Frontiers in Cell and Developmental Biology最新文献

Introduction: The potassium voltage-gated channel Kv2.1 plays a crucial role in the development of the brain's ventricular system. Defects in the development of this system affect the formation of the Reissner fiber, a rope-like structure produced by the flexural and subcommissural organs that secrete Scospondin.

Methods: The development of the Reissner fiber has been studied during normal development and in zebrafish mutants deficient in activity of the two Kv2.1 subunits - Kcnb1 and Kcng4b using a combination of immunohistochemistry and transgenic lines expressing EGFP in the subcommissural organ and floor plate.

Results: The Reissner fiber develops in stages. First, the midline floor plate cells, originating from the embryonic organizer, secrete Scospondin, forming the posterior Reissner fiber. This allows us to define the posterior Reissner fiber as the acellular derivative of the embryonic organizer. The fiber separates from the floor plate, beginning in the hindbrain and extends through the neural tube, from the most anterior floor plate (i.e. the flexural organ) anteriorly to the ampulla terminalis. Second, the subcommissural organ, which is derived from the anterior roof plate, begins secreting Scospondin. This forms the anterior Reissner fiber, which spans the cerebral aqueduct. Third, the anterior Reissner fiber connects to the flexural organ, where the two fibers fuse. Fourth, after the floor plate ceases to express Scospondin, the Reissner fiber derived from the subcommissural organ replaces the transient posterior fiber derived from the floor plate. Like the subcommissural organ, the flexural organ is an attachment point for the Reissner fiber. Reissner fiber assembly involves the formation of individual microfilaments that fuse in several steps to form the single fiber.

Discussion: Analysis of zebrafish mutants of Kv2.1 subunits (Kcnb1 and Kcng4b) revealed that Kv2.1 negatively regulates Scospondin production at several levels. These mutations have opposing effects on the transcript levels of several genes involved in Reissner fiber development (sspo, lgals2, and chl1a/camel), affect the subcommissural organ and microfilament formation, and impact Reissner fiber assembly.

Traditional approaches to biomaterial design face numerous challenges, including high trial-and-error costs, long development cycle, and the difficulty in deciphering the complex relationship between material properties and biological responses. With the rise of artificial intelligence (AI) technology, its capabilities in processing high-dimensional data and constructing complex mapping relationships have brought revolutionary changes to biomaterial design. This article reviews the four core applications of AI in the design of biomaterials. Firstly, based on the therapeutic needs of diseases, the functions of materials are clarified and formulations are generated. Secondly, high-throughput prediction and virtual screening of material properties using AI models significantly reduce development costs. Furthermore, the performance of materials and production efficiency can be enhanced by optimizing material formulas and processing techniques through AI. Finally, AI is used to predict the interaction between materials and cells or tissues, and to assess the safety and efficacy of the materials. This paper systematically explores how AI empowers biomaterial design, driving its advancement toward precision and intelligence, thereby providing robust support for the realization of personalized and precision medicine.

MYC performs a dual role in DNA Damage Response (DDR), promoting genomic instability through replication stress, R-loop formation, and topoisomerase-mediated damage, while simultaneously activating DNA repair pathways to maintain cell survival. This review provides a comprehensive analysis of how MYC inhibition affects DDR pathway dependencies. In fact, when MYC is inhibited, cancer cells lose both their proficient DNA repair capacity and their protective mechanisms against replication stress. This creates a therapeutic window in which combining MYC inhibitors with DDR-targeting agents may achieve synergistic anti-cancer effects. Central to this approach is the exploration of rational combination strategies that pair MYC inhibitors with various DDR modulators including Poly (ADP-ribose) polymerase (PARP) inhibitors, ATR/CHK1 inhibitors, and other DNA repair pathway disruptors. This review summarizes preclinical evidence demonstrating enhanced therapeutic efficacy when MYC inhibition is combined with DDR-targeting agents and discusses early clinical findings that support this promising therapeutic strategy.

Introduction: Preeclampsia (PE) is a hypertensive disorder in pregnancy, influencing global health risks due to its poorly understood aetiology involving immune mismatches. Oocyte Donation increases PE risk due to complete HLA incompatibility, leading to immune activation. MicroRNAs (miRNAs) emerged as crucial regulators in placental development, immune regulation, and endothelial function, acting as post-transcriptional gene regulators. This study aims to explore whether specific miRNAs, previously implicated in PE, can be used to distinguish preeclamptic and non-preeclamptic mothers undergoing oocyte donation pregnancy.

Methods: This prospective study enrolled 20 mothers, divided into four groups: oocyte donation normotensive, oocyte donation preeclamptic, spontaneous normotensive, and spontaneous preeclamptic mothers. Maternal and cord blood samples were collected postpartum, along with placental biopsies. Tissue samples underwent histological examination. Total miRNAs were extracted from plasma, cord blood, and placenta and quantified via digital droplet PCR. The secretome analysis of cytokine/chemokines was performed on the mother's plasma and cord blood by Luminex ELISA.

