The characteristics of hematopoietic stem cells from autoimmune-prone mice and the role of neural cell adhesion molecules in abnormal proliferation of these cells in MRL/lpr mice

Wang, Xiaoli; Hisha, Hiroko; Song, Changye; Mizokami, Tomomi; Okazaki, Satoshi; Li, Qing; Feng, Wei; Katô, Junko; Jiang, Shi‐Wen; Fan, Hao; Ikehara, Susumu

doi:10.3324/haematol.10603

Cited by 8 publications

(3 citation statements)

References 31 publications

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“…NCAM is expressed on both bone marrow stroma and HSCs (14,15) and participates in the maintenance of HSCs in culture (16). Importantly, NCAM is a target for 2 sialyltransferases, ST8Sia II and ST8Sia IV, both of which independently produce an unusual glycan, polysialic acid (polySia) (17).…”

mentioning

confidence: 99%

Polysialic acid governs T-cell development by regulating progenitor access to the thymus

Drake¹,

Stock²,

Nathan³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Although the polysialyltransferase ST8Sia IV is expressed in both primary and secondary human lymphoid organs, its product, polysialic acid (polySia), has been largely overlooked by immunologists. In contrast, polySia expression and function in the nervous system has been well characterized. In this context, polySia modulates cellular adhesion, migration, cytokine response, and contactdependent differentiation. Provocatively, these same processes are vital components of immune development and function. We previously established that mouse multipotent hematopoietic progenitors use ST8Sia IV to express polySia on their cell surfaces. Here, we demonstrate that, relative to wild-type controls, ST8Sia IV ؊/؊ mice have a 30% reduction in total thymocytes and a concomitant deficiency in the earliest thymocyte precursors. T-cell progenitors originate in the bone marrow and are mobilized to the blood at regular intervals by unknown signals. We performed in vivo reconstitution experiments in which ST8Sia IV ؊/؊ progenitors competed with wild-type cells to repopulate depleted or deficient immune subsets. Progenitors lacking polySi exhibited a specific defect in T-cell development because of an inability to access the thymus. This phenotype probably reflects a decreased capacity of the ST8Sia IV ؊/؊ progenitors to escape from the bone marrow niche. Collectively, these results provide evidence that polySia is involved in hematopoietic development.bone marrow niche ͉ hematopoiesis ͉ mobilization ͉ development

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mentioning

confidence: 99%

Polysialic acid governs T-cell development by regulating progenitor access to the thymus

Drake¹,

Stock²,

Nathan³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Earlier studies [31,32] have shown that adhesion molecules play an important role in transmembrane signal transduction, and participate in tissue injury in MRL/lpr mice. In lupus-like symptoms of MRL/lpr mice, the inter-cellular adhesion molecules are closely relat-ed to the severity of lupus nephritis [30].…”

Section: Discussionmentioning

confidence: 99%

Cognitive impairment of MRL mice is related to NMDA receptor-mediated inflammatory response and production of adhesion molecules in MRL/lpr mice-derived micro-vascular endothelial cells

