoQ, and Fabp genes), possibly due to having been primed to undergo such differentiation in vivo prior to cell isolation, and (ii) different angiogenesis-related gene expression in vitro and decreased proangiogenic potential after transplantation in nude mice. These results provided evidence that the T2DM environment impairs BMMSC expansion and select functions pertinent to their efficacy when used in autologous cell therapies.

Highlights

The formation of CFU-Fs was significantly (p < 0.05) lower in the bone marrow-derived multipotent stromal cells (BMMSCs) harvested from the Zucker diabetic fatty (ZDF) than from the Zucker lean (ZL) rats (Figure 1A,B)
The average colony size formed by BMMSCs from the diabetic ZDF animals was significantly lower compared to that obtained with the cells from non-diabetic ZL animals
The results provided evidence that BMMSCs harvested from the Type 2 diabetes mellitus (T2DM) bone marrow microenvironment differed from BMMSCs harvested from the non-diabetic milieu as follows: (i) there were fewer cells; (ii) they exhibited impaired functionality but increased adipogenic differentiation when cultured under normoglycemic conditions; and (iii) they had decreased proangiogenic potential after transplantation in a non-diabetic milieu

Summary

Introduction

In addition to macro- and micro-vascular complications such as cardiovascular diseases, retinopathy, neuropathy, nephropathy, and prolonged/incomplete wound healing, T2DM is associated with increased bone fragility [1] and impaired bone healing [2,3,4]. In the bone marrow, T2DM induces microvascular rarefaction and vascular endothelial cell dysfunction [5], reduces osteoblastogenesis, and increases adiposity [6,7]. These conditions have been implicated in changing the stem cell niche, resulting in a compromised function of the bone marrow-derived multipotent stromal cells (BMMSCs)/mesenchymal stem cells (MSCs)

Methods

Results

Conclusion