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Cell Jul 2023Wnt ligands oligomerize Frizzled (Fzd) and Lrp5/6 receptors to control the specification and activity of stem cells in many species. How Wnt signaling is selectively...
Wnt ligands oligomerize Frizzled (Fzd) and Lrp5/6 receptors to control the specification and activity of stem cells in many species. How Wnt signaling is selectively activated in different stem cell populations, often within the same organ, is not understood. In lung alveoli, we show that distinct Wnt receptors are expressed by epithelial (Fzd5/6), endothelial (Fzd4), and stromal (Fzd1) cells. Fzd5 is uniquely required for alveolar epithelial stem cell activity, whereas fibroblasts utilize distinct Fzd receptors. Using an expanded repertoire of Fzd-Lrp agonists, we could activate canonical Wnt signaling in alveolar epithelial stem cells via either Fzd5 or, unexpectedly, non-canonical Fzd6. A Fzd5 agonist (Fzd5) or Fzd6 stimulated alveolar epithelial stem cell activity and promoted survival in mice after lung injury, but only Fzd6 promoted an alveolar fate in airway-derived progenitors. Therefore, we identify a potential strategy for promoting regeneration without exacerbating fibrosis during lung injury.
Topics: Mice; Animals; Lung Injury; Wnt Proteins; Frizzled Receptors; Wnt Signaling Pathway; Alveolar Epithelial Cells; Stem Cells
PubMed: 37321220
DOI: 10.1016/j.cell.2023.05.022 -
Circulation Dec 2023Reducing cardiovascular disease burden among women remains challenging. Epidemiologic studies have indicated that polycystic ovary syndrome (PCOS), the most common...
BACKGROUND
Reducing cardiovascular disease burden among women remains challenging. Epidemiologic studies have indicated that polycystic ovary syndrome (PCOS), the most common endocrine disease in women of reproductive age, is associated with an increased prevalence and extent of coronary artery disease. However, the mechanism through which PCOS affects cardiac health in women remains unclear.
METHODS
Prenatal anti-Müllerian hormone treatment or peripubertal letrozole infusion was used to establish mouse models of PCOS. RNA sequencing was performed to determine global transcriptomic changes in the hearts of PCOS mice. Flow cytometry and immunofluorescence staining were performed to detect myocardial macrophage accumulation in multiple PCOS models. Parabiosis models, cell-tracking experiments, and in vivo gene silencing approaches were used to explore the mechanisms underlying increased macrophage infiltration in PCOS mouse hearts. Permanent coronary ligation was performed to establish myocardial infarction (MI). Histologic analysis and small-animal imaging modalities (eg, magnetic resonance imaging and echocardiography) were performed to evaluate the effects of PCOS on injury after MI. Women with PCOS and control participants (n=200) were recruited to confirm findings observed in animal models.
RESULTS
Transcriptomic profiling and immunostaining revealed that hearts from PCOS mice were characterized by increased macrophage accumulation. Parabiosis studies revealed that monocyte-derived macrophages were significantly increased in the hearts of PCOS mice because of enhanced circulating Ly6C monocyte supply. Compared with control mice, PCOS mice showed a significant increase in splenic Ly6C monocyte output, associated with elevated hematopoietic progenitors in the spleen and sympathetic tone. Plasma norepinephrine (a sympathetic neurotransmitter) levels and spleen size were consistently increased in women with PCOS when compared with those in control participants, and norepinephrine levels were significantly correlated with circulating CD14CD16 monocyte counts. Compared with animals without PCOS, PCOS animals showed significantly exacerbated atherosclerotic plaque development and post-MI cardiac remodeling. Conditional silencing in PCOS mice significantly suppressed cardiac inflammation and improved cardiac injury after MI.
CONCLUSIONS
Our data documented previously unrecognized mechanisms through which PCOS could affect cardiovascular health in women. PCOS may promote myocardial macrophage accumulation and post-MI cardiac remodeling because of augmented splenic myelopoiesis.
Topics: Pregnancy; Female; Humans; Mice; Animals; Polycystic Ovary Syndrome; Ventricular Remodeling; Myocardial Infarction; Heart Injuries; Inflammation; Norepinephrine
PubMed: 37937441
DOI: 10.1161/CIRCULATIONAHA.123.065827 -
The Journal of Clinical Investigation Sep 2023Interest in cardioimmunology has reached new heights as the experimental cardiology field works to tap the unrealized potential of immunotherapy for clinical care.... (Review)
Review
Interest in cardioimmunology has reached new heights as the experimental cardiology field works to tap the unrealized potential of immunotherapy for clinical care. Within this space is the cardiac macrophage, a key modulator of cardiac function in health and disease. After a myocardial infarction, myeloid macrophages both protect and harm the heart. To varying degrees, such outcomes are a function of myeloid ontogeny and heterogeneity, as well as functional cellular plasticity. Diversity is further shaped by the extracellular milieu, which fluctuates considerably after coronary occlusion. Ischemic limitation of nutrients constrains the metabolic potential of immune cells, and accumulating evidence supports a paradigm whereby macrophage metabolism is coupled to divergent inflammatory consequences, although experimental evidence for this in the heart is just emerging. Herein we examine the heterogeneous cardiac macrophage response following ischemic injury, with a focus on integrating putative contributions of immunometabolism and implications for therapeutically relevant cardiac injury versus cardiac repair.
Topics: Humans; Myocardial Infarction; Heart; Heart Injuries; Cell Plasticity; Macrophages
PubMed: 37712418
DOI: 10.1172/JCI171953