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

Shuster-Hyman, Hannah; Siddiqui, Fyyaz; Gallagher, Denis; Gauthier-Fisher, Andrée; Librach, Clifford L.

doi:10.1016/j.jcyt.2022.10.014

Cited by 3 publications

(12 citation statements)

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“…Corroborating our previous study where we reported significant mitigation of LPS-induced proinflammatory cytokines in the brain by peripherally administered HUCPVC [ 23 ], in this study we demonstrate the potential of HUCPVC potential to modulate neuroinflammation by measuring LPS-induced microglial activation in the hippocampus (Fig. 3 A,B,C ) and cortex (Fig.…”

Section: Resultssupporting

confidence: 87%

“…Enzymatic activity and expression of IDO, which is also present in brain endothelial cells, perivascular macrophages, astrocytes, and microglia [ 33 ], have a direct influence on brain tryptophan metabolism [ 34 ]. Our previous study demonstrated significant mitigation of LPS-induced proinflammatory cytokines in the brain by peripherally administered HUCPVC in mice [ 23 ]. Thus, we sought to investigate the impact of the immunomodulatory potential of HUCPVC on the gene expression profile of Ido1 and the subsequent metabolic enzymes of the pathway in the LPS-activated CNS (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, IDO activation is shown to be crucial for depressive-like behavior in mice treated with LPS for 24 h [ 11 , 32 ]. We have previously reported that HUCPVC modulate neuroinflammation and depressive behavior after 24 h of LPS injection in mice [ 23 ]. In this study, we report that HUCPVC regulate IDO at the transcriptional level and the enzyme’s activation in the brain, as assessed by kynurenine:tryptophan ratio.…”

Section: Discussionmentioning

confidence: 99%

“…There has been a considerable lack of understanding of the basis of systemically administered MSC’s ability to provide neuroprotection in many diseases and injury models. In our previous study using an LPS-induced mouse model of neuroinflammation and depression, we have demonstrated phagocytosis-driven immunomodulation by peripherally infused HUCPVCs [ 23 ]. Here, the canonical mechanism of innate immune cascade was shown to be comprised of MSC-induced recruitment of neutrophils and their subsequent rapid clearance by recipient macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously demonstrated the efficacy of MSC in mitigating neuroinflammation and depressive behavior in both stress-induced, as well as LPS-induced preclinical models of depression and, have also outlined a phagocytosis-driven immunomodulation mechanism [ 22 , 23 ]. In the current study, we aim to investigate the immunomodulatory and neuroprotective capabilities of a young source of MSC, HUCPVC, isolated from the perivascular region of a first trimester human umbilical cord, through a potential impact on kynurenine pathway modulation in an LPS-based mouse model of neuroinflammation; which to our knowledge has never been explored.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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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.

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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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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

Lopez,

Shuster-Hyman,

Marco

et al. 2023

Stem Cells International

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First trimester (FTM) and term human umbilical cord perivascular cells are promising mesenchymal stromal cell candidates to mitigate side effects of oncotherapy, but their safety for cancer patients remains to be determined. This study was designed to determine if human umbilical cord perivascular cells modulate tumor growth when injected systemically in a tumor-bearing mouse model. Immunodeficient mice-bearing palpable subcutaneous SK-MEL-28 human melanoma tumors were randomized to receive a tail vein injection of three human umbilical cord perivascular cell lines resuspended in hank’s buffer saline solution (vehicle) or vehicle only, as a control. Fibroblast cells were included as a cell control in some experiments. Tumor size was monitored weekly and weighed at 3-weeks postinjection. Cell fate and tumor cell proliferation, apoptosis, vascularization as well as tumor-associated immune cells were assessed using immunostaining and flow cytometry. Serum tumor necrosis factor alpha and C-reactive protein levels were measured using enzyme-linked immunosorbent assays. Transwell coculture models were used to study the paracrine effects of multiple lines of human umbilical cord cells on human melanoma cell lines as well as breast cancer cell lines. Systemic administration of FTM and term human umbilical cord perivascular cells, but not fibroblast cells, prevented melanoma tumor growth in a tumor-bearing animal model by modulating tumor cell proliferation and systemic inflammatory mechanisms. Cancer cell- and donor-dependent paracrine effects on cancer cell growth were observed in vitro. Our preclinical studies thus suggest that, with regards to its effects on tumor growth, systemic administration of FTM and term human umbilical cord perivascular cells may be a safe cell therapy to address the side effects of cancer.

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Mesenchymal Stromal Cell Therapy for Thoracic Surgeons: An Update

Petrella,

Cassina,

Libretti

et al. 2023

JPM

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Stem cells are undifferentiated cells presenting extensive self-renewal features and the ability to differentiate “in vitro” and “in vivo” into a range of lineage cells, like chondrogenic, osteogenic and adipogenic lineages when cultured in specific inducing media. Two major domains of clinical applications of stem cells in thoracic surgery have been investigated: regenerative medicine, which is a section of translational research in tissue engineering focusing on the replacement, renewal or regeneration of cells, tissues and organs to re-establish damaged physiologic functions; drug loading and delivery, representing a new branch proposing stem cells as carriers to provide selected districts with anti-cancer agents for targeted treatments.

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

Cited by 3 publications

References 67 publications

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

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

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

Mesenchymal Stromal Cell Therapy for Thoracic Surgeons: An Update

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