Murine neonatal cardiac B cells promote cardiomyocyte proliferation and heart regeneration
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE205115 | GEO | 2023/06/02
REPOSITORIES: GEO
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Project description:mRNA vaccines are promising alternatives to conventional vaccines in many aspects. We previously developed a lipopolyplex (LPP)-based mRNA vaccine (SW0123) that demonstrated robust immunogenicity and strong protective capacity against SARS-CoV-2 infection in both mice and rhesus macaques. However, the immune profiles and mechanisms of pulmonary protection induced by SW0123 remain unclear. Through high-resolution single cell analysis, we found that SW0123 vaccination effectively suppressed SARS-CoV-2-induced inflammatory responses by inhibiting the recruitment of pro-inflammatory macrophages and increasing the frequency of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). In addition, the apoptotic process in both lung epithelial and endothelial cells was significantly inhibited, which was proposed to be one major mechanism contributing to vaccine-induced lung protection. Cell-cell interaction in lung compartment was also altered by vaccination. These data collectively unraveled the mechanisms by which the SW0123 protects against lung damage caused by SARS-CoV-2 infection. reduces cardiac function, leading to cardiac remodeling and heart failure. However, the early neonatal mice have a strong ability in cardiomyocyte proliferation and cardiac regeneration after heart damage such as apical resection. Besides of cardiomyocytes, non-myocytes in heart tissue also play important roles in the regeneration process. Previous studies showed that cardiac macrophages, regulatory T cells and CD4+ T cells are all involved in regulating the myocardial regeneration process. However, the roles of other cardiac immune cells in cardiac regeneration remains to be elucidated. B cells is a prominent immune cell in injured heart; here we discovered the indispensable function of cardiac B cells in improving cardiomyocyte proliferation and heart regeneration in neonatal mice.
2022-10-12 | GSE209615 | GEO
Project description:mRNA vaccines are promising alternatives to conventional vaccines in many aspects. We previously developed a lipopolyplex (LPP)-based mRNA vaccine (SW0123) that demonstrated robust immunogenicity and strong protective capacity against SARS-CoV-2 infection in both mice and rhesus macaques. However, the immune profiles and mechanisms of pulmonary protection induced by SW0123 remain unclear. Through high-resolution single cell analysis, we found that SW0123 vaccination effectively suppressed SARS-CoV-2-induced inflammatory responses by inhibiting the recruitment of pro-inflammatory macrophages and increasing the frequency of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). In addition, the apoptotic process in both lung epithelial and endothelial cells was significantly inhibited, which was proposed to be one major mechanism contributing to vaccine-induced lung protection. Cell-cell interaction in lung compartment was also altered by vaccination. These data collectively unraveled the mechanisms by which the SW0123 protects against lung damage caused by SARS-CoV-2 infection. reduces cardiac function, leading to cardiac remodeling and heart failure. However, the early neonatal mice have a strong ability in cardiomyocyte proliferation and cardiac regeneration after heart damage such as apical resection. Besides of cardiomyocytes, non-myocytes in heart tissue also play important roles in the regeneration process. Previous studies showed that cardiac macrophages, regulatory T cells and CD4+ T cells are all involved in regulating the myocardial regeneration process. However, the roles of other cardiac immune cells in cardiac regeneration remains to be elucidated. B cells is a prominent immune cell in injured heart; here we discovered the indispensable function of cardiac B cells in improving cardiomyocyte proliferation and heart regeneration in neonatal mice.
2022-10-12 | GSE208565 | GEO
Project description:The adult mammalian heart has little regenerative capacity after myocardial infarction (MI) while neonatal mouse heart regenerates without scarring or dysfunction. However, the underlying pathways are poorly defined. We sought to derive insights into the pathways regulating neonatal development of the mouse heart and cardiac regeneration post-MI. Total RNA-seq of mouse heart through the first 10 days of postnatal life (referred to as P3, P5, P10) revealed a previously unobserved transition in microRNA expression between P3 and P5 associated specifically with altered expression of protein-coding genes on the focal adhesion pathway and cessation of cardiomyocyte cell division. We found profound changes in the coding and non-coding transcriptome after neonatal MI, with evidence of essentially complete healing by P10. Over two thirds of each of the mRNAs, lncRNAs and microRNAs that were differentially expressed in the post-MI heart were differentially expressed during normal postnatal development, suggesting a common regulatory pathway for normal cardiac development and post-MI cardiac regeneration. We selected exemplars of miRNAs implicated in our data set as regulators of cardiomyocyte proliferation. Several of these showed evidence of a functional influence on mouse cardiomyocyte cell division. In addition, a subset of these microRNAs, miR-144-3p, miR-195a-5p, miR-451a and miR-6240 showed evidence of functional conservation in human cardiomyocytes. The sets of mRNAs, miRNAs and lncRNAs that we report here merit further investigation as gatekeepers of cell division in the postnatal heart and as targets for extension of the period of cardiac regeneration beyond the neonatal period.
