Mesenchymal stem cells instruct a beneficial phenotype in reactive astrocytes

Abstract

Transplanted mesenchymal stromal/stem cells (MSC) ameliorate the clinical course of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), reducing inflammation and demyelination. These effects are mediated by instructive cross‐talk between MSC and immune and neural cells. Astroglial reaction to injury is a prominent feature of both EAE and MS. Astrocytes constitute a relevant target to control disease onset and progression and, based on their potential to acquire stem cell properties in situ, to foster recovery in the post‐acute phase of pathology. We have assessed how MSC impact astrocytes in vitro and ex vivo in EAE. Expression of astroglial factors implicated in EAE pathogenesis was quantified by real‐time PCR in astrocytes co‐cultured with MSC or isolated from EAE cerebral cortex; astrocyte morphology and expression of activation markers were analyzed by confocal microscopy. The acquisition of neural stem cell properties by astrocytes was evaluated by neurosphere assay. Our study shows that MSC prevented astrogliosis, reduced mRNA expression of inflammatory cytokines that sustain immune cell infiltration in EAE, as well as protein expression of endothelin‐1, an astrocyte‐derived factor that inhibits remyelination and contributes to neurodegeneration and disease progression in MS. Moreover, our data reveal that MSC promoted the acquisition of progenitor traits by astrocytes. These data indicate that MSC attenuate detrimental features of reactive astroglia and, based on the reacquisition of stem cell properties, also suggest that astrocytes may be empowered in their protective and reparative actions by MSC.

Microglia-derived CCL2 has a prime role in neocortex neuroinflammation

“…It has been demonstrated that among these secreted factors, IL-1α, TNF-α, and complement component 1, subcomponent q (C1q) are all required as initiators of neurotoxic A1 astrocytes induction in vivo , and that A1 astrocytes significantly decrease in number only when treated with the anti-inflammatory TGF-β or fibroblast growth factor (FGF) [ 95 ]. In light of this evidence, it can be hypothesized that the effect of MSCs is mediated by a possibly still unknown inducer of the protective A2 phenotype (see also [ 30 ].…”

“…After treatment with MSCs, the massive microgliosis observed in the neocortex of EAE-affected mice appears to be effectively counteracted, featuring reduced cell hypertrophy, reduced IBA1 and Ccl2 /CCL2 expression, increased neuroprotective SALL1, and reduced NVU adjoining processes. Thus, microglia respond directly to MSC treatment, or indirectly, through resident cell effectors such as astrocytes that have been recently demonstrated to respond to MSC treatment, reacquiring stem cell properties and protective and reparative actions [ 30 ]. Direct modulation of the microglia phenotype by MSCs has been demonstrated in vitro in co-cultures of microglia and MSCs [ 41 ].…”

“…The paucity of inflammatory infiltrates that characterizes the pathogenic profile of gray matter vs. white matter in EAE prompted us to investigate the response to inflammation of oligodendrocyte cell precursors, as well as the structural and functional status of BBB microvessels in the cerebral cortex of mice affected with MOG-induced EAE [10,11,28,29]. In addition, we and others recently investigated the response of brain astrocytes in EAE, also monitoring the status of neuroinflammation and astrogliosis upon treatment with bone marrow-derived mesenchymal stem cells (MSCs) [30,31]. MSC-based therapy has been demonstrated to improve the clinical course of autoimmune/neurodegenerative disorders, reducing neuroinflammation and promoting remyelination [32][33][34][35][36].…”

Mesenchymal stem cells for lysosomal storage and polyglutamine disorders: Possible shared mechanisms

“…Indeed, MSC can “sense” the environment created by the signals emitted by injured tissues and home to target areas where they secrete an array of molecules, including cytokines/chemokines and neurotrophic factors 59 . MSC can even induce alterations in the secretion of certain factors in host cells through an orchestrated crosstalk 53,60 . Their paracrine mechanisms can be mediated through direct diffusion into the extracellular space or by material encapsulated in small vesicles.…”

“…59 MSC can even induce alterations in the secretion of certain factors in host cells through an orchestrated crosstalk. 53,60 Their paracrine mechanisms can be mediated through direct diffusion into the extracellular space or by material encapsulated in small vesicles. These vesicles can contain signalling lipids, mRNAs, regulatory miRNAs or even small organelles, which may also support the survival/ recovery of host cells.…”