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Animal models to study cardiac regeneration.
Permanent fibrosis and chronic deterioration of heart function in patients after myocardial infarction present a major health-care burden worldwide. In contrast to the restricted potential for cellular and functional regeneration of the adult mammalian heart, a robust capacity for cardiac regeneration is seen during the neonatal period in mammals as well as in the adults of many fish and amphibian species. However, we lack a complete understanding as to why cardiac regeneration takes place more efficiently in some species than in others. The capacity of the heart to regenerate after injury is controlled by a complex network of cellular and molecular mechanisms that form a regulatory landscape, either permitting or restricting regeneration. In this Review, we provide an overview of the diverse array of vertebrates that have been studied for their cardiac regenerative potential and discuss differential heart regeneration outcomes in closely related species. Additionally, we summarize current knowledge about the core mechanisms that regulate cardiac regeneration across vertebrate species.
Macrophages directly contribute collagen to scar formation during zebrafish heart regeneration and mouse heart repair.
Canonical roles for macrophages in mediating the fibrotic response after a heart attack include extracellular matrix turnover and activation of cardiac fibroblasts to initiate collagen deposition. Here we reveal that macrophages directly contribute collagen to the forming post-injury scar. Unbiased transcriptomics shows an upregulation of collagens in both zebrafish and mouse macrophages following heart injury. Adoptive transfer of macrophages, from either collagen-tagged zebrafish or adult mouse GFPtpz-collagen donors, enhances scar formation via cell autonomous production of collagen. In zebrafish, the majority of tagged collagen localises proximal to the injury, within the overlying epicardial region, suggesting a possible distinction between macrophage-deposited collagen and that predominantly laid-down by myofibroblasts. Macrophage-specific targeting of col4a3bpa and cognate col4a1 in zebrafish significantly reduces scarring in cryoinjured hosts. Our findings contrast with the current model of scarring, whereby collagen deposition is exclusively attributed to myofibroblasts, and implicate macrophages as direct contributors to fibrosis during heart repair.
Functional Heterogeneity within the Developing Zebrafish Epicardium.
The epicardium is essential during cardiac development, homeostasis, and repair, and yet fundamental insights into its underlying cell biology, notably epicardium formation, lineage heterogeneity, and functional cross-talk with other cell types in the heart, are currently lacking. In this study, we investigated epicardial heterogeneity and the functional diversity of discrete epicardial subpopulations in the developing zebrafish heart. Single-cell RNA sequencing uncovered three epicardial subpopulations with specific genetic programs and distinctive spatial distribution. Perturbation of unique gene signatures uncovered specific functions associated with each subpopulation and established epicardial roles in cell adhesion, migration, and chemotaxis as a mechanism for recruitment of leukocytes into the heart. Understanding which mechanisms epicardial cells employ to establish a functional epicardium and how they communicate with other cardiovascular cell types during development will bring us closer to repairing cellular relationships that are disrupted during cardiovascular disease.
Functional heterogeneity within the developing zebrafish epicardium
The epicardium is essential during cardiac development, homeostasis and repair and yet fundamental insights into its underlying cell biology, notably epicardium formation, lineage heterogeneity and functional cross-talk with other cell types in the heart, are currently lacking. In this study, we investigated epicardial heterogeneity and the functional diversity of discrete epicardial subpopulations in the developing zebrafish heart. Single-cell RNA-sequencing uncovered three epicardial subpopulations with specific genetic programmes and distinctive spatial distribution within the developing heart. Perturbation of unique gene signatures uncovered distinct functions associated with each subpopulation and established novel epicardial roles in cell adhesion, migration, and chemotaxis as a mechanism for recruitment of leukocytes into the heart. This work elucidates the mutual spatiotemporal relationships between different epicardial subpopulations and assigns unique function to each during cardiac development. Understanding which mechanisms cells employ to establish a functional epicardium and to communicate with other cardiovascular cell types during development will bring us closer to repairing cellular relationships that are disrupted during cardiovascular disease.
