BACKGROUND The efficiency and quality of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are crucial for regenerative medicine, disease modeling, drug screening, and the study of the development events during cardiac specification. However, their applications have been hampered by the differentiation efficiency, poor maturation, and high interline variability. Recent studies have reported that histamine plays important roles in hematopoietic stem cell proliferation and neutrophil maturation. However, its roles in cardiovascular tissue regeneration have not been thoroughly investigated. In the current study, we identified a novel physiological function of the histamine/histamine 1 receptor (H1R) signal in regulating the differentiation of hiPSC-CMs and heart development. METHODS Transgenic zebrafish model (cmlc2: mCherry) was treated with histamine and histamine receptor (HR) antagonists. Histological morphology and ultrastructure of zebrafish heart were measured. Histamine-deficient pregnant mice (HDC-/-) were treated with H1R antagonist (pyrilamine) by intragastric administration from E8.5 to E18.5. Cardiac histological morphology and ultrastructure were analyzed in neonatal mice, and cardiac function in adult mice was measured. In vitro, histamine and HR antagonists were administrated in the culture medium during hiPSC-CM differentiation at different stages. The efficiency and maturation of cardiac differentiation were evaluated. Finally, histamine-treated hiPSC-CMs were transplanted into ischemic myocardium to detect the possible therapeutic effect. RESULTS Administration of H1R antagonist during heart development induced cardiac dysplasia in zebrafish. Furthermore, using histidine decarboxylase (HDC) knockout mice, we examined abnormal swelling of myocardial mitochondria and autophagy formation under the condition of endogenous histamine deficiency. Histamine significantly promoted myocardial differentiation from human induced pluripotent stem cells (hiPSCs) with better structure and function via a H1R-dependent signal. The activation of histamine/H1R signaling pathway augmented hiPSC-derived cardiomyocyte (hiPSC-CM) differentiation through the ERK1/2-STAT3 signaling pathway. In addition, histamine-pre-treated hiPSC-CMs were transplanted into the ischemic hearts of myocardial injured mice and exhibited better survival and myocardial protection. CONCLUSIONS Thus, these findings indicated that histamine/H1R and its downstream signals were not only involved in cardiac differentiation but also provided a better survival environment for stem cell transplanted into ischemic myocardium.

中文翻译：

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组胺/ H1R信号通路的破坏抑制了人类诱导的多能干细胞的心脏分化和成熟。

背景技术人类诱导的多能干细胞衍生的心肌细胞（hiPSC-CM）的效率和质量对于再生医学，疾病建模，药物筛选以及研究心脏规范中的发展事件至关重要。然而，它们的应用受到分化效率，不良的成熟和高的株间变异性的阻碍。最近的研究报道，组胺在造血干细胞增殖和中性粒细胞成熟中起重要作用。然而，其在心血管组织再生中的作用尚未得到彻底研究。在当前的研究中，我们确定了组胺/组胺1受体（H1R）信号在调节hiPSC-CMs分化和心脏发育中的新型生理功能。方法转基因斑马鱼模型（cmlc2：mCherry）用组胺和组胺受体（HR）拮抗剂治疗。测量了斑马鱼心脏的组织形态学和超微结构。通过从E8.5到E18.5进行胃内给药，用H1R拮抗剂（吡拉明）治疗组胺缺乏的妊娠小鼠（HDC-/-）。分析新生小鼠的心脏组织形态和超微结构，并测量成年小鼠的心脏功能。在体外，在hiPSC-CM分化的不同阶段，在培养基中施用组胺和HR拮抗剂。评估了心脏分化的效率和成熟度。最后，将经组胺处理的hiPSC-CMs移植到缺血性心肌中，以检测可能的治疗效果。结果在心脏发育过程中施用H1R拮抗剂可诱发斑马鱼的心脏发育异常。此外，使用组氨酸脱羧酶（HDC）敲除小鼠，我们检查了内源性组胺缺乏的情况下心肌线粒体的异常肿胀和自噬形成。组胺通过H1R依赖性信号显着促进人分化为具有更好结构和功能的人诱导多能干细胞（hiPSC）的心肌分化。组胺/ H1R信号通路的激活通过ERK1 / 2-STAT3信号通路增强了hiPSC衍生的心肌细胞（hiPSC-CM）的分化。此外，将组胺预处理的hiPSC-CMs移植到心肌损伤小鼠的缺血心脏中，表现出更好的存活率和心肌保护作用。结论因此，