MSC; bone marrow; cell signaling; osteogenesis; fibroblasts
Abstract :
[en] Leptin plays a central role in maintaining energy balance, with multiple other systemic effects. Despite leptin importance in peripheral regulation of mesenchymal stem cells (MSC) differentiation, little is known on its expression mechanism. Leptin is often described as adipokine, while it is expressed by other cell types. We have recently shown an in vitro leptin expression, enhanced by glucocorticoids in synovial fibroblasts. Here, we investigated leptin expression in MSC from bone marrow (BM-MSC), cord matrix (UMSC), and primary and dedifferentiated chondrocytes (DCH). Results showed that BM-MSC, but not UMSC, expressed leptin that was strongly enhanced by glucocorticoids. Interestingly, chondrocytes gained leptin expression progressively with dedifferentiation. This dedifferentiation was correlated with downregulation of ALK-5 expression, Smad2 phosphorylation (p-Smad2), and gain of ALK-1 expression and Smad1/5 phosphorylation (p-Smad1/5). TGF-β1 was shown to signal via ALK-5-Smad2/3 and/or ALK-1-Smad1/5 pathways. In BM-MSC, TGF-β1 increased p-Smad2 expression and markedly inhibited endogenous- and glucocorticoidinduced leptin expression, while ALK-5 inhibitor (SB431542) induced and restored this expression. In addition, both prednisolone and
<br />SB431542 increased p-Smad1/5 expression. These results suggested ALK-5-Smad2 pathway as inhibitor of leptin expression, while ALK-1-Smad1/5 as activator. Indeed, Smad1 expression silencing induced leptin expression inhibition. Furthermore, prednisolone enhanced the expression of TGF-βRII while decreasing p-Smad2 in BM-MSC and SVF but not in UMSC. In vitro differentiation revealed differential osteogenic potential in SVF, BM-MSC and UMSC that correlates to their leptin expression potential. Our results suggest that ALK-1/ALK-5 balance regulates leptin expression in MSC. It also underlines UMSC as leptin non-producer MSC for cell therapy protocols where leptin expression is not suitable.
Disciplines :
Hematology
Author, co-author :
Zeddou, M.
RELIC, Biserka ; Centre Hospitalier Universitaire de Liège - CHU > Rhumatologie
MALAISE, Olivier ; Centre Hospitalier Universitaire de Liège - CHU > Frais communs médecine
CHARLIER, Edith ; Centre Hospitalier Universitaire de Liège - CHU > Rhumatologie
Desouroux, A.
BEGUIN, Yves ; Centre Hospitalier Universitaire de Liège - CHU > Hématologie clinique
DE SENY, Dominique ; Centre Hospitalier Universitaire de Liège - CHU > Rhumatologie
Malaise, Michel ; Université de Liège - ULiège > Département des sciences cliniques > Rhumatologie
Language :
English
Title :
Differential signalling through ALK-1 and ALK-5 regulates leptin expression in Mesenchymal Stem Cells
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