Distinct epicardial gene regulatory programs drive development and regeneration of the zebrafish heart
Unlike the adult mammalian heart, which has limited regenerative capacity, the zebrafish heart fully regenerates following injury. Reactivation of cardiac developmental programs is considered key to successfully regenerating the heart, yet the regulation underlying the response to injury remains elusive. Here, we compared the transcriptome and epigenome of the developing and regenerating zebrafish epicardia. We identified epicardial enhancer elements with specific activity during development or during adult heart regeneration. By generating gene regulatory networks associated with epicardial development and regeneration, we inferred genetic programs driving each of these processes, which were largely distinct. Loss of Hif1ab, Nrf1, Tbx2b, and Zbtb7a, central regulators of the regenerating epicardial network, in injured hearts resulted in elevated epicardial cell numbers infiltrating the wound and excess fibrosis after cryoinjury. Our work identifies differences between the regulatory blueprint deployed during epicardial development and regeneration, underlining that heart regeneration goes beyond the reactivation of developmental programs.
Animal models to study cardiac regeneration
Permanent fibrosis and chronic deterioration of heart function in patients after myocardial infarction present a major health-care burden worldwide. In contrast to the restricted potential for cellular and functional regeneration of the adult mammalian heart, a robust capacity for cardiac regeneration is seen during the neonatal period in mammals as well as in the adults of many fish and amphibian species. However, we lack a complete understanding as to why cardiac regeneration takes place more efficiently in some species than in others. The capacity of the heart to regenerate after injury is controlled by a complex network of cellular and molecular mechanisms that form a regulatory landscape, either permitting or restricting regeneration. In this Review, we provide an overview of the diverse array of vertebrates that have been studied for their cardiac regenerative potential and discuss differential heart regeneration outcomes in closely related species. Additionally, we summarize current knowledge about the core mechanisms that regulate cardiac regeneration across vertebrate species.
A blood atlas of COVID-19 defines hallmarks of disease severity and specificity
SummaryTreatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete understanding of potentially druggable immune mediators of disease. To advance this, we present a comprehensive multi-omic blood atlas in patients with varying COVID-19 severity and compare with influenza, sepsis and healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity revealed cells, their inflammatory mediators and networks as potential therapeutic targets, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Tensor and matrix decomposition of the overall dataset revealed feature groupings linked with disease severity and specificity. Our systems-based integrative approach and blood atlas will inform future drug development, clinical trial design and personalised medicine approaches for COVID-19.
Altered Impulsivity Across Drug-Naïve Parkinsonism, Isolated Rapid Eye Movement Sleep Behavior Disorder, and Their High-Risk Relatives.
OBJECTIVE: To determine multidimensional impulsivity levels across different early stages of α-synucleinopathy. METHODS: This cross-sectional study investigated motor and decisional impulsivity levels using a panel of computerized tasks among drug-naïve parkinsonism patients, isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) patients and their first-degree relatives (iRBD-FDRs), and control participants. Trait impulsivity and impulse control behaviors were assessed by self-reported questionnaires. RESULTS: A total of 27 drug-naïve parkinsonism patients, 157 iRBD patients, 66 iRBD-FDRs, and 82 control participants were recruited. Parkinsonism and iRBD patients had fewer numbers of extracted beads in beads task 1 and 2 (both p
Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation
Propiogenic substrates and gut bacteria produce propionate, a post-translational protein modifier. In this study, we used a mouse model of propionic acidaemia (PA) to study how disturbances to propionate metabolism result in histone modifications and changes to gene expression that affect cardiac function. Plasma propionate surrogates were raised in PA mice, but female hearts manifested more profound changes in acyl-CoAs, histone propionylation and acetylation, and transcription. These resulted in moderate diastolic dysfunction with raised diastolic Ca2+, expanded end-systolic ventricular volume and reduced stroke volume. Propionate was traced to histone H3 propionylation and caused increased acetylation genome-wide, including at promoters of Pde9a and Mme, genes related to contractile dysfunction through downscaled cGMP signaling. The less severe phenotype in male hearts correlated with β-alanine buildup. Raising β-alanine in cultured myocytes treated with propionate reduced propionyl-CoA levels, indicating a mechanistic relationship. Thus, we linked perturbed propionate metabolism to epigenetic changes that impact cardiac function.
