Immune Regulatory Neural Stem/Precursor Cells Protect from Central Nervous System Autoimmunity by Restraining Dendritic Cell Function

Abstract

BackgroundThe systemic injection of neural stem/precursor cells (NPCs) provides remarkable amelioration of the clinico-pathological features of experimental autoimmune encephalomyelitis (EAE). This is dependent on the capacity of transplanted NPCs to engage concurrent mechanisms of action within specific microenvironments in vivo. Among a wide range of therapeutic actions alternative to cell replacement, neuroprotective and immune modulatory capacities of transplanted NPCs have been described. However, lacking is a detailed understanding of the mechanisms by which NPCs exert their therapeutic plasticity. This study was designed to identify the first candidate that exemplifies and sustains the immune modulatory capacity of transplanted NPCs.Methodology/Principal FindingsTo achieve the exclusive targeting of the peripheral immune system, SJL mice with PLP-induced EAE were injected subcutaneously with NPCs and the treatment commenced prior to disease onset. NPC-injected EAE mice showed significant clinical improvement, as compared to controls. Exogenous NPCs lacking the expression of major neural antigens were reliably (and for long-term) found at the level of draining lymph nodes, while establishing sophisticated anatomical interactions with lymph node cells. Importantly, injected NPCs were never found in organs other than lymph nodes, including the brain and the spinal cord. Draining lymph nodes from transplanted mice showed focal up-regulation of major developmental stem cell regulators, such as BMP-4, Noggin and Sonic hedgehog. In lymph nodes, injected NPCs hampered the activation of myeloid dendritic cells (DCs) and steadily restrained the expansion of antigen-specific encephalitogenic T cells. Both ex vivo and in vitro experiments identified a novel highly NPC-specific–BMP-4-dependent–mechanism hindering the DC maturation.Conclusion/SignificanceThe study described herein, identifies the first member of the TGF β/BMP family of stem cell regulators as a novel tolerogenic factor released by NPCs. Full exploitation of this pathway as an efficient tool for vaccination therapy in autoimmune inflammatory conditions is underway.

How stem cells speak with host immune cells in inflammatory brain diseases

“…Furthermore, exclusive targeting of the peripheral immune system has been reported in relapsing EAE in mice after subcutaneous NPC injection (Pluchino et al, 2009b). NPC-injected EAE mice showed significant clinical improvement, despite the absence of injected cells in the CNS.…”

“…Here, stem cells extensively interact with the host immune system to inhibit the activation and proliferation of T cells (Gerdoni et al, 2007), the maturation of DCs (Pluchino et al, 2009b), or the emigration of spleen neutrophils toward the damaged brain (Lee et al, 2008). Overall, these pioneering studies demonstrated the therapeutic efficacy of MSCs and NPCs in animal models of inflammatory damage, but left (partly) open the question of whether or not stem cell integration in the nervous system is indispensable for the therapeutic outcomes observed.…”

“…Peripheral immune modulation has also been observed following systemic MSC and NPC transplantation in EAE, owing to a remarkable accumulation of transplanted cells at the level of secondary lymphoid organs, where T-cell proliferation and production of proinflammatory cytokines were inhibited (Einstein et al, 2007;Pluchino et al, 2009b;Zappia et al, 2005). Furthermore, exclusive targeting of the peripheral immune system has been reported in relapsing EAE in mice after subcutaneous NPC injection (Pluchino et al, 2009b).…”

“…NPC-injected EAE mice showed significant clinical improvement, despite the absence of injected cells in the CNS. Instead, undifferentiated NPCs were consistently found at the level of the perivascular areas in draining lymph nodes, where they hindered the activation of myeloid DCs to APCs by a bone morphogenetic protein (BMP)-4-dependent mechanism that reduced the pathogenicity of antigen-specific T cells (Pluchino et al, 2009b).…”

“…Data in Table 1 are in part summarized in (Chamberlain et al, 2008;Hall et al, 2006;Martino and Pluchino 2006;Pluchino et al, 2009b;Rojewski et al, 2008;Uccelli et al, 2008;Yuan et al, 2011). (Cusimano et al, 2012;Jaderstad et al, 2010) aracrine IDO-kynurenine MSCs (h) T cells, DCs T cell apoptosis, inhibition of antigen presentation (Lanz et al, 2010;Matysiak et al, 2008Matysiak et al, , 2011Meisel et al, 2004;Plumas et al, 2005 Bonnamain et al, 2012;Chabannes et al, 2007;Moll et al, 2011) Paracrine VEGF NPCs Microglia/macrophages Inhibition of microglial activation, proliferation and phagocytosis (Horie et al, 2011;Kim et al, 2009a;Mosher et al, 2012) Paracrine LIF NPCs Th17 cells Inhibition of Th17 cell differentiation (Cao et al, 2011;Horie et al, 2011;Kim et al, 2009a;Mosher et al, 2012) Paracrine Galectins MSCs/NPCs T cells Inhibition of T cell proliferation (Gieseke et al, 2010;Sioud 2011;Yamane et al, 2010Yamane et al, , 2011 Endocrine/Paracrine TSG-6 MSCs Macrophages Inhibition of macrophage activation, proliferation and phagocytosis (Fisher-Shoval et al, 2012;Lee et al, 2009;Roddy et al, 2011) EVs miR transfer MSCs/NPCs Multiple Post-transcriptional regulation (Bruno et al, 2009;Chen et al, 2010;…”