Allogeneic bone marrow transplantation and donor lymphocyte infusion in a mouse model of irradiation-induced myelodysplastic/myeloproliferation syndrome (MD/MPS): evidence for a graft-versus-MD/MPS effect

Sprangers, Ben; Wijmeersch, Bart Van; Luyckx, Ariane; Somer, Lien De; Rutgeerts, Omer; Lenaerts, Caroline; Landuyt, Willy; Boeckx, Nancy; Dubois, Bénédicte; Wolf‐Peeters, Chris De; Waer, Mark; Billiau, An

doi:10.1038/leu.2008.298

Cited by 5 publications

(6 citation statements)

References 39 publications

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“…32 Another long-term study (up to 80 days after irradiation) showed that SJL mice developed a severe wasting syndrome with a higher mortality rate. 33 The authors showed that SJL mice died due to myeloproliferation, leukemic transformation, and infection. Likewise, we observed higher mortality in SJL recipient mice after a longer period of time (up to 60 days) after the irradiation and BMT (not shown).…”

Section: Discussionmentioning

confidence: 99%

Autonomic Dysfunction Determines Stress‐Induced Cardiovascular and Immune Complications in Mice

Batchu

Smolock

Dyachenko

et al. 2015

JAHA

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BackgroundClinical studies suggest that acute inflammation in patients with elevated heart rate (HR) increases morbidity and mortality. The SJL/J (SJL) inbred mouse strain is a unique genetic model that has higher HR and systemic and vascular inflammation compared with C3HeB/FeJ (C3HeB) mice. The goal of this study was to investigate the role of stress on cardiac and vascular complications between 2 strains.Methods and ResultsRadiotelemetry was used for continuous recordings of HR and blood pressure in mice. Hemodynamic differences between mouse strains were very small without stress; however, tail-cuff training generated mild stress and significantly increased HR (≈2-fold) in SJL compared with C3HeB mice. Circulating proinflammatory monocytes (CD11b+Ly6CHi) significantly increased in SJL mice but not in C3HeB mice after stress. Presence of Ly6C+ cells in injured carotids was elevated only in SJL mice after stress; however, a transfer of bone marrow cells from SJL/C3HeB to C3HeB/SJL chimeras had no effect on HR or vascular inflammation following stress. Arterial inflammation (VCAM-1+) was greater in SJL inbred mice or SJL recipient chimeras, even without stress or injury. HR variability was reduced in SJL mice compared with C3HeB mice.ConclusionsWe found that impaired parasympathetic activity is central for stress-induced elevation of HR and systemic and vascular inflammation; however, immune cells from stress-susceptible mice had no effect on HR or vascular inflammation in stress-protected mice.

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Section: Discussionmentioning

confidence: 99%

Autonomic Dysfunction Determines Stress‐Induced Cardiovascular and Immune Complications in Mice

Batchu

Smolock

Dyachenko

et al. 2015

JAHA

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“…However, up to now there is no exact mechanism explaining the regulatory effects of allogeneic NA-BMCs. Although, the irradiation dosage is equivalent to the current protocols used in other transplantation settings [29] , this minimal dosage probably permits survival of significant numbers of endogenous host stem cells that can be activated after transplantation of allogeneic NA-BMCs. It is possible, that the therapeutic benefit of allogeneic NA-BMCs on improved survival can only be observed using this radiation setting.…”

Section: Discussionmentioning

confidence: 99%

Allogeneic Non-Adherent Bone Marrow Cells Facilitate Hematopoietic Recovery but Do Not Lead to Allogeneic Engraftment