2018-02-02 | E-MTAB-6272 | biostudies-arrayexpress
Project description:For a short period of time in mammalian neonates, the mammalian heart can regenerate via cardiomyocyte proliferation. This regenerative capacity is largely absent in adults. In other organisms, including zebrafish, damaged hearts can regenerate throughout their lifespans. Many studies have been performed to understand the mechanisms of cardiomyocyte de-differentiation and proliferation during heart regeneration however, the underlying reason why adult zebrafish and young mammalian cardiomyocytes are primed to enter cell cycle have not been identified. Here we show the primed state of a pro-regenerative cardiomyocyte is dictated by its amino acid profile and metabolic state. Adult zebrafish cardiomyocyte regeneration is a result of amino acid-primed mTOR activation. Zebrafish and neonatal mouse cardiomyocytes display elevated glutamine levels, predisposing them to amino acid-driven activation of mTORC1. Injury initiates Wnt/β-catenin signalling that instigates primed mTORC1 activation, Lin28 expression and metabolic remodeling necessary for zebrafish cardiomyocyte regeneration. These studies reveal a unique mTORC1 primed state in zebrafish and mammalian regeneration competent cardiomyocytes.
2022-02-15 | PXD011791 | Pride
Project description:Mammalian hearts had the capability to regenerate cardiomyocyte and completely recover after heart injury within a limited time window after birth. It has been shown that sphingosine 1-phospahte receptor 1 (S1pr1) was highly expressed in cardiomyocytes and played an important role in heart development and pathological cardiac remodeling. Herein, we aim to investigate the role of CM-S1pr1 for cardiac regeneration and tissue repair after heart injury. We generated cardiomyocyte (CM)-specific S1pr1 knock-out mice and showed that CM-specific S1pr1 loss-of-function significantly severely reduced cardiomyocyte proliferation and heart regeneration in neonatal mice after both apex resection and myocardial infarction, whereas S1pr1 gain-of-function by AAV9-mediated CM-specific overexpression of S1pr1 significantly boosted cardiac regeneration and improved cardiac functions after heart injuries. We next identified that S1pr1 activated AKT/mTOR/CyclinD1 and Bcl-2 signaling pathways, and thus promoted cardiomyocyte proliferation and inhibited CM apoptosis, respectively.Of note, we applied CM-targeted gene therapy by AAV9-cTNT to specifically overexpress S1pr1 in cardiomyocytes and achieved an efficient S1pr1 overexpression in CMs in vivo. This CM-targeted strategy to overexpress S1pr1 significantly enhanced cardiac regeneration and improved cardiac functions after myocardial infarction in an adult mouse model, suggesting a potential strategy to boost adult cardiac regeneration in vivo.
2024-08-01 | GSE241722 | GEO
Project description:Adult mammalian hearts do not regenerate following ischemic injury, causing permanent damage to the myocardium, often leading to heart failure. In contrast, neonatal mouse hearts can fully regenerate after injury, however this ability is lost shortly after birth. Loss of regenerative capacity coincides with profound changes in the epigenetic landscape. Yet, the mechanisms controlling cardiomyocyte proliferation remain poorly understood. To identify epigenetic mechanisms that underlie cardiomyocyte regeneration in response to ischemic injury, we subjected mice to sham or ischemia-reperfusion injury (IR) and performed RNA-Seq at multiple timepoints after injury. Multiple SWI/SNF chromatin remodeling complex subunits were upregulated after IR, including the AT-rich interactive domain-containing protein 1A (Arid1a), which has previously been implicated in tissue regeneration. Here, we show that Arid1a is abundantly expressed in cardiomyocytes during development, and is reactivated in a subset of adult cardiomyocytes after IR. Moreover, ARID1A is highly expressed in cardiomyocytes in human failing hearts, suggesting an important function in injury response. Cardiomyocyte-specific Arid1a ablation in neonatal mice induced cardiomyocyte hyperplasia, and severe cardiac enlargement at 2 weeks of age. Arid1a mutant hearts display increased expression of key cell cycle genes. Using ChIP-Seq and protein interaction studies we show that Arid1a functionally interacts with HIPPO signaling, thereby regulating neonatal cardiomyocyte proliferation. Furthermore, suppression of Arid1a in adult cardiomyocytes after IR induced cell cycle activity in border zone cardiomyocytes. These data suggest that Arid1a regulates cardiomyocyte proliferation and function. Upregulation of Arid1a in cardiomyocytes after injury may suppress proliferation and regeneration. Modulation of ARID1A after ischemic injury may be a novel therapeutic target to enhance cardiac regeneration.
