Unraveling the Big Sleep:Molecular Aspects of Stem Cell Dormancy and Hibernation

Tissue-resident stem cells may enter a dormant state, also known as quiescence, which allows them to withstand metabolic stress and unfavorable conditions. Similarly, hibernating mammals can also enter a state of dormancy used to evade hostile circumstances, such as food shortage and low ambient temperatures. In hibernation, the dormant state of the individual and its cells is commonly known as torpor, and is characterized by metabolic suppression in individual cells. Given that both conditions represent cell survival strategies, we here compare the molecular aspects of cellular quiescence, particularly of well-studied hematopoietic stem cells, and torpor at the cellular level. Critical processes of dormancy are reviewed, including the suppression of the cell cycle, changes in metabolic characteristics, and cellular mechanisms of dealing with damage. Key factors shared by hematopoietic stem cell quiescence and torpor include a reversible activation of factors inhibiting the cell cycle, a shift in metabolism from glucose to fatty acid oxidation, downregulation of mitochondrial activity, key changes in hypoxia-inducible factor one alpha (HIF-1α), mTOR, reversible protein phosphorylation and autophagy, and increased radiation resistance. This similarity is remarkable in view of the difference in cell populations, as stem cell quiescence regards proliferating cells, while torpor mainly involves terminally differentiated cells. A future perspective is provided how to advance our understanding of the crucial pathways that allow stem cells and hibernating animals to engage in their 'great slumbers.'</p

Phase specific suppression of neutrophil function in hibernating Syrian hamster

Hibernation consists of alternating periods of reduced metabolism (torpor) with brief periods of metabolism similar to summer euthermia (arousal). The function of the innate immune system is reduced during hibernation, of which the underlying mechanisms are incompletely understood. Here, we studied neutrophil functionality during hibernation in Syrian hamsters. The inflammatory response to LPS-induced endotoxemia is inhibited in hibernation, partly mediated by reduced IL-6 production in early arousal. Furthermore, neutrophil pathogen binding, phagocytosis and oxidative burst is profoundly reduced in early arousal. Functionality of both summer and early arousal neutrophils was repressed in plasma from early arousal and mixed plasma from early arousal and summer euthermic, but restored by summer euthermic plasma, signifying that a plasma factor in early arousal inhibits TLR-recognition. Identification of the inhibiting factor may offer a target to modulate neutrophil function with relevance to (auto-)inflammatory diseases

Hibernation and hemostasis

Hibernating mammals have developed many physiological adaptations to accommodate their decreased metabolism, body temperature, heart rate and prolonged immobility without suffering organ injury. During hibernation, the animals must suppress blood clotting to survive prolonged periods of immobility and decreased blood flow that could otherwise lead to the formation of potentially lethal clots. Conversely, upon arousal hibernators must be able to quickly restore normal clotting activity to avoid bleeding. Studies in multiple species of hibernating mammals have shown reversible decreases in circulating platelets, cells involved in hemostasis, as well as in protein coagulation factors during torpor. Hibernator platelets themselves also have adaptations that allow them to survive in the cold, while those from non-hibernating mammals undergo lesions during cold exposure that lead to their rapid clearance from circulation when re-transfused. While platelets lack a nucleus with DNA, they contain RNA and other organelles including mitochondria, in which metabolic adaptations may play a role in hibernator’s platelet resistance to cold induced lesions. Finally, the breakdown of clots, fibrinolysis, is accelerated during torpor. Collectively, these reversible physiological and metabolic adaptations allow hibernating mammals to survive low blood flow, low body temperature, and immobility without the formation of clots during torpor, yet have normal hemostasis when not hibernating. In this review we summarize blood clotting changes and the underlying mechanisms in multiple species of hibernating mammals. We also discuss possible medical applications to improve cold preservation of platelets and antithrombotic therapy

Hibernation and hemostasis

Hibernating mammals have developed many physiological adaptations to accommodate their decreased metabolism, body temperature, heart rate and prolonged immobility without suffering organ injury. During hibernation, the animals must suppress blood clotting to survive prolonged periods of immobility and decreased blood flow that could otherwise lead to the formation of potentially lethal clots. Conversely, upon arousal hibernators must be able to quickly restore normal clotting activity to avoid bleeding. Studies in multiple species of hibernating mammals have shown reversible decreases in circulating platelets, cells involved in hemostasis, as well as in protein coagulation factors during torpor. Hibernator platelets themselves also have adaptations that allow them to survive in the cold, while those from non-hibernating mammals undergo lesions during cold exposure that lead to their rapid clearance from circulation when re-transfused. While platelets lack a nucleus with DNA, they contain RNA and other organelles including mitochondria, in which metabolic adaptations may play a role in hibernator's platelet resistance to cold induced lesions. Finally, the breakdown of clots, fibrinolysis, is accelerated during torpor. Collectively, these reversible physiological and metabolic adaptations allow hibernating mammals to survive low blood flow, low body temperature, and immobility without the formation of clots during torpor, yet have normal hemostasis when not hibernating. In this review we summarize blood clotting changes and the underlying mechanisms in multiple species of hibernating mammals. We also discuss possible medical applications to improve cold preservation of platelets and antithrombotic therapy.</p

