scholarly journals Impaired muscle force production and higher fatigability in a mouse model of sickle cell disease

2017 ◽  
Vol 63 ◽  
pp. 37-44 ◽  
Author(s):  
Benjamin Chatel ◽  
Christophe Hourdé ◽  
Julien Gondin ◽  
Alexandre Fouré ◽  
Yann Le Fur ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Mouse Model ◽  
Sickle Cell ◽  
Muscle Force ◽  
Force Production ◽  
Cell Disease ◽  
Muscle Force Production

scholarly journals Respiratory muscle force and lung volume changes in a population of children with sickle cell disease

2013 ◽  
Vol 163 (1) ◽  
pp. 112-117 ◽  
Author(s):  
Bruce A. Ong ◽  
Jason Caboot ◽  
Abbas Jawad ◽  
Joseph McDonough ◽  
Tannoa Jackson ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Lung Volume ◽  
Respiratory Muscle ◽  
Muscle Force ◽  
Cell Disease ◽  
Volume Changes

scholarly journals Reconstruction of Sickle Cell Disease with Circulating Sickling Red Blood Cells in Novel Humanized Cytokines and Liver Mistrg Mice

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Yuanbin Song ◽  
Rana Gbyli ◽  
Liang Shan ◽  
Wei Liu ◽  
Yimeng Gao ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Mouse Model ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Red Cell ◽  
Cell Disease ◽  
Ineffective Erythropoiesis ◽  
Cd34 Cells

In vivo models of human erythropoiesis with generation of circulating mature human red blood cells (huRBC) have remained elusive, limiting studies of primary human red cell disorders. In our prior study, we have generated the first combined cytokine-liver humanized immunodeficient mouse model (huHepMISTRG-Fah) with fully mature, circulating huRBC when engrafted with human CD34+ hematopoietic stem and progenitor cells (HSPCs)1. Here we present for the first time a humanized mouse model of human sickle cell disease (SCD) which replicates the hallmark pathophysiologic finding of vaso-occlusion in mice engrafted with primary patient-derived SCD HSPCs. SCD is an inherited blood disorder caused by a single point mutation in the beta-globin gene. Murine models of SCD exclusively express human globins in mouse red blood cells in the background of murine globin knockouts2 which exclusively contain murine erythropoiesis and red cells and thus fail to capture the heterogeneity encountered in patients. To determine whether enhanced erythropoiesis and most importantly circulating huRBC in engrafted huHepMISTRG-Fah mice would be sufficient to replicate the pathophysiology of SCD, we engrafted it with adult SCD BM CD34+ cells as well as age-matched control BM CD34+ cells. Overall huCD45+ and erythroid engraftment in BM (Fig. a, b) and PB (Fig. c, d) were similar between control or SCD. Using multispectral imaging flow cytometry, we observed sickling huRBCs (7-11 sickling huRBCs/ 100 huRBCs) in the PB of SCD (Fig. e) but not in control CD34+ (Fig. f) engrafted mice. To determine whether circulating huRBC would result in vaso-occlusion and associated findings in SCD engrafted huHepMISTRG-Fah mice, we evaluated histological sections of lung, liver, spleen, and kidney from control and SCD CD34+ engrafted mice. SCD CD34+ engrafted mice lungs showed an increase in alveolar macrophages (arrowheads) associated with alveolar hemorrhage and thrombosis (arrows) but not observed control engrafted mice (Fig. g). Spleens of SCD engrafted mice showed erythroid precursor expansion, sickled erythrocytes in the sinusoids (arrowheads), and vascular occlusion and thrombosis (arrows) (Fig. h). Liver architecture was disrupted in SCD engrafted mice with RBCs in sinusoids and microvascular thromboses (Fig. i). Congestion of capillary loops and peritubular capillaries and glomeruli engorged with sickled RBCs was evident in kidneys (Fig. j) of SCD but not control CD34+ engrafted mice. SCD is characterized by ineffective erythropoiesis due to structural abnormalities in erythroid precursors3. As a functional structural unit, erythroblastic islands (EBIs) represent a specialized niche for erythropoiesis, where a central macrophage is surrounded by developing erythroblasts of varying differentiation states4. In our study, both SCD (Fig. k) and control (Fig. l) CD34+ engrafted mice exhibited EBIs with huCD169+ huCD14+ central macrophages surrounded by varying stages of huCD235a+ erythroid progenitors, including enucleated huRBCs (arrows). This implies that huHepMISTRG-Fah mice have the capability to generate human EBIs in vivo and thus represent a valuable tool to not only study the effects of mature RBC but also to elucidate mechanisms of ineffective erythropoiesis in SCD and other red cell disorders. In conclusion, we successfully engrafted adult SCD patient BM derived CD34+ cells in huHepMISTRG-Fah mice and detected circulating, sickling huRBCs in the mouse PB. We observed pathological changes in the lung, spleen, liver and kidney, which are comparable to what is seen in the established SCD mouse models and in patients. In addition, huHepMISTRG-Fah mice offer the opportunity to study the role of the central macrophage in human erythropoiesis in health and disease in an immunologically advantageous context. This novel mouse model could therefore serve to open novel avenues for therapeutic advances in SCD. Reference 1. Song Y, Shan L, Gybli R, et. al. In Vivo reconstruction of Human Erythropoiesis with Circulating Mature Human RBCs in Humanized Liver Mistrg Mice. Blood. 2019;134:338. 2. Ryan TM, Ciavatta DJ, Townes TM. Knockout-transgenic mouse model of sickle cell disease. Science. 1997;278(5339):873-876. 3. Blouin MJ, De Paepe ME, Trudel M. Altered hematopoiesis in murine sickle cell disease. Blood. 1999;94(4):1451-1459. 4. Manwani D, Bieker JJ. The erythroblastic island. Curr Top Dev Biol. 2008;82:23-53. Disclosures Xu: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Flavell:Zai labs: Consultancy; GSK: Consultancy.

