心肌细胞直接重编程的研究进展

心肌细胞直接重编程是一种新兴的心脏再生技术,它使用表观遗传修饰技术将心脏成纤维细胞转化为终末分化的心肌细胞。该文介绍了心肌细胞直接重编程的研究进展、所面临的问题以及未来的发展方向。     

心脏成纤维细胞直接重编程研究进展

心脏成纤维细胞作为一种间充质细胞,调控着生理和病理状态下心肌细胞生物学和电生理活动,并在心肌梗死时通过替代已破坏的心肌细胞来保持心肌结构的完整性。近年来,运用转录因子、microRNAs将心脏成纤维细胞直接重编程为心肌样细胞的相关研究取得了一系列进展。本文总结了近年心脏直接重编程体外和体内相关实验研究,并分析这一技术在修复坏死心肌和改善心功能方面的临床应用前景。     

成纤维细胞重编程为心肌细胞

<正>大多数的心力衰竭是由于缺乏心肌细胞。科学家们长期渴望着心脏能够再具备新心肌细胞。曾经试用过许多方法,设法使心脏重新生出心肌,如移植干细胞或它们的衍生物,至今仅稍有收获。最近,Leda等介绍一种新方案:将成纤维细胞重编程为心肌细胞。     

体细胞重编程为诱导性多能干细胞的研究进展

诱导性多能干细胞技术构想来源于细胞核移植技术,将外源特异转录因子导人体细胞后,体细胞进行重编程,最终分化为具有胚胎干细胞特性和功能的多能干细胞。诱导性多能干细胞在疾病动物模型上的应用已经取得了进展,人们已经成功建立了自体细胞治疗的疾病实验动物模型。诱导性多能干细胞的研究回避了长期以来人们对胚胎使用问题的伦理问题,为干细胞的研究提供了新的方法和理论依据,为人类疾病的治疗带来了新的希望和契机。     

心脏肌成纤维细胞活化的力学调控

在心肌修复或纤维化过程中,以成纤维细胞为主的多种前体细胞向心脏肌成纤维细胞(CMFs)活化,合成大量细胞外基质成分,并持续存在于心肌瘢痕中。CMFs活化除了受促纤维化因子的调控外,还受力学因素的影响。ECM刚度增加及循环应变的改变能促进CMFs活化推动心肌纤维化持续进展。通过调控CMFs对机械应力的敏感性来抑制CMFs活化的方法有可能成为心肌纤维化治疗的新选择。     

血液细胞重编程为神经细胞的研究进展

阿尔茨海默病、帕金森病等神经退行性疾病是人口老龄化进程中必然出现的一类疾病.随着人口老龄化加剧,神经退行性疾病的患病率不断上升.当前对神经退行性疾病的治疗仍停留在通过药物控制其病情进展阶段.近年来,细胞替代疗法治疗神经退行性疾病展现出了巨大潜力.现阶段体细胞重编程技术领域发展迅速且成果颇丰,其实质是使用某些转录因子、小...     

近端肾小管上皮细胞代谢重编程在急性肾损伤中的研究进展

肾脏是一个高代谢器官,尤其是近端肾小管上皮细胞,在生理情况下主要依赖脂肪酸氧化供能,但是在急性肾损伤(AKI)期间,线粒体和过氧化物酶体功能障碍,近端肾小管上皮细胞发生代谢重编程,能量供应转向糖酵解,生成乳酸,并伴脂肪酸氧化紊乱及糖异生受损,短期内代谢重编程可能是对肾脏有益的能量代偿,但是该过程中也会加重肾损伤。本文就近端肾小管上皮细胞代谢重编程在AKI中的作用进行综述。     

心脏成纤维细胞结构与功能

心脏成纤维细胞（card iac fibrob lasts）以其细胞数量而言,在心脏中是一个庞大的细胞群体。它们形成了心肌层的结构、生物化学、机械-电等方面的特性。即便如此,它们却经常在心脏功能的研究中被人们所忽略。本综述扼要阐述了成纤维细胞起源及鉴定,结构和功能以及在生理和病理条件下的意义。     

Direct Visualization of Cardiac Radiofrequency Ablation Lesions

Effective ablation of atrial fibrillation and other cardiac arrhythmias requires precise catheter navigation and controlled delivery of energy to cardiac tissue. In this study, we summarize our initial experience using a fiber optic direct visualization catheter to evaluate and guide placement of endocardial radiofrequency (RF) ablation lesions. RF lesions were created in cadaveric porcine hearts and examined in a blood-filled field using a direct visualization catheter. Direct visualization of RF lesions was repeated in vivo using an ovine model. Lesions and interlesion gaps were clearly identifiable using the direct visualization catheter. It was possible to place lesions in proximity to anatomical landmarks and in relation to one another. Catheter-generated images correlated well with lesion appearance on gross examination. Direct catheter-based visualization is a feasible technique for guiding RF lesion placement, estimating lesion size, and identifying interlesion gaps. Future work is needed to correlate surface appearance with transmurality and electrical isolation.     

