The vertebrate CNS is surrounded by the meninges, a protective barrier comprised of the outer dura mater and the inner leptomeninges, which includes the arachnoid and pial layers. While the dura mater contains lymphatic vessels, no conventional lymphatics have been found within the brain or leptomeninges. However, non-lumenized cells called Brain/Mural Lymphatic Endothelial Cells or Fluorescent Granule Perithelial cells (muLECs/BLECs/FGPs) that share a developmental program and gene expression with peripheral lymphatic vessels have been described in the meninges of zebrafish. Here we identify a structurally and functionally similar cell type in the mammalian leptomeninges that we name Leptomeningeal Lymphatic Endothelial Cells (LLEC). As in zebrafish, LLECs express multiple lymphatic markers, containing very large, spherical inclusions, and develop independently from the meningeal macrophage lineage. Mouse LLECs also internalize macromolecules from the cerebrospinal fluid, including Amyloid-β, the toxic driver of Alzheimer's disease progression. Finally, we identify morphologically similar cells co-expressing LLEC markers in human post-mortem leptomeninges. Given that LLECs share molecular, morphological, and functional characteristics with both lymphatics and macrophages, we propose they represent a novel, evolutionary conserved cell type with potential roles in homeostasis and immune organization of the meninges.
Tissue resident macrophages have vital homeostatic roles in many tissues but their roles are less well defined in the heart. The present study aimed to identify the density, polarisation status and distribution of macrophages in the healthy murine heart and to investigate their ability to respond to immune challenge. Histological analysis of hearts from CSF-1 receptor (csf1-GFP; MacGreen) and CX3CR1 (Cx3cr1GFP/+) reporter mice revealed a sparse population of GFP positive macrophages that were evenly distributed throughout the left and right ventricular free walls and septum. F4/80+CD11b+ cardiac macrophages, sorted from myocardial homogenates, were able to phagocytose fluorescent beads in vitro and expressed markers typical of both ‘M1’ (IL-1β, TNF and CCR2) and ‘M2’ activation (Ym1, Arg 1, RELMα and IL-10), suggesting no specific polarisation in healthy myocardium. Exposure to Th2 challenge by infection of mice with helminth parasites Schistosoma mansoni, or Heligmosomoides polygyrus, resulted in an increase in cardiac macrophage density, adoption of a stellate morphology and increased expression of Ym1, RELMα and CD206 (mannose receptor), indicative of ‘M2’ polarisation. This was dependent on recruitment of Ly6ChighCCR2+ monocytes and was accompanied by an increase in collagen content.In conclusion, in the healthy heart resident macrophages are relatively sparse and have a phagocytic role. Following Th2 challenge this population expands due to monocyte recruitment and adopts an ‘M2’ phenotype associated with increased tissue fibrosis.
Corticosteroids influence the development and function of the heart and its response to injury and pressure overload via actions on glucocorticoid (GR) and mineralocorticoid (MR) receptors. Systemic corticosteroid concentration depends largely on the activity of the hypothalamic–pituitary–adrenal (HPA) axis, but glucocorticoid can also be regenerated from intrinsically inert metabolites by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), selectively increasing glucocorticoid levels within cells and tissues. Extensive studies have revealed the roles for glucocorticoid regeneration by 11β-HSD1 in liver, adipose, brain and other tissues, but until recently, there has been little focus on the heart. This article reviews the evidence for glucocorticoid metabolism by 11β-HSD1 in the heart and for a role of 11β-HSD1 activity in determining the myocardial growth and physiological function. We also consider the potential of 11β-HSD1 as a therapeutic target to enhance repair after myocardial infarction and to prevent the development of cardiac remodelling and heart failure.