scholarly journals Gabapentin alleviates chronic spontaneous pain and acute hypoxia‐related pain in a mouse model of sickle cell disease

2019 ◽  
Vol 187 (2) ◽  
pp. 246-260
Author(s):  
Katelyn E. Sadler ◽  
Sarah N. Langer ◽  
Anthony D. Menzel ◽  
Francie Moehring ◽  
Ashley N. Erb ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Mouse Model ◽  
Sickle Cell ◽  
Acute Hypoxia ◽  
Spontaneous Pain ◽  
Cell Disease

Mechanisms of vascular instability in a transgenic mouse model of sickle cell disease

2000 ◽  
Vol 279 (6) ◽  
pp. R1949-R1955 ◽  
Author(s):  
K. A. Nath ◽  
V. Shah ◽  
J. J. Haggard ◽  
A. J. Croatt ◽  
L. A. Smith ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Lipid Peroxidation ◽  
Sickle Cell Disease ◽  
Mouse Model ◽  
Systolic Blood Pressure ◽  
Transgenic Mouse ◽  
Sickle Cell ◽  
Transgenic Mouse Model ◽  
Cell Disease

We investigated a transgenic mouse model of sickle cell disease, homozygous for deletion of mouse β-globin and containing transgenes for human βSand βS-antillesglobins linked to the transgene for human α-globin. In these mice, basal cGMP production in aortic rings is increased, whereas relaxation to an endothelium-dependent vasodilator, A-23187, is impaired. In contrast, aortic expression of endothelial nitric oxide synthase (NOS) is unaltered in sickle mice, whereas expression of inducible NOS is not detected in either group; plasma nitrate/nitrite concentrations and NOS activity are similar in both groups. Increased cGMP may reflect the stimulatory effect of peroxides (an activator of guanylate cyclase), because lipid peroxidation is increased in aortae and in plasma in sickle mice. Despite increased vascular cGMP levels in sickle mice, conscious systolic blood pressure is comparable to that of aged-matched controls; sickle mice, however, evince a greater rise in systolic blood pressure in response to nitro-l-arginine methyl ester, an inhibitor of NOS. Systemic concentrations of the vasoconstrictive oxidative product 8-isoprostane are increased in sickle mice. We conclude that vascular responses are altered in this transgenic sickle mouse and are accompanied by increased lipid peroxidation and production of cGMP; we suggest that oxidant-inducible vasoconstrictor systems such as isoprostanes may oppose nitric oxide-dependent and nitric oxide-independent mechanisms of vasodilatation in this transgenic sickle mouse. Destabilization of the vasoactive balance in the sickle vasculature by clinically relevant states may predispose to vasoocclusive disease.

scholarly journals Thrombin-independent contribution of tissue factor to inflammation and cardiac hypertrophy in a mouse model of sickle cell disease

Blood ◽  
2016 ◽  
Vol 127 (10) ◽  
pp. 1371-1373 ◽  
Author(s):  
Erica M. Sparkenbaugh ◽  
Pichika Chantrathammachart ◽  
Kasemsiri Chandarajoti ◽  
Nigel Mackman ◽  
Nigel S. Key ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Mouse Model ◽  
Cardiac Hypertrophy ◽  
Tissue Factor ◽  
Sickle Cell ◽  
Cell Disease ◽  
Independent Contribution

scholarly journals Splenic Morphological Changes Are Accompanied by Altered Baseline Immunity in a Mouse Model of Sickle-Cell Disease

2012 ◽  
Vol 181 (5) ◽  
pp. 1725-1734 ◽  
Author(s):  
Steven M. Szczepanek ◽  
Jeffrey T. McNamara ◽  
Eric R. Secor ◽  
Prabitha Natarajan ◽  
Linda A. Guernsey ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Mouse Model ◽  
Sickle Cell ◽  
Morphological Changes ◽  
Cell Disease

scholarly journals Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease

Blood ◽  
2014 ◽  
Vol 123 (11) ◽  
pp. 1747-1756 ◽  
Author(s):  
Erica M. Sparkenbaugh ◽  
Pichika Chantrathammachart ◽  
Jacqueline Mickelson ◽  
Joanne van Ryn ◽  
Robert P. Hebbel ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Mouse Model ◽  
Sickle Cell ◽  
Vascular Inflammation ◽  
Vascular Pathology ◽  
Cell Disease ◽  
Potential Target ◽  
Key Points ◽  
Thrombotic Complications ◽  
Differential Contribution

Key Points Inhibition of FXa or thrombin might be considered to reduce thrombotic complications and vascular inflammation in sickle cell patients. PAR-2 could be a potential target to inhibit vascular pathology associated with sickle cell disease.

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