First trimester human umbilical cord perivascular cells (HUCPVC) modulate the kynurenine pathway and glutamate neurotransmission in an LPS-induced mouse model of neuroinflammation.

BACKGROUND: The Kynurenine Pathway (KP) of tryptophan degradation and glutamate toxicity is implicated in several neurological disorders, including depression. The therapeutic potential of mesenchymal stromal cells (MSC), owing to their well documented phagocytosis-driven mechanism of immunomodulation and neuroprotection, has been tested in many neurological disorders. However, their potential to influence KP and the glutamatergic system has not yet been investigated. Hence, this study sought to investigate the effect of HUCPVC, a rich and potent source of MSC, on Lipopolysaccharide (LPS)-activated KP metabolites, KP enzymes, and key components of glutamate neurotransmission. METHODS: The immunomodulatory effect of peripherally administered HUCPVC on the expression profile of kynurenine pathway metabolites and enzymes was assessed in the plasma and brain of mice treated with LPS using LCMS and QPCR. An assessment of the glutamatergic system, including selected receptors, transporters and related proteins was also conducted by QPCR, immunohistochemistry and Western blot. RESULTS: HUCPVC were found to modulate LPS-induced activation of KP enzymes and metabolites in the brain associated with neurotoxicity. Moreover, the reduced expression of the glutamatergic components due to LPS was also found to be significantly improved by HUCPVC. CONCLUSIONS: The immunomodulatory properties of HUCPVC appear to confer neuroprotection, at least in part, through their ability to modulate the KP in the brain. This KP modulation enhances neuroprotective regulators and downregulates neurotoxic consequences, including glutamate neurotoxicity, which is associated with neuroinflammation and depressive behavior.

Time course and mechanistic analysis of human umbilical cord perivascular cell mitigation of lipopolysaccharide-induced systemic and neurological inflammation.

BACKGROUND AIMS: Because of their potent immunomodulatory and anti-inflammatory properties, mesenchymal stromal cells are a major focus in the field of stem cell therapy. However, the precise mechanisms underlying this are not entirely understood. Human umbilical cord perivascular cells (HUCPVCs) are a promising cell therapy candidate. This study was designed to evaluate the time course and mechanisms by which HUCPVCs mitigate lipopolysaccharide (LPS)-induced systemic and neurological inflammation in immunocompetent mice. To explore the underlying mechanisms, the authors investigated the biodistribution and fate of HUCPVCs. METHODS: Male C57BL/6 mice were randomly allocated to four groups: control, LPS, HUCPVCs or LPS + HUCPVCs. Quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and cytokine arrays were used to assess changes in pro-inflammatory mediators systemically and in the brain. Depressive-like behavioral changes were evaluated via a forced swim test. Quantum dot (qDot) labeling and immunohistochemistry were used to assess the biodistribution and fate of HUCPVCs and interactions with recipient innate immune cells. RESULTS: A single intravenously delivered dose of HUCPVCs significantly reduced the systemic inflammation induced by LPS within the first 24 h after administration. HUCPVC treatment abrogated the upregulated expression of pro-inflammatory genes in the hippocampus and cortex and attenuated depressive-like behavior induced by LPS treatment. Biodistribution analysis revealed that HUCPVC-derived qDots rapidly accumulated in the lungs and demonstrated limited in vivo persistence. Furthermore, qDot signals were associated with major recipient innate immune cells and promoted a shift in macrophages toward a regulatory phenotype in the lungs. CONCLUSIONS: Overall, this study demonstrates that HUCPVCs can successfully reduce systemic and neurological inflammation induced by LPS within the first 24 h after administration. Biodistribution and fate analyses suggest a critical role for the innate immune system in the HUCPVC-based immunomodulation mechanism.

Mesenchymal Stromal Cells Modulate Peripheral Stress-Induced Innate Immune Activation Indirectly Limiting the Emergence of Neuroinflammation-Driven Depressive and Anxiety-like Behaviors.

BACKGROUND: Hyperactivation of innate immunity has been implicated in the etiology of mood disorders, including major depressive disorder (MDD). Mesenchymal stromal cells (MSCs) have demonstrated potent immunomodulatory capabilities in the context of chronic inflammatory disease and injury but have yet to be evaluated in stress-based preclinical models of MDD. We sought to test the ability of intravenous MSCs to modulate innate immune activation and behavioral patterns associated with repeated social defeat (RSD). METHODS: Murine RSD-induced innate immune activation as well as depressive and anxiety-like behaviors were assessed in unstressed, RSD, and RSD + human MSC groups. Biodistribution and fate studies were performed to inform potential mechanisms of action. RESULTS: MSCs reduced stress-induced circulating proinflammatory cytokines, monocytes, neuroinflammation, and depressive and anxiety-like behaviors. Biodistribution analyses indicated that infused MSCs distributed within peripheral organs without homing to the brain. Murine neutrophils targeted MSCs in the lungs within hours of administration. MSCs and recipient neutrophils were cleared by recipient macrophages promoting a switch toward a regulatory phenotype and systemic resolution of inflammation. CONCLUSIONS: Peripheral delivery of MSCs modulates central nervous system inflammatory processes and aberrant behavioral patterns in a stress-based rodent model of MDD and anxiety. Recent studies suggest that host immune cell-mediated phagocytosis of MSCs in vivo can trigger an immunomodulatory cascade, resulting in resolution of inflammation. Our data suggest that similar mechanisms may protect distal organs, including the brain, from systemic, stress-induced proinflammatory spikes and may uncover unexpected targets in the periphery for novel or adjunct treatment for a subset of patients with MDD.