Guan¹,

Wang²

2023

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Systemic lupus erythematosus (SLE) is a chronic recurrent autoimmune disease affecting almost all organs. This study was conducted to investigate cognitive impairment of SLE mice (MRL/lpr mice), and explore associated pathological mechanism. Behavior tests (open-field test, elevated plus-maze test, forced swimming test, sucrose preference test, and Morris water maze test) were conducted in MRL/MPJ and MRL/lpr mice. ELISA test was performed to determine levels of antibodies (anti-dsDNA, anti-RPA, anti-ACA, and anti-NR2a/b) and inflammatory factors [tumour necrosis factor α (TNF-α), interleukin (IL)-6, . Micro-vascular endothelial cells (MVECs) were isolated, identified, and divided into MVECs (NC), anti-NR2a/2b, memantine, glycine, dexamethasone, and IL-1β groups. Cell proliferation was measured using cell counting kit-8 (CCK-8) assay, and Western blotting was applied to evaluate ELAM-1, VCAM-1, ICAM-1, IKBα, p-IKBα expression. MRL/lpr mice demonstrated lower locomotion/exploration ability, higher anxiety, obvious depression symptoms, lower learning/memory capability compared with MRL/MPJ mice. MRL/lpr mice demonstrated high levels of anti-NR2a/b antibody and auto-antibodies. NMDA receptor antagonist (memantine) significantly increased, and NMDA receptor agonist (glycine) significantly decreased MVECs proliferation compared with NC group (p < 0.05). Memantine significantly reduced and glycine predominantly enhanced TNF-α, IL-6, IL-8, and IL-10 levels compared with NC group (p < 0.05). NMDA receptor antagonist and agonist modulated adhesion molecules expression in MVECs. ELAM-1, VCAM-1, and ICAM-1 expressions were significantly down-modulated in memantine group, and remarkably up-modulated in glycine group compared with NC group (p < 0.05). NMDA receptor antagonist and agonist regulated phosphorylation of p-IKBα. The above effects of memantine evenly equaled to dexamethasone, and glycine evenly equaled to IL-1β. In conclusion, cognitive impairment of MRL mice might be associated with NMDA receptor-mediated inflammatory response and production of adhesion molecules in MRL/lpr mice-derived MVECs.

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“…29 The autoimmunity, including nephritis can be ameliorated in the LPR model by allogeneic bone-marrow transplantation, 30 supporting the hypothesis that autoimmunity is a stem-cell disease in this mouse model. 31 A recent study by Du et al demonstrated that the lack of functional FAS or FAS-ligand on tubular epithelial cells of grafts from LPR or GLD mice protected allografts. Protection was demonstrated by a reduced serum creatinine and better survival of LPR or GLD grafts versus FAS-system-intact grafts.…”

Section: Discussionmentioning

confidence: 99%

Lupus nephritis reoccurs following transplantation in the lupus prone mouse

Hamar

Wang

Godó

et al. 2009

Lupus

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The incidence and pathomechanism of recurrent lupus nephritis (RLN) after transplantation is not clearly understood. Burning out of the autoimmune process or local immunoregulatory mechanisms in the kidney may be responsible for the low incidence of recurrence. These mechanisms cannot be investigated in human subjects, due to post-transplant immunosuppression. To investigate the pathomechanisms of RLN, male and female kidneys were transplanted from FAS deficient lupus prone (LPR) or control (FAS intact) MRL mice into either LPR or MRL recipients. Urinary protein and blood urea were assessed. Double negative (DN) lymphocyte proliferation was determined by flow cytometry. Two months after transplantation inflammatory infiltration of the glomerular, vascular and interstitial compartments were determined. Renal function as demonstrated by blood urea levels was normal in MRL recipients, but elevated in LPR recipients, independent of the donor strain. Paralleling functional results, inflammatory infiltration was mild or absent in MRL recipients of MRL grafts, and mild to moderate in MRL recipients of LPR grafts, suggesting that kidney removal from the autoimmune (LPR) environment significantly reduced inflammation. Graft infiltration was most severe in LPR recipients: grafts were similarly inflamed independent of the donor. All LPR recipients had significantly less CD4+ Th cells versus MRL mice. Transplantation of LPR grafts into MRL recipients reduced CD4+ Th cell percentage, accompanied by a slight induction of lupus autoantibody production. Our results demonstrate that lupus nephritis is not kidney specific in the LPR model with recurrence after transplantation in the absence of immunosuppression.

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The characteristics of hematopoietic stem cells from autoimmune-prone mice and the role of neural cell adhesion molecules in abnormal proliferation of these cells in MRL/lpr mice

Cited by 8 publications

References 31 publications

Polysialic acid governs T-cell development by regulating progenitor access to the thymus

Polysialic acid governs T-cell development by regulating progenitor access to the thymus

Cognitive impairment of MRL mice is related to NMDA receptor-mediated inflammatory response and production of adhesion molecules in MRL/lpr mice-derived micro-vascular endothelial cells

Lupus nephritis reoccurs following transplantation in the lupus prone mouse

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