预防出生缺陷是提高人口质量的重要手段。出生缺陷是新生儿先天机体或功能的异常，表现在身体、智力或对社会的影响。中国儿童人口基数庞大，随着国家生育政策的调整，预防出生缺陷显得尤为重要。多数出生缺陷的致病原因及发病机制还没有明晰，有效的治疗和干预策略更亟待研究与开发。
本专栏聚焦“出生缺陷与细胞再生”，汇集了山西医科大学、首都儿科研究所、北京工业大学等专家的5篇相关综述及五篇研究论文，旨在为该研究方向的学者提供科学知识资源和研究参考。
（1）5篇综述分别介绍了出生缺陷的研究进展，其中《New Insights into Neural Tube Closure: Folic Acid NonResponsive Neural Tube Defects》总结提出了叶酸不应答型神经管畸形的概念，并对其遗传、营养、环境及母体等风险因素，致病机制等研究进展进行综述，从一个新的研究视角为出生缺陷的防治提供新思路。《Role of Histone Modifications in the Congenital Heart Disease》综述了组蛋白驱动的表观遗传机制在先天性心脏病病因学中发挥重要作用。《Etiology of Hypospadias: a Systematic Review of Genetic Variants》关注出生缺陷疾病—尿道下裂致病基因及其风险因素，该病发病率已上升到第4位。此外，《Ⅰ型神经纤维瘤病相关信号通路及微环境组分异常》综述了Ⅰ型神经纤维瘤病相关信号通路及肿瘤微环境的研究现状，可以启发临床NF1的早期诊断、治疗、预防和药物研发。《心脏衰老与线粒体治疗》从发育终端问题衰老的角度，综述了新生细胞线粒体对心脏衰老的影响，及改善作用机制。这些文章从多角度、多层次综述出生缺陷的发生机制，并从预防、干预和药物研究等视角做了较为系统的总结。
（2）研究论文也是围绕出生缺陷和细胞再生领域。《组蛋白去甲基化酶KDM5A调控H3K4me3参与神经管畸形发生的分子机制》研究发现了叶酸缺乏时，KDM5A调控组蛋白修饰导致NTDs的发病机制，为预防NTDs提供一个重要的靶点。《低叶酸和维甲酸诱导神经管畸形小鼠模型胎脑的转录物组学分析》比较了两种常见的神经管畸形小鼠模型的胎脑转录组，发现新的神经管发育异常基因，可能有助于早期筛查和病因研究。《碳酸锂联合长春新碱促进儿童急性T淋巴细胞白血病细胞增殖抑制和凋亡》发现了碳酸锂和长春新碱通过抑制细胞增殖、促进凋亡作用治疗儿童T-淋巴细胞白血病，是临床药物研发的很好案例。《诱导多能干细胞来源的间充质干细胞的治疗潜力与应用风险》一文对诱导多能干细胞衍生的间充质干细胞和骨髓源、脂肪源以及脐带源的间充质干细胞进行高通量测序数据比对，发现多能干细胞来源的间充质干细胞更适合作为细胞治疗的潜在来源，尤其在神经疾病治疗中具有巨大潜力。《人多能诱导干细胞来源功能性胰岛β细胞的体外定向分化方法的建立》建立了从hiPSC到功能性胰岛β细胞的分化策略和技术路线，为胰岛β细胞体外分化和功能重现探索了新的途径。
总体而言，本专栏的综述文章和研究成果不仅为该学科领域的学术探讨注入了新的知识进展，也为临床实践提供了新的方向参考，反映了出生缺陷研究与细胞再生治疗之间的交汇与共同发展趋势。希望通过本期专栏，让更多读者深入理解出生缺陷的现状与防治的紧迫性，更期望激发更多科研人员投身于出生缺陷与细胞再生的研究事业中，共同努力提升出生人口质量，为我国乃至全球的儿童健康发展贡献力量。

Neural tube defects (NTDs) are common, severe, and complicated congenital malformations that are the result of the interaction and interplay of genetic, nutritional, and environmental factors. Maternal periconceptional folic acid (FA) supplementation is a significantly effective strategy for primary prevention of a proportion of NTDs. However, there still exists a portion of NTD cases that are intrinsically resistant to FA therapies, which are widely referred to as “FA-non-responsive NTDs” or “FA-resistant NTDs” . These diseases have a complex etiology, involving genetic, nutritional, environmental and maternal factors. This review integrates the genetic, nutritional, environmental and maternal risk factors associated with FA non-responsive NTDs and reveals the progress of research on their pathogenic mechanisms. Among them, the genetic factors cover three aspects: mouse mutants and strains, FA one-carbon metabolism genes, and key apoptosis genes, which provide possible genetic testing loci for prenatal diagnosis of these children. Nutritional factors concentrate on the roles of inositol and methionine, delineating their possible mechanisms of action and suggesting new directions for early nutritional interventions in NTDs management. In addition, this paper explores the possible mechanisms by which vitamin B12, a cofactor in the FA one-carbon metabolism, in FA-non-responsive NTDs development. We posit that a combination of FA and other vitamins may enhance treatment strategies for these malformations. At last, this paper also reviews the influence of environmental and maternal factors on FA non-responsive NTDs, aiming to provide health recommendations for early pregnancy for at-risk populations. In summary, this article reviews and evaluates research advancement concerning FA non-responsive NTD risk factors and pathogenesis, providing novel insights into the current prevention and treatment of this disease and related birth defects.