Involvement of orexin type-2 receptors in genetic absence epilepsy rats.
INTRODUCTION: Orexin is a neuropeptide neurotransmitter that regulates the sleep/wake cycle produced by the lateral hypothalamus neurons. Recent studies have shown the involvement of orexin system in epilepsy. Limited data is available about the possible role of orexins in the pathophysiology of absence seizures. This study aims to understand the role of orexinergic signaling through the orexin-type 2 receptor (OX2R) in the pathophysiology of absence epilepsy. The pharmacological effect of a selective OX2R agonist, YNT-185 on spike-and-wave-discharges (SWDs) and the OX2R receptor protein levels in the cortex and thalamus in adult GAERS were investigated. METHODS: The effect of intracerebroventricular (ICV) (100, 300, and 600 nmol/10 μL), intrathalamic (30 and 40 nmol/500 nL), and intracortical (40 nmol/500 nL) microinjections of YNT-185 on the duration and number of spontaneous SWDs were evaluated in adult GAERS. The percentage of slow-wave sleep (SWS) and spectral characteristics of background EEG were analyzed after the ICV application of 600 nmol YNT-185. The level of OX2R expression in the somatosensory cortex and projecting thalamic nuclei of adult GAERS were examined by Western blot and compared with the non-epileptic Wistar rats. RESULTS: We showed that ICV administration of YNT-185 suppressed the cumulative duration of SWDs in GAERS compared to the saline-administered control group (p
Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells.
Malignancy is enabled by pro-growth mutations and adequate energy provision. However, global metabolic activation would be self-terminating if it depleted tumor resources. Cancer cells could avoid this by rationing resources, e.g., dynamically switching between "baseline" and "activated" metabolic states. Using single-cell metabolic phenotyping of pancreatic ductal adenocarcinoma cells, we identify MIA-PaCa-2 as having broad heterogeneity of fermentative metabolism. Sorting by a readout of lactic acid permeability separates cells by fermentative and respiratory rates. Contrasting phenotypes persist for 4 days and are unrelated to cell cycling or glycolytic/respiratory gene expression; however, transcriptomics links metabolically active cells with interleukin-6 receptor (IL-6R)-STAT3 signaling. We verify this by IL-6R/STAT3 knockdowns and sorting by IL-6R status. IL-6R/STAT3 activates fermentation and transcription of its inhibitor, SOCS3, resulting in delayed negative feedback that underpins transitions between metabolic states. Among cells manifesting wide metabolic heterogeneity, dynamic IL-6R/STAT3 signaling may allow cell cohorts to take turns in progressing energy-intense processes without depleting shared resources.
Development and Evolution of Thalamocortical Connectivity.
Conscious perception in mammals depends on precise circuit connectivity between cerebral cortex and thalamus; the evolution and development of these structures are closely linked. During the wiring of reciprocal thalamus-cortex connections, thalamocortical axons (TCAs) first navigate forebrain regions that had undergone substantial evolutionary modifications. In particular, the organization of the pallial-subpallial boundary (PSPB) diverged significantly between mammals, reptiles, and birds. In mammals, transient cell populations in internal capsule and early corticofugal projections from subplate neurons closely interact with TCAs to guide pathfinding through ventral forebrain and PSPB crossing. Prior to thalamocortical axon arrival, cortical areas are initially patterned by intrinsic genetic factors. Thalamocortical axons then innervate cortex in a topographically organized manner to enable sensory input to refine cortical arealization. Here, we review the mechanisms underlying the guidance of thalamocortical axons across forebrain boundaries, the implications of PSPB evolution for thalamocortical axon pathfinding, and the reciprocal influence between thalamus and cortex during development.
The effect of and correction for through-slice dephasing on 2D gradient-echo double angle B 1 + mapping.
