Neural precursor cell–secreted TGF-β2 redirects inflammatory monocyte-derived cells in CNS autoimmunity

Abstract

In multiple sclerosis, the pathological interaction between autoreactive Th cells and mononuclear phagocytes in the CNS drives initiation and maintenance of chronic neuroinflammation. Here, we found that intrathecal transplantation of neural stem/precursor cells (NPCs) in mice with experimental autoimmune encephalomyelitis (EAE) impairs the accumulation of inflammatory monocyte-derived cells (MCs) in the CNS, leading to improved clinical outcome. Secretion of IL-23, IL-1, and TNF-α, the cytokines required for terminal differentiation of Th cells, decreased in the CNS of NPC-treated mice, consequently inhibiting the induction of GM-CSF-producing pathogenic Th cells. In vivo and in vitro transcriptome analyses showed that NPC-secreted factors inhibit MC differentiation and activation, favoring the switch toward an antiinflammatory phenotype. Tgfb2-/- NPCs transplanted into EAE mice were ineffective in impairing MC accumulation within the CNS and failed to drive clinical improvement. Moreover, intrathecal delivery of TGF-β2 during the effector phase of EAE ameliorated disease severity. Taken together, these observations identify TGF-β2 as the crucial mediator of NPC immunomodulation. This study provides evidence that intrathecally transplanted NPCs interfere with the CNS-restricted inflammation of EAE by reprogramming infiltrating MCs into antiinflammatory myeloid cells via secretion of TGF-β2.

Neural Stem Cells of the Subventricular Zone Contribute to Neuroprotection of the Corpus Callosum after Cuprizone-Induced Demyelination

“…It is known that eNPCs can regulate microglia density and function as well as its activity by VEGF secretion (Mosher et al, 2012). Thus, we can speculate that in this lesion model the lack of eNPC-secreted growth factors, such as VEGF (Mosher et al, 2012;Bacigaluppi et al, 2016) or TGF-␤ (De Feo et al, 2017), might be responsible for the increased microglia activation.…”

Harnessing the Neural Stem Cell Secretome for Regenerative Neuroimmunology

“…A follow-up study from the same group demonstrated similar results are observed from transplanted hNSCs derived from induced pluripotent stem cells (iPSCs; Plaisted et al, 2016). Furthermore, a recent study in a non-viral mouse model of MS, experimental autoimmune encephalomyelitis (EAE), demonstrated that mouse embryonic NSC-secreted TGF-β2 inhibits the differentiation of pro-inflammatory monocyte-derived dendritic cells in vivo and in vitro (De Feo et al, 2017).…”

Extracellular Vesicles Containing IL-4 Modulate Neuroinflammation in a Mouse Model of Multiple Sclerosis

“…By the injection of IL-4 + Mfg-e8 + EVs into liquoral space, we can directly target meningeal resident cells with patrolling activity and newly infiltrating phagocytes, such as monocyte-dendritic cells, which are extensively described as main effector cells in EAE. 30,31 As shown in Figures 6 and 7, using IL-4 + EVs targeted with Mfg-e8, we can induce an anti-inflammatory phenotype in CD11b + cells, similar to gene therapy with IL-4. 14 Myeloid cells in the meningeal compartment and in the choroid plexus have been recently indicated as a crucial checkpoint in human and experimental neuroinflammation.…”