Spatiotemporal regulation of hydrogen sulfide signaling in the kidney

Hydrogen sulfide (H2S) has long been recognized as a putrid, toxic gas. However, as a result of intensive biochemical research in the past two decades, H2S is now considered to be the third gasotransmitter alongside nitric oxide (NO) and carbon monoxide (CO) in mammalian systems. H2S-producing enzymes are expressed in all organs, playing an important role in their physiology. In the kidney, H2S is a critical regulator of vascular and cellular function, although the mechanisms that affect (sub)cellular levels of H2S are not precisely understood. H2S modulates systemic and renal blood flow, glomerular filtration rate and the renin-angiotensin axis through direct inhibition of nitric oxide synthesis. Further, H2S affects cellular function by modulating protein activity via post-translational protein modification: a process termed persulfidation. Persulfidation modulates protein activity, protein localization and protein-protein interactions. Additionally, acute kidney injury (AKI) due to mitochondrial dysfunction, which occurs during hypoxia or ischemia-reperfusion (IR), is attenuated by H2S. H2S enhances ATP production, prevents damage due to free radicals and regulates endoplasmic reticulum stress during IR. In this review, we discuss current insights in the (sub)cellular regulation of H2S anabolism, retention and catabolism, with relevance to spatiotemporal regulation of renal H2S levels. Together, H2S is a versatile gasotransmitter with pleiotropic effects on renal function and offers protection against AKI. Unraveling the mechanisms that modulate (sub)cellular signaling of H2S not only expands fundamental insight in the regulation of functional effects mediated by H2S, but can also provide novel therapeutic targets to prevent kidney injury due to hypoxic or ischemic injury

Prognostic value of serial score measurements of the national early warning score, the quick sequential organ failure assessment and the systemic inflammatory response syndrome to predict clinical outcome in early sepsis

BACKGROUND AND IMPORTANCE: Sepsis is a common and potentially lethal syndrome, and early recognition is critical to prevent deterioration. Yet, currently available scores to facilitate recognition of sepsis lack prognostic accuracy. OBJECTIVE: To identify the optimal time-point to determine NEWS, qSOFA and SIRS for the prediction of clinical deterioration in early sepsis and to determine whether the change in these scores over time improves their prognostic accuracy. DESIGN: Post hoc analysis of prospectively collected data. SETTINGS AND PARTICIPANTS: This study was performed in the emergency department (ED) of a tertiary-care teaching hospital. Adult medical patients with (potential) sepsis were included. OUTCOME MEASURES AND ANALYSIS: The primary outcome was clinical deterioration within 72 h after admission, defined as organ failure development, the composite outcome of ICU-admission and death. Secondary outcomes were the composite of ICU-admission/death and a rise in SOFA at least 2. Scores were calculated at the ED with 30-min intervals. ROC analyses were constructed to compare the prognostic accuracy of the scores. RESULTS: In total, 1750 patients were included, of which 360 (20.6%) deteriorated and 79 (4.5%) went to the ICU or died within 72 h. The NEWS at triage (AUC, 0.62; 95% CI, 0.59-0.65) had a higher accuracy than qSOFA (AUC, 0.60; 95% CI, 0.56-0.63) and SIRS (AUC, 0.59; 95% CI, 0.56-0.63) for predicting deterioration. The AUC of the NEWS at 1 h (0.65; 95% CI, 0.63-0.69) and 150 min after triage (0.64; 95% CI, 0.61-0.68) was higher than the AUC of the NEWS at triage. The qSOFA had the highest AUC at 90 min after triage (0.62; 95% CI, 0.58-0.65), whereas the SIRS had the highest AUC at 60 min after triage (0.60; 95% CI, 0.56-0.63); both are not significantly different from triage. The NEWS had a better accuracy to predict ICU-admission/death <72 h compared with qSOFA (AUC difference, 0.092) and SIRS (AUC difference, 0.137). No differences were found for the prediction of a rise in SOFA at least 2 within 72 h between the scores. Patients with the largest improvement in any of the scores were more prone to deteriorate. CONCLUSION: NEWS had a higher prognostic accuracy to predict deterioration compared with SIRS and qSOFA; the highest accuracy was reached at 1 h after triage

