U.K. scientists have shown how induced neural stem cells (iNSCs) derived from skin cells can reduce chronic neuroinflammation in the brains of a mouse model of multiple sclerosis (MS), and could potentially be used to hold back or repair damage to nerve cells and myelin. The University of Cambridge team, co-led by Stefano Pluchino, Ph.D., in the department of clinical neuroscience, demonstrated that injecting either embryo-derived neural stem cells (NSCs) or iNSCs directly into the animals’ cerebrospinal fluid (CSF) led to reduced CSF levels of succinate, which triggered inflammatory macrophages and microglia to switch back into an anti-inflammatory phenotype.

“Our mouse study suggests that using a patient's reprogrammed cells could provide a route to personalized treatment of chronic inflammatory diseases, including progressive forms of MS,” says Dr. Pluchino, lead author of the study.

The interdisciplinary research team, including co-led by Christian Frezza, Ph.D., at the University of Cambridge MRC Cancer Unit, and first author Luca Peruzzotti-Jametti, M.D., a Wellcome Trust Research Training Fellow, report their results in Cell Stem Cell, in a paper entitled “Macrophage-Derived Extracellular Succinate Licenses Neural Stem Cells to Suppress Chronic Neuroinflammation.”

Previous work by the Cambridge team has shown how NSC transplantation can help to reduce inflammation in animal models of inflammatory central nervous system (CNS) disorders. However, to date, NSCs have have been sourced from embryos, which limits their availability for clinical use. Stem cells derived from donors could also potentially trigger the recipient’s immune system to turn against the transplanted cells. More recent work has shown that iNSCs can be derived directly from patients’ own skin cells, suggesting that these autologous iNSCs could represent a valid alternative to NSCs for clinical applications.

Progressive forms of MS are characterized by chronic CNS inflammation, which is sustained by activated inflammatory mononuclear phagocytes (MPs), including microglia and monocyte-derived infiltrating macrophages. The MPs are activated by proinflammatory stimuli that switch their metabolism, triggering the cells to cause inflammatory responses. One of the factors implicated in this metabolic flip is the inflammatory metabolite succinate. “Recent evidence suggests that, within this metabolic rewiring, type 1 inflammatory MPs accumulate succinate, with important pathophysiological implications,”  the authors write. “…metabolism is emerging as an important therapeutic target to modulate the activation of both macrophages and microglia, and succinate-related pathways have key immune modulatory functions for acute and chronic inflammatory diseases.”

Given that NSCs had already been shown to have immune modulatory properties, the team hypothesized that the cells may exert therapeutic effects in chronic neuroinflammation by modulating metabolism of MPs and so reduce their inflammatory activities, which would hold back secondary damage to the CNS. They investigated whether NSC and iNSCs could counteract the metabolic changes in type 1 inflammatory MPs both in vitro and in the experimental autoimmune encephalopmyelitis (EAE) mouse model of MS.

The results showed that injections of either iNSCs of NSCs into the CSF were equally effective at reducing inflammation and damage to nerve axons and myelin. The injected cells induced a specific phenotypic switch of MPs that was associated with reduced levels of succinate in the CSF and reduction in chronic inflammation. The observation that iNSCs were as effective as somatic NSCs was encouraging. “This is particularly promising as these cells could be more readily obtainable than conventional NSCs and would not carry the risk of an adverse immune response,” Dr. Pluchino states.

In vitro analyses using both mouse and human NSCs demonstrated that succinate released by inflammatory MPs activates the succinate receptor 1 (SUCNR1)/GPR91 on the cells, triggering them to secrete prostaglandin E2 and scavenge extracellular succinate, which causes reprogramming of the MPs back to an anti-inflammatory phenotype. In further in vivo studies, transplanted NSCs that were engineered to lack the relevant succinate receptor had only very slight beneficial effects in the EAE mouse models. “These data confirm the requirement of a functional SUCNR1 signaling pathway in the regulation of the anti-inflammatory and neuroprotective effects of NSC transplants in vivo and underline the importance of succinate scavenging as a predominant anti-inflammatory mechanism of action of NSCs,”  the authors claim.

In principle, stem cells have a far more wide-reaching therapeutic potential than either small molecules or biologics, the team comments, and this potential could be exploited to treat inflammatory and degenerative diseases such as MS. “Part drug and part device, stem cells could work as biological disease-modifying agents (DMAs) that sense diverse signals, migrate to specific sites in the body, integrate inputs to make decisions, and execute complex response behaviors in the context of a specific tissue microenvironment. All of these attributes could be harnessed to treat several disease processes, including the persistent MP-driven inflammation and tissue degeneration that occur in progressive MS.

“Our work identifies a novel anti-inflammatory mechanism that underpins the regenerative potential of somatic cells and directly induced NSCs, thus paving the way for a new era of personalized stem cell medicines for chronic inflammatory and degenerative neurological diseases.” they conclude. 



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