First Trimester Human Umbilical Cord Perivascular cells (HUCPVC) Modulate the Kynurenine Pathway and Glutamate Neurotransmission in an LPS-induced Mouse Model of Neuroinflammation

Abstract

Background The Kynurenine Pathway (KP) of tryptophan degradation and glutamate toxicity is implicated in several neurological disorders, including depression. Although mesenchymal stromal cells (MSC)-mediated immunomodulation and neuroprotection have been studied in many of these disorders, 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 enzymes and metabolites was assessed in the plasma and brain of mice treated with LPS. An assessment of the glutamatergic system, including selected receptors, transporters and proteins was also conducted. 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.

Human Umbilical Cord Perivascular Cells Prevent Tumor Growth in a Melanoma Tumor-Bearing Mouse Model and Modulate Breast Cancer and Melanoma Cells in a Cell Line-Dependent Manner In Vitro

“…Our in vivo experiments demonstrate that HUCPVC delivered systemically do not actively home to tumors, which suggests that the inhibitory effect they have on tumor growth is likely to be largely a systemic endocrine effect rather than occurring by a localized paracrine mechanism [8]. The colocalization of HUCPVC with macrophages in the lungs and liver, as observed in other models in our lab previously [8,19,26], indicates a potential role for HUCPVC in regulating immune cells and inflammation. Our initial investigations on M2 macrophage markers do not support an effect on macrophage polarization in this model, at least not at the time points investigated.…”

“…Cell Culture. Previously established and extensively characterized lines of FTM and term HUCPVC [8,[17][18][19][20] (Figure S1) and human fibroblasts (HS-68, ATCC) were expanded in Alpha-Modified Minimum Essential Medium (αMEM) (Hyclone), with 2.5% human platelet lysate (HPL) good manufacturing practice grade plus cell culture supplement (Compass Biomedical) and 1% penicillin and streptomycin (Gibco). Human melanoma cells (SK-Mel-28, A375, ATCC), and three breast cancer cells (SK-BR-3, ATCC, and HTB-30), (MCF7, ATCC, and HTB-22), and (MDA-MB-231, ATCC, and HTB-26) were expanded in a similar fashion using ATCC-Formulated Eagle's Essential Medium, supplemented with 10% fetal bovine serum (FBS) (Hyclone) and 1% penicillin and streptomycin.…”

“…HUCPVC are isolated noninvasively and may be a good allogeneic cell therapy candidate, exhibiting a superior expansion capacity and a higher degree of immune privilege, compared to bone marrow-derived (BM-) MSC [14][15][16]. In general, HUCPVC express high levels of markers associated with an MSC phenotype (CD90, CD44, CD73, and CD105) and a subpopulation of these cells express pericyte-associated markers CD146 and PDGFRbeta, as well as immunoprivilege-associated molecule HLA-G in culture, albeit to varying levels [8,[17][18][19][20]. Additionally, HUCPVC show significant multilineage differentiation and proliferation capacity in culture, and their paracrine and immunomodulatory properties have been well characterized.…”

The role of immune inflammatory response and inflammatory infiltrates in major depression disorder and atopic dermatitis: new insights from machine learning

“…Elevated inflammatory factors are associated with the development and severity of MDD. Mesenchymal cells may influence the development and symptom severity of depression by suppressing the inflammatory responses or modulating immune cell activity (Siddiqui et al, 2023;Xiong, Mahmood, & Chopp, 2024). Thus, mesenchymal cell proliferation may be associated with the development of MDD by influencing the immune-inflammatory responses.…”