Congenital heart disease (CHD) refers to congenital structural abnormalities of the heart, including defects in the myocardial wall, valves, and major blood vessels. While genetic factors such as mutations and aberrant gene expression during embryogenesis contribute to CHD, they only account for part of cases. There are more and more studies on epigenetic histone modifications in CHD, suggesting that they are increasingly important in the pathogenesis of CHD. With the development of mass spectrometry-based proteomics technology, a spectrum of novel histone post-translational modifications, such as succinylation, glycosylation, lactylation, and β-hydroxybutyrylation, have been uncovered to contribute to various diseases. However, it remains unclear how these novel modifications regulate gene expression and pathological processes during the development and progression of CHD. This article will delve into the mechanisms of various histone modifications that regulate genes associated with cardiac development. It will approach the topic from both the perspective of classic histone modifications and novel histone modifications, aiming to unveil the significance of histone-driven epigenetic mechanisms in the etiology of CHD. Furthermore, it seeks to offer insights into the etiology of CHD, providing a theoretical basis for clinical treatment and timely prevention of this condition.

Hypospadias, characterized by abnormal position of the urethral opening, is the second most common congenital anomaly in men. Its incidence is increasing year by year, and it has become the fourth largest birth defect disease in China. Not only does it bring both physical and psychological distress to the patients, but its surgical repair and long-term postoperative management also occupy a large amount of social economic and medical resources. Hypospadias can be isolated or present as a manifestation of some syndrome. At present, there are a variety of methods used to define and evaluate hypospadias, and it is imperative to develop a uniform classification standard to standardize care and surgical methods. In humans, the normal development of the penis structure has experienced an early androgen-independent stage and a late androgen-dependent sexual differentiation stage. In addition to genetic changes, endocrine or external environmental influences can cause damage or loss of the basic elements of penile development, which can induce hypospadias. Therefore, the disease is the result of genetic, endocrine and environmental factors and their interaction, with genetic factors generally considered to be more important than others. Based on different population cohorts, this paper elucidates the causes of hypospadias from the perspective of classical genetic variation, involving gene polymorphism, single nucleotide polymorphism and copy number variation of genes in normal biological processes such as growth differentiation of reproductive nodules, gonadal development and testis differentiation, androgen and estrogen production, etc. Moreover, the candidate genes related to human hypospadias are summarized. This paper will provide theoretical basis for the screening, intervention and clinical treatment of hypospadias, and contribute to improve the quality of birth population.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder caused by mutations of the NF1 gene, which is characterized by multiple café-au-lait macules and neurofibromas. There are still no standardized treatment strategies for NF1 internationally. The NF1 gene is large and encodes neurofibromin (NF) that participates in cell proliferation. The disease mechanism is complex, which presents major challenges for drug development. Various signaling pathways including the RAF/MEK/ERK, PI3K/AKT/mTOR, WNT/β-catenin, and HIPPO/TAZ/YAP pathways have been studied in NF1. MEK1/2 inhibitors targeting the RAF/MEK/ERK pathway, such as selumetinib, have been approved for the treatment of NF1 and inoperable plexiform neurofibromas (PNF). Recent studies highlighted the crucial role of the NF1 tumor microenvironment, comprising Schwann cells (SCs) and their precursors, mast cells, macrophages, T cells, dendritic cells, the extracellular matrix, and surrounding blood vessels, in NF1 pathogenesis. Current treatments for NF1 include tumor resection, radiotherapy, and pharmacotherapy, all of which have limitations. There is an urgent need for exploration of novel therapeutic agents targeting NF1 signaling pathways and the tumor microenvironment. This review summarizes the current research progress in NF1-related signaling pathways and the microenvironment components. It specifically highlights the changes of the signaling pathways caused by NF1 gene mutations and the abnormal tumor microenvironment components, and analyzes the possible pathogenesis of NF1 to provide new insights for early diagnosis, treatment, prevention, and drug development in clinical NF1 management.

