The hibernating 13-lined ground squirrel as a model organism for potential cold storage of platelets

Cooper, Scott; Richters, Karl E; Melin, Travis; Liu, Zhi Jian; Hordyk, Peter J.; Benrud, Ryan; Geiser, Lauren R.; Cash, Steve E; Shelley, Carl Simon; Howard, Donald; Ereth, Mark H.; Sola‐Visner, Martha

doi:10.1152/ajpregu.00018.2012

Cited by 26 publications

(47 citation statements)

References 25 publications

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“…The mean platelet volume during hibernation is larger in hibernators than July animals, consistent with continued platelet synthesis, but could also be explained by an increase in red blood cell fragments or other small debris the size of platelets formed during hibernation. Newly produced reticulated platelets do not appear in the blood until 48 h postarousal (22). One possible explanation for these seemingly contradictory observations is that megakaryocytes continue to produce proteins necessary for platelet production during torpor, but that the newly synthesize platelets are only gradually released into circulation at levels below the detection of the reticulated platelet assay.…”

Section: Discussionmentioning

confidence: 99%

Effects of hibernation on bone marrow transcriptome in thirteen-lined ground squirrels

Cooper

Sell

Fahrenkrog

et al. 2016

Physiological Genomics

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M. Effects of hibernation on bone marrow transcriptome in thirteen-lined ground squirrels. Physiol Genomics 48: 513-525, 2016. First published May 20, 2016 doi:10.1152/physiolgenomics.00120.2015.-Mammalian hibernators adapt to prolonged periods of immobility, hypometabolism, hypothermia, and oxidative stress, each capable of reducing bone marrow activity. In this study bone marrow transcriptomes were compared among thirteen-lined ground squirrels collected in July, winter torpor, and winter interbout arousal (IBA). The results were consistent with a suppression of acquired immune responses, and a shift to innate immune responses during hibernation through higher complement expression. Consistent with the increase in adipocytes found in bone marrow of hibernators, expression of genes associated with white adipose tissue are higher during hibernation. Genes that should strengthen the bone by increasing extracellular matrix were higher during hibernation, especially the collagen genes. Finally, expression of heat shock proteins were lower, and cold-response genes were higher, during hibernation. No differential expression of hematopoietic genes involved in erythrocyte or megakaryocyte production was observed. This global view of the changes in the bone marrow transcriptome over both short term (torpor vs. IBA) and long term (torpor vs. July) hypothermia can explain several observations made about circulating blood cells and the structure and strength of the bone during hibernation. erythrocyte; leukocyte; megakaryocyte; osteoblast; adipose BONE MARROW IS A COMPLEX ORGAN consisting of many different cell types and stem cell pools. These cells express both unique and common sets of genes and likely influence each other's activities. Hematopoietic stem cells can differentiate into lymphoid progenitor cells that produce natural killer cells and lymphocytes, or into myeloid progenitor cells that give rise to erythrocytes, the remaining leukocytes, and megakaryocytes. Megakaryocytes in turn shed anucleated platelets involved in blood clotting and inflammation. Bone marrow resident mesenchymal stem cells can differentiate to produce resident bone cells including osteoblasts, adipocytes, and chondrocytes (64). Osteoblasts can terminally differentiate into osteocytes and are involved in maintaining bone strength and extracellular matrix production. Bone marrow adipose composition is affected by age, diet, and disease states. Bone marrow may also contain skeletal muscle and hepatocyte stem cell pools. Because of the rapid rate of mitosis by multiple resident stem cell pools, bone marrow is sensitive to damage by radiation and chemotherapy, leaving patients immunocompromised and anemic (25). Bone mineral density and collagen are decreased by prolonged disuse such as bed rest or immobilization (45,86). Recent studies have also demonstrated an increase in neutrophils, natural killer cells, and lymphocytes and a decrease in monocytes in patients subjected to 60 days of bed rest (38). Finally, bone marrow adipocytes increase in ...

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Section: Discussionmentioning

confidence: 99%

Effects of hibernation on bone marrow transcriptome in thirteen-lined ground squirrels

Cooper

Sell

Fahrenkrog

et al. 2016

Physiological Genomics

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“…Because of this units of human platelets cannot be stored in the cold and can only be stored for 3–4 days at 22°C, increasing the risk of bacterial contamination and resulting in half of all units being discarded (Engelfriet, Reesink et al 2000, Jacobs, Palavecino et al 2001). The characteristics of cold storage lesions are observed in several mammalian species, but do not appear to occur in mammalian hibernators (Cooper, Richters et al 2012, de Vrij, Vogelaar et al 2014). …”

Section: Introductionmentioning

confidence: 99%

“…The hibernators will have some protection because their lower body temperatures decrease both primary and secondary hemostasis by reducing the activity of the enzymes and receptors involved in both processes (Van Poucke, Stevens et al 2014). However, hibernators have also adapted to this extreme decrease in blood flow by reversibly decreasing platelet, monocyte, neutrophil, vWF, FVIII, and FIX levels (Suomalainen and Lehto 1952, Svihla, Bowman et al 1952, Svihla, Bowman et al 1952, Svihla, Bowman et al 1953, Smith, Lewis et al 1954, Lechler and Penick 1963, Pivorun and Sinnamon 1981, Cooper, Richters et al 2012, de Vrij, Vogelaar et al 2014, Cooper, Sell et al 2016). …”