Cecal Ligation and Puncture-Induced Sepsis Promotes Brown Adipose Tissue Inflammation Without Any Impact on Expression of Thermogenic-Related Genes

Background and Aims: The negative effects of chronic low-level inflammation on adipose tissue physiology have been extensively demonstrated, whereas the effects of acute inflammation are less studied. Here, we aimed to investigate the effects of sepsis-induced acute inflammation on gene expression markers of brown and white adipose tissue functionality. Methods: Brown adipose tissue (BAT) and perirenal white adipose tissue (prWAT) gene expression markers were analyzed in cecal ligation and puncture (CLP)-induced sepsis mice model. Results: CLP-induced sepsis attenuated expression of adipogenesis-related genes, in parallel to increased Tnf, Il6, and Ltf gene expression in prWAT. In contrast, CLP-induced sepsis resulted in increased expression of pro-inflammatory genes (Il6, Ltf, and Lbp) in BAT, without affecting expression of genes encoding for thermogenic activity. Conclusion: Sepsis promotes both prWAT and BAT inflammation, associated with reduced adipogenesis-related gene expression in prWAT, without significant effects on BAT thermogenic genes

Use of sepsis-related diagnostic criteria in primary care:a survey among general practitioners

BACKGROUND: Use of sepsis-criteria in hospital settings is effective in realizing early recognition, adequate treatment and reduction of sepsis-associated morbidity and mortality. Whether general practitioners (GPs) use these diagnostic criteria is unknown. OBJECTIVE: To gauge the knowledge and use of various diagnostic criteria. To determine which parameters GPs associate with an increased likelihood of sepsis. METHODS: Two thousand five hundred and sixty GPs were invited and 229 agreed to participate in a survey, reached out to through e-mail and WhatsApp groups. The survey consisted of two parts: the first part aimed to obtain information about the GP, training and knowledge about sepsis recognition, and the second part tested specific knowledge using six realistic cases. RESULTS: Two hundred and six questionnaires, representing a response rate of 8.1%, were eligible for analysis. Gut feeling (98.1%) was the most used diagnostic method, while systemic inflammatory response syndrome (37.9%), quick Sequential Organ Failure Assessment (qSOFA) (7.8%) and UK Sepsis Trust criteria (UKSTc) (1.5%) were used by the minority of the GPs. Few of the responding GPs had heard of either the qSOFA (27.7%) or the UKSTc (11.7%). Recognition of sepsis varied greatly between GPs. GPs most strongly associated the individual signs of the qSOFA (mental status, systolic blood pressure, capillary refill time and respiratory rate) with diagnosing sepsis in the test cases. CONCLUSIONS: GPs mostly use gut feeling to diagnose sepsis and are frequently not familiar with the 'sepsis-criteria' used in hospital settings, although clinical reasoning was mostly in line with the qSOFA score. In order to improve sepsis recognition in primary care, GPs should be educated in the use of available screening tools

Predicting deterioration of patients with early sepsis at the emergency department using continuous heart rate variability analysis:a model-based approach

Background: Sepsis is a life-threatening disease with an in-hospital mortality rate of approximately 20%. Physicians at the emergency department (ED) have to estimate the risk of deterioration in the coming hours or days and decide whether the patient should be admitted to the general ward, ICU or can be discharged. Current risk stratification tools are based on measurements of vital parameters at a single timepoint. Here, we performed a time, frequency, and trend analysis on continuous electrocardiograms (ECG) at the ED to try and predict deterioration of septic patients. Methods: Patients were connected to a mobile bedside monitor that continuously recorded ECG waveforms from triage at the ED up to 48 h. Patients were post-hoc stratified into three groups depending on the development of organ dysfunction: no organ dysfunction, stable organ dysfunction or progressive organ dysfunction (i.e., deterioration). Patients with de novo organ dysfunction and those admitted to the ICU or died were also stratified to the group of progressive organ dysfunction. Heart rate variability (HRV) features over time were compared between the three groups. Results: In total 171 unique ED visits with suspected sepsis were included between January 2017 and December 2018. HRV features were calculated over 5-min time windows and summarized into 3-h intervals for analysis. For each interval, the mean and slope of each feature was calculated. Of all analyzed features, the average of the NN-interval, ultra-low frequency, very low frequency, low frequency and total power were different between the groups at multiple points in time. Conclusions: We showed that continuous ECG recordings can be automatically analyzed and used to extract HRV features associated with clinical deterioration in sepsis. The predictive accuracy of our current model based on HRV features derived from the ECG only shows the potential of HRV measurements at the ED. Unlike other risk stratification tools employing multiple vital parameters this does not require manual calculation of the score and can be used on continuous data over time. Trial registration The protocol of this study is published by Quinten et al., 2017.</p