With the acceleration of population aging, all kinds of cardiovascular diseases caused bycardiac aging have become a health problem that cannot be ignored. In the heart, about 95% of ATP come from the cardiomyocytes to maintain the pumping function. Mitochondrial dysfunction can lead to myocardial energy deficiency, cardiomyocytes damage and death, or myocardial senescence. Therefore, the intact function of mitochondria plays an important role in maintaining the normal function of the heart and is considered as a key feature of cardiac aging. This paper reviews cardiac aging and mitochondrial dysfunction, and mainly summarizes the characteristics of aging heart and the changes in mitochondrial structure and function of senescent cardiomyocytes. We focus on the five major factors leading to cardiac aging caused by mitochondrial dysfunction, including changes in the mitochondrial numbers and morphology, mitochondrial DNA mutations, mitochondrial quality control failures, mitochondrial enzyme changes, and mitochondria-related metabolites and stress signals changes. We also summarize the treatment methods and mechanism of cardiac aging by targeting mitochondria, anddiscuss the current status and future direction of mitochondrial therapy for cardiac aging.

Neural tube defects (NTDs) represent a critical area of study within congenital anomalies, with folate known for its preventative role. However, the mechanisms underlying its protective effects remain largely unknown. This study investigates the potential molecular mechanisms involving lysine demethylase 5A (KDM5A) and its subsequent alteration of histone H3K4me3 in the development of NTDs under folate deficiency. We used chromatin immunoprecipitation along with Cut&Tag to examine the function of KDM5A in a low-folate cell model and a mouse model of folate-deficient NTDs. Quantitative reverse transcription PCR (qRT-PCR) and Western blot analyses demonstrated a marked reduction in KDM5A expression in the low-folate cell model (P<0.05). In addition, chromatin immunoprecipitation (ChIP) followed by quantitative PCR (ChIP-qPCR) analysis confirmed the increased accumulation of histone H3K4me3 in the promoter regions of important neurodevelopmental genes, Axin2 and Atoh1, with folate deficiency (P<0.05). By creating a KDM5A-knockout cell model, Cut&Tag experiments was used to confirm the preferential enrichment of H3K4me3 on neurodevelopmental genes. In the brains of folate-deficient NTDs models, decreased expression of KDM5A and upregulated Axin2 and Atoh1 expression were observed, along with increased H3K4me3 enrichment at respective gene promoters (P<0.05). Collectively, these findings highlight the important function of KDM5A in NTDs with folate deficiency. KDM5A affects the expression of genes related to neurodevelopment by modifying H3K4me3 downstream. This study enhances our comprehension of the development of NTDs by examining the impact of disrupted folate metabolism and abnormal regulation of histone modification by KDM5A. It provides valuable insights into potential treatments for reducing birth defects and improving reproductive health.

Neural tube defects (NTDs) are a class of major birth defects associated with the central nervous system. With the promotion of folic acid supplementation policy in pregnant women, the incidence of folic acid is decreasing year by year, which makes it difficult to obtain clinical specimens. Therefore, it is particularly important to establish reliable animal models to study the pathogenesis of NTDs. In this study, the NTDs mouse model induced by low folate combined with methotrexate (MTX) and the NTDs mouse model induced by retinoic acid (RA) were respectively established. transcriptome sequencing (RNA-seq) was performed on the brain tissue of NTDs fetal mice and differential expression profiles were analyzed. The results were verified by real-time quantitative polymerase chain reaction (RT-qPCR). The results showed that the incidence of NTDs induced by low folate combined with MTX was 21.7%. RA-induced fetal mice showed strong teratogenicity, with a deformity rate of 73.2%. Compared with normal fetal mice, 1 443 differentially expressed genes (DEGs) were screened in NTDs mice induced by low folate combined with MTX. Totally 3 070 DEGs were screened in RA-induced NTDs mice. Bioinformatics analysis of DEGs showed that the up-regulated genes were mainly involved in the antero-posterior axis development, regionalization, pattern differentiation and other biological processes. KEGG enrichment showed that up-regulated genes were associated with myocardial contraction, cardiomyopathy, and neuroactive ligand-receptor interactions. Veen intersection analysis of DEGs in the two models showed that a total of 132 DEGs were significantly up-regulated in both sets of models, including the Hox gene family. The results were verified by RT-qPCR and found to be consistent with those of RNA-seq. In this study, RNA-seq and differential expression profiles were analyzed in the fetal brains of two NTDs mice, and it was found that the abnormal expression of Hox might lead to the occurrence of NTDs, which provided exploration and reflection for the subsequent pathogenesis research.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive tumor, in which T precursor cells undergo malignant transformation, and the side effects and drug resistance of chemotherapy drugs are still difficult problems hindering the success of treatment. Vincristine (VCR) is a traditional chemotherapy drug for children with significant efficacy in T-ALL, but its side effects are obvious. Lithium carbonate (Li₂CO₃) can enhance the efficacy of other chemotherapy drugs, but studies of its combination with VCR have not been reported. The purpose of this study is to investigate the effects of Li₂CO₃ combined with VCR on the proliferation, apoptosis and cell cycle of two pediatric T-ALL cell lines, CCRF-CEM and Jurkat cells. The results of thiazolyl blue tetrazolium bromide (MTT) colorimetric assay showed that the viability of both cells decreased with the increase of the concentration of VCR or Li₂CO₃ alone, which compared with the control group (P<0.05). The survival rates of the two kinds of cells were different under the same Li₂CO₃ concentration (P<0.01). Compared with the VCR group, the cell viability and half maximal inhibitory concentration (IC₅₀) values of Li₂CO₃ combined with VCR group were reduced in the two kinds of cells, and the coefficient of drug interaction (CDI) between Li₂CO₃ and VCR was less than 1. Flow cytometry showed Li₂CO₃ combined with VCR group had the highest proportion of G₂/M and apoptotic cells of the two kinds of cells among the control, Li₂CO₃, VCR and, Li₂CO₃ combined with VCR group. And there were significant differences between Li₂CO₃ combined with VCR group and VCR group (P<0.05). In conclusion, our experimental results suggest that the combination of Li₂CO₃ and VCR inhibits of T-ALL cell proliferation, arrests the cell cycle in the G₂/M phase and increases cell apoptosis, which provides a new experimental basis for the clinical treatment of pediatric T-ALL, the reduction of VCR side effects, and also new ideas for drug development.

