Cell Metabolism
·
2024
·
IF 27.7
Xiaoqian Ji,Zihao Chen,Qiyuan Wang,Bin Li,Yan Wei,Yun Li,Jianqing Lin,Weisheng Cheng,Yijie Guo,Shilin Wu,Longkun Mao,Yuzhou Xiang,Tian Lan,Shanshan Gu,Meng Wei,Joe Z. Zhang,Lan Jiang,Jia Wang,Jin Xu,Nan Cao
Utilization of lipids as energy substrates after birth causes cardiomyocyte (CM) cell-cycle arrest and loss of regenerative capacity in mammalian hearts. Beyond energy provision, proper management of lipid composition is crucial for cellular and organismal health, but its role in heart regeneration remains unclear. Here, we demonstrate widespread sphingolipid metabolism remodeling in neonatal hearts after injury and find that SphK1 and SphK2, isoenzymes producing the same sphingolipid metabolite sphingosine-1-phosphate (S1P), differently regulate cardiac regeneration. SphK2 is downregulated during heart development and determines CM proliferation via nuclear S1P-dependent modulation of histone acetylation. Reactivation of SphK2 induces adult CM cell-cycle re-entry and cytokinesis, thereby enhancing regeneration. Conversely, SphK1 is upregulated during development and promotes fibrosis through an S1P autocrine mechanism in cardiac fibroblasts. By fine-tuning the activity of each SphK isoform, we develop a therapy that simultaneously promotes myocardial repair and restricts fibrotic scarring to regenerate the infarcted adult hearts.
研究领域:
心血管生物学
·
再生医学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2023
·
IF 8.2
Wang Wei,Chen Xiao-kang,Zhou Lu,Wang Feng,He Yan-ji,Lu Bing-jun,Hu Ze-gang,Li Zhu-xin,Xia Xue-wei,Wang Wei Eric,Zeng Chun-yu,Li Liang-peng
Stimulation of adult cardiomyocyte proliferation is a promising strategy for treating myocardial infarction (MI). Earlier studies have shown increased CCL2 levels in plasma and cardiac tissue both in MI patients and mouse models. In present study we investigated the role of CCL2 in cardiac regeneration and the underlying mechanisms. MI was induced in adult mice by permanent ligation of the left anterior descending artery, we showed that the serum and cardiac CCL2 levels were significantly increased in MI mice. Intramyocardial injection of recombinant CCL2 (rCCL2, 1 μg) immediately after the surgery significantly promoted cardiomyocyte proliferation, improved survival rate and cardiac function, and diminished scar sizes in post-MI mice. Alongside these beneficial effects, we observed an increased angiogenesis and decreased cardiomyocyte apoptosis in post-MI mice. Conversely, treatment with a selective CCL2 synthesis inhibitor Bindarit (30 μM) suppressed both CCL2 expression and cardiomyocyte proliferation in P1 neonatal rat ventricle myocytes (NRVMs). We demonstrated in NRVMs that the CCL2 stimulated cardiomyocyte proliferation through STAT3 signaling: treatment with rCCL2 (100 ng/mL) significantly increased the phosphorylation levels of STAT3, whereas a STAT3 phosphorylation inhibitor Stattic (30 μM) suppressed rCCL2-induced cardiomyocyte proliferation. In conclusion, this study suggests that CCL2 promotes cardiac regeneration via activation of STAT3 signaling, underscoring its potential as a therapeutic agent for managing MI and associated heart failure.
研究领域:
心脏病学
·
分子生物学
·
再生医学
✓ 已验证
DOI
PubMed
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-20
·
IF 15.7
Xiao Yi,Zhang Hao,Liu Xu,Xu Pengfei,Du Heng,Wang Jiawan,Shen Jianghua,Li Yujing,Wang Yuhan,He Chuting,Feng Haiping,Liu Jingfang,Zhou Yanan,Liu Siqi,Gao Zeyu,Zang Jingyi,Bi Jinmiao,Tang Tie-Shan,Gu Qi,Wei Tuo,Wang Jun,Song Moshi
Heart injury has been characterized by the irreversible loss of cardiomyocytes comprising the contractile tissues of the heart and thus strategies enabling adult cardiomyocyte proliferation are highly desired for treating various heart diseases. Here, we test the ability of human induced pluripotent stem cell-derived primitive macrophages (hiPMs) and their conditioned medium (hiPM-cm) to promote human cardiomyocyte proliferation and enhance cardiac regeneration in adult mice. We find that hiPMs promote human cardiomyocyte proliferation, which is recapitulated by hiPM-cm through the activation of multiple pro-proliferative pathways, and a secreted proteome analysis identifies five proteins participating in this activation. Subsequent in vivo experiments show that hiPM-cm promotes adult cardiomyocyte proliferation in mice. Lastly, hiPM-cm enhances cardiac regeneration and improves contractile function in injured adult mouse hearts. Together, our study demonstrates the efficacy of using hiPM-cm in promoting adult cardiomyocyte proliferation and cardiac regeneration to serve as an innovative treatment for heart disease.
研究领域:
心脏病学
·
干细胞研究
·
再生医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2024
·
IF 5.4
Juan Zhang,Beibei Zhang,Linlin Zhang,Xiaoxia Xu,Qiwei Cheng,Yuzhou Wang,Yaqiong Li,Ru Jiang,Shaobo Duan,Lianzhong Zhang
Myocardial infarction (MI) leads to substantial cellular necrosis as a consequence of reduced blood flow and oxygen deprivation. Stimulating cardiomyocyte proliferation and angiogenesis can promote functional recovery after cardiac events. In this study, we explored a novel therapeutic strategy for MI by synthesizing a biomimetic nanovesicle (NV). This biomimetic NVs are composed of exosomes sourced from umbilical cord mesenchymal stem cells, which have been loaded with placental growth factors (PLGF) and surface-engineered with a cardiac-targeting peptide (CHP) through covalent bonding, termed Exo-P-C NVs. With the help of the myocardial targeting effect of homing peptides, NVs can be enriched in the MI site, thus improve cardiac regeneration, reduce fibrosis, stimulate cardiomyocyte proliferation, and promote angiogenesis, ultimately resulted in improved cardiac functional recovery. It was demonstrated that Exo-P-C NVs have the potential to offer novel therapeutic strategies for the improvement of cardiac function and management of myocardial infarction.
研究领域:
心血管医学
·
纳米技术
·
干细胞生物学
·
治疗递送系统
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）