Section: Introductionmentioning

confidence: 99%

“…During torpor, ground squirrel platelets go through reorganization of their circumferential microtubule ring to form long rods and circulating platelet levels drop by 90%, returning to normal levels within two hours post arousal (Reddick, Poole et al 1973, Reznik, Reznik-Schuller et al 1975, Cooper, Richters et al 2012, de Vrij, Vogelaar et al 2014). This rapid release is not consistent with new synthesis of platelets, but rather release of platelets that had been sequestered (Cooper, Richters et al 2012).…”

Section: Introductionmentioning

confidence: 99%

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Temperature effects on the activity, shape, and storage of platelets from 13-lined ground squirrels

et al. 2017

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The objective of this study is to determine how a hibernating mammal avoids the formation of blood clots under periods of low blood flow. A microfluidic vascular injury model was performed to differentiate the effects of temperature and shear rate on platelet adhesion to collagen. Human and ground squirrel whole blood was incubated at 15 or 37°C and then passed through a microfluidic chamber over a 250 μm strip of type I fibrillar collagen at that temperature and shear rates of 50 s−1 or 300 s−1 to simulate torpid and aroused conditions respectively. At 15°C, both human and ground squirrel platelets showed a 90–95% decrease in accumulation on collagen independent of shear rate. At 37°C, human platelet accumulation reduced by 50% at 50 s−1 compared to 300 s−1, while ground squirrel platelet accumulation dropped by 80%. When compared to platelets from non-hibernating animals, platelets from animals collected after arousal from torpor showed a 60% decrease in binding at 37°C and 300 s−1, but a 2.5-fold increase in binding at 15°C and 50 s−1. vWF binding in platelets from hibernating ground squirrels were decreased by 50% relative to non-hibernating platelets. The source of the plasma that platelets were stored in did not affect the results indicating that the decreased vWF binding was a property of the platelets. Upon chilling, ground squirrel platelets increase microtubule assembly leading to the formation of long rods. This shape change is concurrent with sequestration of platelets in the liver and not the spleen. In conclusion, it appears that ground squirrel platelets are sequestered in the liver during torpor, have reduced binding capacity for plasma vWF, and lower accumulation on collagen at low shear rates and after storage at cold temperatures, while still being activated by external agonists. These adaptations would protect the animals from spontaneous thrombus formation during torpor but allow them to restore normal platelet function upon arousal.

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“…Hibernating mammals have adapted to this extreme decrease in blood flow and associated risk of DVT by reversibly decreasing platelet, monocyte, neutrophil, FVIII, and FIX levels (Suomalainen and Lehto 1952; Svihla et al 1952a, b, 1953; Smith et al 1954; Lechler and Penick 1963; Pivorun and Sinnamon 1981; Cooper et al 2012; de Vrij et al 2014). In contrast, the levels and activities of prothrombin, fibrinogen, and clotting factors V, VII, X–XII do not decrease significantly in torpor compared with non-hibernating animals.…”

Section: Introductionmentioning

confidence: 99%

Von Willebrand factor is reversibly decreased during torpor in 13-lined ground squirrels

et al. 2015

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During torpor in a hibernating mammal, decreased blood flow increases the risk of blood clots such as deep vein thrombi (DVT). In other animal models platelets, neutrophils, monocytes and von Willebrand factor (VWF) have been found in DVT. Previous research has shown that hibernating mammals decrease their levels of platelets and clotting factors VIII (FVIII) and IX (FIX), increasing both bleeding time and activated partial throm-boplastin time. In this study, FVIII, FIX and VWF activities and mRNA levels were measured in torpid and non-hibernating ground squirrels (Ictidomys tridecemlineatus). Here, we show that VWF high molecular weight multimers, collagen-binding activity, lung mRNA and promoter activity decrease during torpor. The VWF multimers reappear in plasma within 2 h of arousal in the spring. Similarly, FIX activity and liver mRNA both dropped threefold during torpor. In contrast, FVIII liver mRNA levels increased twofold while its activity dropped threefold, consistent with a post-transcriptional decrease in FVIII stability in the plasma due to decreased VWF levels. Finally, both neutrophils and monocytes are decreased eightfold during torpor which could slow the formation of DVT. In addition to providing insight in how blood clotting can be regulated to allow mammals to survive in extreme environments, hibernating ground squirrels provide an interesting model for studying.

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The hibernating 13-lined ground squirrel as a model organism for potential cold storage of platelets

Cited by 26 publications

References 25 publications

Effects of hibernation on bone marrow transcriptome in thirteen-lined ground squirrels

Effects of hibernation on bone marrow transcriptome in thirteen-lined ground squirrels

Temperature effects on the activity, shape, and storage of platelets from 13-lined ground squirrels

Von Willebrand factor is reversibly decreased during torpor in 13-lined ground squirrels

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