et al. 2009

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BackgroundNon adherent bone marrow derived cells (NA-BMCs) have recently been described to give rise to multiple mesenchymal phenotypes and have an impact in tissue regeneration. Therefore, the effects of murine bone marrow derived NA-BMCs were investigated with regard to engraftment capacities in allogeneic and syngeneic stem cell transplantation using transgenic, human CD4+, murine CD4−/−, HLA-DR3+ mice.Methodology/Principal FindingsBone marrow cells were harvested from C57Bl/6 and Balb/c wild-type mice, expanded to NA-BMCs for 4 days and characterized by flow cytometry before transplantation in lethally irradiated recipient mice. Chimerism was detected using flow cytometry for MHC-I (H-2D[b], H-2K[d]), mu/huCD4, and huHLA-DR3). Culturing of bone marrow cells in a dexamethasone containing DMEM medium induced expansion of non adherent cells expressing CD11b, CD45, and CD90. Analysis of the CD45+ showed depletion of CD4+, CD8+, CD19+, and CD117+ cells. Expanded syngeneic and allogeneic NA-BMCs were transplanted into triple transgenic mice. Syngeneic NA-BMCs protected 83% of mice from death (n = 8, CD4+ donor chimerism of 5.8±2.4% [day 40], P<.001). Allogeneic NA-BMCs preserved 62.5% (n = 8) of mice from death without detectable hematopoietic donor chimerism. Transplantation of syngeneic bone marrow cells preserved 100%, transplantation of allogeneic bone marrow cells 33% of mice from death.Conclusions/SignificanceNA-BMCs triggered endogenous hematopoiesis and induced faster recovery compared to bone marrow controls. These findings may be of relevance in the refinement of strategies in the treatment of hematological malignancies.

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“…The protocols to generate radiation chimeras and perform bone marrow transplantation assays have been described previously. 41 Briefly, WT mice and Nix 2 /2 mice were firstly subjected to g-irradiation at a dose of 8.5 Gy from a 60 Co source (Institute of Zoology, Chinese Academy of Sciences), and then the prepared bone marrow cells (5 3 10 6 cells per mice) were injected into the tail vein of the irradiated mice. Four weeks after transplantation, the reconstituted mice were tested to analyze FeCl 3 -induced thrombosis of the carotid artery, tail-bleeding time, and platelet activation as described previously.…”

Section: Radiation Chimeras and Bone Marrow Transplantation Assaymentioning

confidence: 99%

Nix-mediated mitophagy regulates platelet activation and life span

Zhang

Siraj

et al. 2019

Blood Advances

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Key Points• Nix controls platelet activation/arterial thrombosis, regulating platelet mitochondria quality/activity in (patho)physiological settings.• Knockout of Nix increases the life span of platelets by inhibiting autophagic degradation of the mitochondrial protein Bcl-xL. Platelet activation requires fully functional mitochondria, which provide a vital energy source and control the life span of platelets. Previous reports have shown that both general autophagy and selective mitophagy are critical for platelet function. However, the underlying mechanisms remain incompletely understood. Here, we show that Nix, a previously characterized mitophagy receptor that plays a role in red blood cell maturation, also mediates mitophagy in platelets. Genetic ablation of Nix impairs mitochondrial quality, platelet activation, and FeCl 3 -induced carotid arterial thrombosis without affecting the expression of platelet glycoproteins (GPs) such as GPIb, GPVI, and a IIb b 3 . Metabolic analysis revealed decreased mitochondrial membrane potential, enhanced mitochondrial reactive oxygen species level, diminished oxygen consumption rate, and compromised adenosine triphosphate production in Nix 2/2 platelets. Transplantation of wildtype (WT) bone marrow cells or transfusion of WT platelets into Nix-deficient mice rescued defects in platelet function and thrombosis, suggesting a platelet-autonomous role (acting on platelets, but not other cells) of Nix in platelet activation. Interestingly, loss of Nix increases the life span of platelets in vivo, likely through preventing autophagic degradation of the mitochondrial protein Bcl-xL. Collectively, our findings reveal a novel mechanistic link between Nix-mediated mitophagy, platelet life span, and platelet physiopathology. Our work suggests that targeting platelet mitophagy Nix might provide new antithrombotic strategies.

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Allogeneic bone marrow transplantation and donor lymphocyte infusion in a mouse model of irradiation-induced myelodysplastic/myeloproliferation syndrome (MD/MPS): evidence for a graft-versus-MD/MPS effect

Cited by 5 publications

References 39 publications

Autonomic Dysfunction Determines Stress‐Induced Cardiovascular and Immune Complications in Mice

Autonomic Dysfunction Determines Stress‐Induced Cardiovascular and Immune Complications in Mice

Allogeneic Non-Adherent Bone Marrow Cells Facilitate Hematopoietic Recovery but Do Not Lead to Allogeneic Engraftment

Nix-mediated mitophagy regulates platelet activation and life span

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