Factors secreted by MSCs in culture
Cultured MSCs express low levels of MHC Class I and are MHC Class II−, CD40−, and CD86−, suggesting these cells would not elicit an immune response [1,2]. The immuno-modulatory capacities of MSCs have been demonstrated by several independent research groups, both in vitro and in vivo, in animal models and in humans [3,4,5]. The immuno-modulatory functions of MSCs were first demonstrated in their ability to suppress in vitro proliferation of T lymphocytes [6]. Since then, several studies have shown that MSCs can modulate many cell types involved in the immune response in vitro. These include natural killer (NK) cells, B lymphocytes and dendritic cells [3,4,5]. The inhibition of T cell proliferation has been shown to be transient, whereby the removal of MSCs reinstates the T cell proliferative state [5]. T cell proliferation inhibition by MSCs is also known to act independently of cell-cell contact with the suppressive effect attributed to the secretion of either Transforming growth factor-β (TGF-β), Hepatocyte growth factor (HGF), Prostaglandin E2 (PGE2), Indoleamine 2,3-dioxygenase (IDO), Nitrous Oxide (NO) or Interluekin-10 (IL-10) [7,8]. This inhibition of proliferation is observed in both autologous and allogeneic responder cells [9]. By demonstrating that this action is not HLA restricted, MSCs are shown to be a good candidate therapy for use allogeneically [10]. MSCs interfere with functioning, differentiation and maturation of dendritic cells. Again, this is not dependent on cell-cell contact with the MSCs, but on soluble factors secreted by the MSCs including IL-6, IL-10, macrophage colony-stimulating factor (M-CSF) and PGE2 [11]. The inhibition of B cells by MSCs is dependent on inflammatory conditions [12]. MSCs in the presence of IFNγ reduce B cell proliferation via the induction of IDO [13]. To inhibit NK cell proliferation, MSCs have been shown to require activation with either IL-2 or IL-15 [14,15].
[1] Javazon EH, Beggs KJ, Flake AW (2004) Mesenchymal stem cells: paradoxes of passaging. Exp Hematol 32: 414-425.
[2]. Dazzi F, Marelli-Berg FM (2008) Mesenchymal stem cells for graft-versus-host disease: close encounters with T cells. Eur J Immunol 38: 1479-1482.
[3]Uccelli A, Moretta L, Pistoia V (2008) Mesenchymal stem cells in health and disease. Nat Rev Immunol 8: 726-736.
[4]Nauta AJ, Fibbe WE (2007) Immunomodulatory properties of mesenchymal stromal cells. Blood 110: 3499-3506.
[5] Locatelli F, Maccario R, Frassoni F (2007) Mesenchymal stromal cells, from indifferent spectators to principal actors. Are we going to witness a revolution in the scenario of allograft and immune-mediated disorders? Haematologica-the Hematology Journal 92: 872-877.
[6]. Maitra B, Szekely E, Gjini K, Laughlin MJ, Dennis J, et al. (2004) Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T-cell activation. Bone Marrow Transplant 33: 597-604.
[7] Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O (2003) HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 31: 890-896.
[8]. Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105: 1815-1822.
[9]. Newton KR, Sala-Soriano E, Varsani H, Stephenson JR, Goldblatt D, et al. (2008) Human dendritic cells infected with an adenoviral vector suppress proliferation of autologous and allogeneic T cells. Immunology 125: 469-479.
[10]. Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC (2003) Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 75: 389-397.
[11]. Spaggiari GM, Abdelrazik H, Becchetti F, Moretta L (2009) MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2. Blood 113: 6576-6583.
[12]. Ghannam S, Pene J, Torcy-Moquet G, Jorgensen C, Yssel H (2010) Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. J Immunol 185: 302-312.
[13]. Schena F, Gambini C, Gregorio A, Mosconi M, Reverberi D, et al. (2010) Interferon-gamma-dependent inhibition of B cell activation by bone marrow-derived mesenchymal stem cells in a murine model of systemic lupus erythematosus. Arthritis Rheum 62: 2776-2786.
[14]. Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M (2006) Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 24: 74-85.
[15]. Maccario R, Podesta M, Moretta A, Cometa A, Comoli P, et al. (2005) Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype. Haematologica 90: 516-525.