Aza-Reversine Promotes Reprogramming of Lung (MRC-5) and Differentiation of Mesenchymal Cells into Osteoblasts

Reversine or 2-(4-morpholinoanilino)-N6-cyclohexyladenine was originally identified as a small organic molecule that induces dedifferentiation of lineage-committed mouse myoblasts, C2C12, and redirects them into lipocytes or osteoblasts under lineage-specific conditions (LISCs). Further, it was proven that this small molecule can induce cell cycle arrest and apoptosis and thus selectively lead cancer cells to cell death. Further studies demonstrated that reversine, and more specifically the C2 position of the purine ring, can tolerate a wide range of substitutions without activity loss. In this study, a piperazine analog of reversine, also known as aza-reversine, and a biotinylated derivative of aza-reversine were synthesized, and their potential medical applications were investigated by transforming the endoderm originates fetal lung cells (MRC-5) into the mesoderm originated osteoblasts and by differentiating mesenchymal cells into osteoblasts. Moreover, the reprogramming capacity of aza-reversine and biotinylated aza-reversine was investigated against MRC-5 cells and mesenchymal cells after the immobilization on PMMA/HEMA polymeric surfaces. The results showed that both aza-reversine and the biofunctionalized, biotinylated analog induced the reprogramming of MRC-5 cells to a more primitive, pluripotent state and can further transform them into osteoblasts under osteogenic culture conditions. These molecules also induced the differentiation of dental and adipose mesenchymal cells to osteoblasts. Thus, the possibility to load a small molecule with useful “information” for delivering that into specific cell targets opens new therapeutic personalized applications.     

Turning scar into muscle

After the demonstration that somatic cells could be reprogrammed to a pluripotent state,exciting new prospects were opened for the cardiac regeneration field.It did not take long for the development of strategies to convert somatic cells directly into cardiomyocytes.Despite the intrinsic difficulties of cell reprogramming,such as low efficiency,the therapeutic possibilities created by the ability to turn scar into muscle are enormous.Here,we discuss some of the major advances and strategies used in direct cardiac reprogramming and examine discrepancies and concerns that still need to be resolved in the field.     

Reprogramming of murine and human somatic cells using a single polycistronic vector

Directed reprogramming of somatic cells by defined factors provides a novel method for the generation of patient-specific stem cells with the potential to bypass both the practical and ethical concerns associated with somatic cell nuclear transfer (SCNT) and human embryonic stem (hES) cells. Although the generation of induced pluripotent stem (iPS) cells has proven a robust technology in mouse and human, a major impediment to the use of iPS cells for therapeutic purposes has been the viral-based delivery of the reprogramming factors because multiple proviral integrations pose the danger of insertional mutagenesis. Here we report a novel approach to reduce the number of viruses necessary to reprogram somatic cells by delivering reprogramming factors in a single virus using 2A “self-cleaving” peptides, which support efficient polycistronic expression from a single promoter. We find that up to four reprogramming factors (Oct4, Sox2, Klf4, and c-Myc) can be expressed from a single virus to generate iPS cells in both embryonic and adult somatic mouse cells and we show that a single proviral copy is sufficient to generate iPS cells from mouse embryonic fibroblasts. In addition we have generated human induced pluripotent stem (hiPS) cell lines from human keratinocytes, demonstrating that a single polycistronic virus can reprogram human somatic cells.     

SARS-CoV-2 Causes Lung Inflammation through Metabolic Reprogramming and RAGE

Clinical studies indicate that patients infected with SARS-CoV-2 develop hyperinflammation, which correlates with increased mortality. The SARS-CoV-2/COVID-19-dependent inflammation is thought to occur via increased cytokine production and hyperactivity of RAGE in several cell types, a phenomenon observed for other disorders and diseases. Metabolic reprogramming has been shown to contribute to inflammation and is considered a hallmark of cancer, neurodegenerative diseases, and viral infections. Malfunctioning glycolysis, which normally aims to convert glucose into pyruvate, leads to the accumulation of advanced glycation end products (AGEs). Being aberrantly generated, AGEs then bind to their receptor, RAGE, and activate several pro-inflammatory genes, such as IL-1b and IL-6, thus, increasing hypoxia and inducing senescence. Using the lung epithelial cell (BEAS-2B) line, we demonstrated that SARS-CoV-2 proteins reprogram the cellular metabolism and increase pyruvate kinase muscle isoform 2 (PKM2). This deregulation promotes the accumulation of AGEs and senescence induction. We showed the ability of the PKM2 stabilizer, Tepp-46, to reverse the observed glycolysis changes/alterations and restore this essential metabolic process.     

Reprogramming of glucose metabolism in hepatocellular carcinoma: Progress and prospects

Hepatocellular carcinoma(HCC) is one of the most lethal cancers, and its rate of incidence is rising annually. Despite the progress in diagnosis and treatment, the overall prognoses of HCC patients remain dismal due to the difficulties in early diagnosis and the high level of tumor invasion, metastasis and recurrence. It is urgent to explore the underlying mechanism of HCC carcinogenesis and progression to find out the specific biomarkers for HCC early diagnosis and the promising target for HCC chemotherapy. Recently, the reprogramming of cancer metabolism has been identified as a hallmark of cancer. The shift from the oxidative phosphorylation metabolic pathway to the glycolysis pathway in HCC meets the demands of rapid cell proliferation and offers a favorable microenvironment for tumor progression. Such metabolic reprogramming could be considered as a critical link between the different HCC genotypes and phenotypes. The regulation of metabolic reprogramming in cancer is complex and may occur via genetic mutations and epigenetic modulations including oncogenes, tumor suppressor genes, signaling pathways, noncoding RNAs, and glycolytic enzymes etc. Understanding the regulatory mechanisms of glycolysis in HCC may enrich our knowledge of hepatocellular carcinogenesis and provide important foundations in the search for novel diagnostic biomarkers and promising therapeutic targets for HCC.