While a regenerative response is limited in the mammalian adult heart, it has been recently shown that the neonatal mammalian heart possesses a marked but transient capacity for regeneration after cardiac injury, including myocardial infarction. These findings evidence that the mammalian heart still retains a regenerative capacity and highlights the concept that the expression of distinct molecular switches (that activate or inhibit cellular mechanisms regulating tissue development and regeneration) vary during different stages of life, indicating that cardiac regeneration is an age-dependent process. Thus, understanding the mechanisms underpinning regeneration in the neonatal-infarcted heart is crucial to develop new treatments aimed at improving cardiovascular regeneration in the adult. The present review summarizes the current knowledge on the pathways and factors that are known to determine cardiac regeneration in the neonatal-infarcted heart. In particular, we will focus on the effects of microRNA manipulation in regulating cardiomyocyte proliferation and regeneration, as well as on the role of the Hippo signaling pathway and Meis1 in the regenerative response of the neonatal-infarcted heart. We will also briefly comment on the role of macrophages in scar formation of the adult-infarcted heart or their contribution for scar-free regeneration of the neonatal mouse heart after myocardial infarction. Although additional research is needed in order to identify other factors that regulate cardiovascular regeneration, these pathways represent potential therapeutic targets for rejuvenation of aging hearts and for improving regeneration of the adult-infarcted heart.
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The small size and high heart rate of the neonatal mouse heart makes structural and functional characterisation particularly challenging. Here, we describe application of electrocardiogram-gated kilohertz visualisation (EKV) ultrasound imaging with high spatio-temporal resolution to non-invasively characterise the postnatal mouse heart during normal growth and regeneration after injury. The 2-D images of the left ventricle (LV) acquired across the cardiac cycle from post-natal day 1 (P1) to P42 revealed significant changes in LV mass from P8 that coincided with a switch from hyperplastic to hypertrophic growth and correlated with ex vivo LV weight. Remodelling of the LV was indicated between P8 and P21 when LV mass and cardiomyocyte size increased with no accompanying change in LV wall thickness. Whereas Doppler imaging showed the expected switch from LV filling driven by atrial contraction to filling by LV relaxation during post-natal week 1, systolic function was retained at the same level from P1 to P42. EKV ultrasound imaging also revealed loss of systolic function after induction of myocardial infarction at P1 and regain of function associated with regeneration of the myocardium by P21. EKV ultrasound imaging thus offers a rapid and convenient method for routine non-invasive characterisation of the neonatal mouse heart.
The neonatal murine heart has been shown to retain a capacity for regeneration following injury until 7 days after birth, after which injury is followed by scar formation (Porello et al ., 2011). However normal physiology and growth characteristics of the heart are poorly defined during this neonatal period. The present study aimed to characterise changes in structure and function of the myocardium during early post-natal growth. Isofluorane anaesthetised mice underwent investigation by ‘b mode’ and Doppler high resolution ultrasound (Visualsonics Vevo 770) at E18.5, 2 days, 4 days, 8 days, 3 weeks and 6 weeks after birth (n = 5–6 per time-point). ECG and temperature were measured throughout assessment. Hearts were then collected, weighed before fixation and paraffin embedding for wheat-germ agglutinin (WGA) and isolectin B4 staining formeasurement of cardiomyocyte cross sectional area (CM-CSA) and blood vessel density. Left ventricular (LV) wall thickness increased from 440 ± 28 mm to 563 ± 16 mm between 2 and 8 post-partum, without a significant increase in CM-CSA, consistent with a phase of CM hyperplasia, rather than hypertrophy. In contrast, the rate of increase in CM-CSA was significantly greater from 8 days after birth, although not accompanied by a further increase in wall thickness until 3 weeks post-partum, consistent with rearrangement of cardiomyocytes to contribute to increased LV end-diastolic and end-systolic area. Throughout this period function, defined by ejection fraction and by myocardial performance index, remained largely stable. The period between 2 and 8 days after birth was also characterised by a reversal in the ratio of E and A waves in the mitral valve Doppler trace from a foetal-like pattern (0.72 ± 0.07) to an adult-like one (1.28 ± 0.04), consistent with maturation of LV filling. Isolectin B4 staining revealed the presence of large diameter vessels at birth, which reduced in size and became more organised towards 6 weeks post-partum. These data provide the first ultrasound characterisation of myocardial structure function during early post-natal growth. They reveal a pattern of myocardial growth that is consistent with a shift from reliance on proliferation early after birth to hypertrophy and realignment of myocytes from 8 days post-partum. This work is supported by a BHF 4 year PhD studentship to RC and by a BHF Centre of Research Excellence Award. Reference Porrello ER, et al. Transient regenerative potential of the neonatal mouse heart. Science. 2011;331:1078–1080
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