Induced pluripotent stem cell-derived mesenchymal stem cells (iMSC) have been proposed as an alternative source to primary mesenchymal stem cells(MSC), showing multiple advantages in disease treatment research. However, it remains unclear which disease type iMSCs are more suitable and whether they carry potential risks. This study utilized high-throughput sequencing data from public databases to compare iMSC with bone marrow-derived MSC (BM-MSC), adipose-derived MSC (AD-MSC), and umbilical cord-derived MSC (UC-MSC). Through various bioinformatics methods, including differential gene expression analysis, functional enrichment analysis, protein-protein interaction network analysis, and CMap database screening. The results indicated that iMSC possesses unique gene transcription characteristics, showing significant differences in gene expression compared to the three commonly used MSC types, particularly in genes related to neural and muscle development and immune regulation. Functional enrichment analysis of the differential genes further confirmed iMSC's potential advantages in treating neuro-related diseases, along with its lower immunogenicity but higher tumorigenic risk. Analysis using the CMap database identified potential gene targets and small molecule inhibitors to mitigate the tumorigenic risk of iMSC, providing possible strategies to reduce the risks associated with iMSC application. In summary, as a potential source for cell therapy, iMSC shows promising advantages in treating neurological diseases, but its safety needs to be validated through further experiments and clinical studies.

Type 1 diabetes is caused by impaired function of pancreatic β-cells and insufficient insulin secretion. Currently, it is primarily managed with exogenous insulin supplementation; however, exogenous insulin cannot precisely regulate blood glucose levels, and severe hypoglycemia can be life-threatening. Islet transplantation serves as an alternative therapy, but faces challenges such as a shortage of organ donors and the risk of cross-species infections from xenogeneic sources of islet β-cells. Thus, obtaining a sufficient and safe supply of islet β-cells remains a significant challenge in cell therapy for type 1 diabetes. This study aims to differentiate human induced pluripotent stem cells (hiPSCs) into islet β-cells in vitro, offering a potential new strategy for treating type 1 diabetes. To achieve this, we utilized a differentiation strategy that combines 2D and 3D culture systems to simulate the in vivo developmental environment of islet β-cells and employed various growth factors to regulate key signaling pathways crucial in pancreatic development and β-cell differentiation, including the Notch, Wnt, and TGF-β/Smad signaling pathways. Our results show that under combined 2D and 3D culture conditions, the expression of specific genes at the stages of definitive endoderm, pancreatic progenitors, pancreatic endocrine cells, and islet β-cells significantly increased (P<0.05). And there was a marked enhancement in insulin content and secretion following glucose stimulation (P<0.05). In summary, this study successfully established a differentiation strategy from hiPSCs to functional islet β-cells, providing a new cell therapy approach for type 1 diabetes. This method not only offers new tools for studying the developmental biology of islet β-cells, but also provides a potential source of islet β-cells for clinical applications, potentially overcoming the limitations of current treatment methods.