PURPOSE: To show that B 0 $$ {\mathrm{B}}_0 $$ variations through slice and slice profile effects are two major confounders affecting 2D dual angle B 1 + $$ {\mathrm{B}}_1^{+} $$ maps using gradient-echo signals and thus need to be corrected to obtain accurate B 1 + $$ {\mathrm{B}}_1^{+} $$ maps. METHODS: The 2D gradient-echo transverse complex signal was Bloch-simulated and integrated across the slice dimension including nonlinear variations in B 0 $$ {\mathrm{B}}_0 $$ inhomogeneities through slice. A nonlinear least squares fit was used to find the B 1 + $$ {\mathrm{B}}_1^{+} $$ factor corresponding to the best match between the two gradient-echo signals experimental ratio and the Bloch-simulated ratio. The correction was validated in phantom and in vivo at 3T. RESULTS: For our RF excitation pulse, the error in the B 1 + $$ {\mathrm{B}}_1^{+} $$ factor scales by approximately 3.8% for every 10 Hz/cm variation in B 0 $$ {\mathrm{B}}_0 $$ along the slice direction. Higher accuracy phantom B 1 + $$ {\mathrm{B}}_1^{+} $$ maps were obtained after applying the proposed correction; the root mean square B 1 + $$ {\mathrm{B}}_1^{+} $$ error relative to the gold standard B 1 + $$ {\mathrm{B}}_1^{+} $$ decreased from 6.4% to 2.6%. In vivo whole-liver T 1 $$ {\mathrm{T}}_1 $$ maps using the corrected B 1 + $$ {\mathrm{B}}_1^{+} $$ map registered a significant decrease in T 1 $$ {\mathrm{T}}_1 $$ gradient through slice. CONCLUSION: B 0 $$ {\mathrm{B}}_0 $$ inhomogeneities varying through slice were seen to have an impact on the accuracy of 2D double angle B 1 + $$ {\mathrm{B}}_1^{+} $$ maps using gradient-echo sequences. Consideration of this confounder is crucial for research relying on accurate knowledge of the true excitation flip angles, as is the case of T 1 $$ {\mathrm{T}}_1 $$ mapping using a spoiled gradient recalled echo sequence.
Mass spectrometry in cerebrospinal fluid uncovers association of glycolysis biomarkers with Alzheimer's disease in a large clinical sample.
Alzheimer's disease (AD) is a complex and heterogeneous neurodegenerative disorder with contributions from multiple pathophysiological pathways. One of the long-recognized and important features of AD is disrupted cerebral glucose metabolism, but the underlying molecular basis remains unclear. In this study, unbiased mass spectrometry was used to survey CSF from a large clinical cohort, comparing patients who are either cognitively unimpaired (CU; n = 68), suffering from mild-cognitive impairment or dementia from AD (MCI-AD, n = 95; DEM-AD, n = 72), or other causes (MCI-other, n = 77; DEM-other, n = 23), or Normal Pressure Hydrocephalus (NPH, n = 57). The results revealed changes related to altered glucose metabolism. In particular, two glycolytic enzymes, pyruvate kinase (PKM) and aldolase A (ALDOA), were found to be upregulated in CSF from patients with AD compared to those with other neurological conditions. Increases in full-length PKM and ALDOA levels in CSF were confirmed with immunoblotting. Levels of these enzymes furthermore correlated negatively with CSF glucose in matching CSF samples. PKM levels were also found to be increased in AD in publicly available brain-tissue data. These results indicate that ALDOA and PKM may act as technically-robust potential biomarkers of glucose metabolism dysregulation in AD.
Transcriptional regulators of arterial and venous identity in the developing mammalian embryo
The complex and hierarchical vascular network of arteries, veins, and capillaries features considerable endothelial heterogeneity, yet the regulatory pathways directing arteriovenous specification, differentiation, and identity are still not fully understood. Recent advances in analysis of endothelial-specific gene-regulatory elements, single-cell RNA sequencing, and cell lineage tracing have both emphasized the importance of transcriptional regulation in this process and shed considerable light on the mechanism and regulation of specification within the endothelium. In this review, we discuss recent advances in our understanding of how endothelial cells acquire arterial and venous identity and the role different transcription factors play in this process.