2023-07-06 | GSE155100 | GEO
Project description:Adult mammalian hearts do not regenerate following ischemic injury, causing permanent damage to the myocardium, often leading to heart failure. In contrast, neonatal mouse hearts can fully regenerate after injury, however this ability is lost shortly after birth. Loss of regenerative capacity coincides with profound changes in the epigenetic landscape. Yet, the mechanisms controlling cardiomyocyte proliferation remain poorly understood. To identify epigenetic mechanisms that underlie cardiomyocyte regeneration in response to ischemic injury, we subjected mice to sham or ischemia-reperfusion injury (IR) and performed RNA-Seq at multiple timepoints after injury. Multiple SWI/SNF chromatin remodeling complex subunits were upregulated after IR, including the AT-rich interactive domain-containing protein 1A (Arid1a), which has previously been implicated in tissue regeneration. Here, we show that Arid1a is abundantly expressed in cardiomyocytes during development, and is reactivated in a subset of adult cardiomyocytes after IR. Moreover, ARID1A is highly expressed in cardiomyocytes in human failing hearts, suggesting an important function in injury response. Cardiomyocyte-specific Arid1a ablation in neonatal mice induced cardiomyocyte hyperplasia, and severe cardiac enlargement at 2 weeks of age. Arid1a mutant hearts display increased expression of key cell cycle genes. Using ChIP-Seq and protein interaction studies we show that Arid1a functionally interacts with HIPPO signaling, thereby regulating neonatal cardiomyocyte proliferation. Furthermore, suppression of Arid1a in adult cardiomyocytes after IR induced cell cycle activity in border zone cardiomyocytes. These data suggest that Arid1a regulates cardiomyocyte proliferation and function. Upregulation of Arid1a in cardiomyocytes after injury may suppress proliferation and regeneration. Modulation of ARID1A after ischemic injury may be a novel therapeutic target to enhance cardiac regeneration.
2023-07-06 | GSE155101 | GEO
Project description:Cardiac metabolism plays a crucial role in producing sufficient energy to sustain cardiac function. However, the role of metabolism in different aspects of cardiomyocyte regeneration remains unclear. Working with the adult zebrafish heart regeneration model, we first find an increase in the levels of mRNAs encoding enzymes regulating glucose and pyruvate metabolism, including pyruvate kinase M1/2 (Pkm) and pyruvate dehydrogenase kinases (Pdks), especially in tissues bordering the damaged area. We further find that impaired glycolysis decreases the number of proliferating cardiomyocytes following injury. These observations are supported by analyses using loss-of-function models for the metabolic regulators Pkma2 and peroxisome proliferator-activated receptor gamma coactivator 1 alpha. Cardiomyocyte-specific loss- and gain-of-function manipulations of pyruvate metabolism using Pdk3 as well as a catalytic subunit of the pyruvate dehydrogenase complex (PDC) reveal its importance in cardiomyocyte dedifferentiation and proliferation after injury. Furthermore, we find that PDK activity can modulate cell cycle progression and protrusive activity in mammalian cardiomyocytes in culture. Our findings reveal new roles for cardiac metabolism and the PDK-PDC axis in cardiomyocyte behavior following cardiac injury.
2020-07-13 | PXD016235 | Pride
Project description:Cardiac maturation lays the foundation for postnatal heart development and disease, yet little is known about the contributions of the microenvironment to cardiomyocyte maturation. By integrating single-cell RNA-sequencing data of mouse hearts at multiple postnatal stages, we construct cellular interactomes and regulatory signaling networks. Here we report switching of fibroblast subtypes from a neonatal to adult state and this drives cardiomyocyte maturation. Molecular and functional maturation of neonatal mouse cardiomyocytes and human embryonic stem cell-derived cardiomyocytes are considerably enhanced upon coculture with corresponding adult cardiac fibroblasts. Further, single-cell analysis of in vivo and in vitro cardiomyocyte maturation trajectories identify highly conserved signaling pathways, pharmacological targeting of which substantially delays cardiomyocyte maturation in postnatal hearts, and markedly enhances cardiomyocyte proliferation and improves cardiac function in infarcted hearts. Together, we identify cardiac fibroblasts as a key constituent in the microenvironment promoting cardiomyocyte maturation, providing insights into how the manipulation of cardiomyocyte maturity may impact on disease development and regeneration.
2020-04-20 | GSE122706 | GEO
Project description:Murine neonatal cardiac B cells promote cardiomyocyte proliferation and heart regeneration
| PRJNA843933 | ENA