Results: In oocyte normotensive the epigenetic (miR-155, miR-17, miR-30) and immune profile (CXCL10, VEGF), displayed only limited variations compared to spontaneous normotensive. Conversely, preeclamptic oocyte recipients exhibited marked molecular dysregulation, characterized by significant upregulation of pro-inflammatory miRNAs (miR-155, miR-17, miR-223) and cytokines (IL-6, IL-1β, TNF-α, IFN-γ) in maternal plasma and placental tissue, indicating heightened immune activation. Notably, miR-30 and let-7c were downregulated. Intriguingly, miRNA expression in umbilical cord plasma was often inversely correlated with maternal and placental profiles, suggesting complex miRNA trafficking and fetal protection mechanisms. Placental histology showed minimal pathological changes in preeclamptic oocyte recipients, contrasting with more severe lesions in preeclamptic spontaneously conceived pregnancies, reflecting differing underlying pathogenic processes.

Conclusion: This study highlights significant alterations in miRNA expression and cytokine profiles associated with PE, particularly in oocyte donation pregnancies. The findings suggested a complex interplay between maternal immune regulation and placental function, with distinct maternal and fetal immune responses. Understanding these molecular and immunological changes may facilitate the development of novel diagnostic biomarkers and targeted therapies to improve maternal and fetal outcomes in PE.

Background: Reciprocal communication between odontogenic tissues underpins the complexity of tooth morphogenesis. Despite mandible serving as the developmental niche and functional platform for tooth germs, their reciprocal signaling mechanisms remain underexplored. Histone acetylation plays a pivotal role in maintaining long-term regulatory equilibrium and physiological homeostasis by establishing stable gene expression patterns. However, whether stable histone acetylation signatures exist during tooth germ morphogenesis and how they might ensure developmental fidelity remain unreported.

Methods: Extracellular vesicles were isolated from E40 miniature pig mandibles, with bioinformatic analysis identifying miR-206 as a key miRNA targeting the epigenetic regulator HDAC4. Mechanistic validation utilized dual-luciferase reporter assays, qRT-PCR, and Western blotting to confirm target interactions in vitro. In vivo assessment, tooth germs were co-cultured with mandibular EVs or lentivirally transduced for miR-206/HDAC4 overexpression/knockdown, then subcutaneously transplanted into nude mice. Harvested tooth germs underwent stereomicroscopic morphological analysis, micro-CT-based 3D reconstruction with mineralization quantification, and H&E histogenesis evaluation to validate the miR-206/HDAC4 regulatory axis.

Results: In vivo and in vitro findings collectively validated miR-206 as the critical regulator within mandibular-derived extracellular vesicles. Exosomal miR-206 suppressed HDAC4 expression in tooth germs, epigenetically mediating morphogenesis and mineralization during early stage of tooth development.

Conclusions: Our identification of the exosomal miR-206/HDAC4 signal axis redefines the mandible as an active epigenetic modulator of odontogenesis. This vesicle-mediated regulation enables long-range delivery of epigenetic effectors-revealing a paradigm shift in tooth development and a druggable target for tooth regeneration.

Introduction: Human pluripotent stem cells (PSCs) have the potential to revolutionize regenerative medicine, but their clinical safety has not been thoroughly investigated. We investigated the in vivo biodistribution, safety evaluation, and in situ tumorigenicity test of specific human iPSC-derived dopaminergic neural precursor cell (DAP) therapeutic products in a severe immunodeficient mouse model and established a method for detecting stereotactic drug delivery and distribution differentiation to support clinical trial dose justification and toxicity monitoring.

Methods: For the biodistribution study, DAPs were injected into the unilateral striatum of NSG mice, and the distribution and differentiation of the transplanted cells were determined via immunofluorescence staining and qPCR at 1-, 28-, 84-, and 168-days post-administration. The toxicity and tumorigenicity studies were carried out on NSG mice by administering saline, 1 × 10⁵ DAP cells, 2 × 10⁵ DAP cells, 0.01% iPSCs (2 × 10⁵ cells) or 1% iPSCs (2 × 10⁵ cells) per animal in accordance with the intended clinical dosage. After 28, 84, and 168 days, the mice were euthanized.

Results: Brain-only discovery of DAP markers (Ki67, FOXA2, OTX2, STEM101, and STEM121) and specific sequences of DAPs was confirmed. From 1- to 184-days, the copy number of Th first decreased but then increased; the expression of STEM121 decreased, and the neuronal cell marker proteins Th and STEM101 increased. Additionally, the differentiation target RNA Th was identified 28 days after administration, and both the differentiation ratio and degree increased. There was no evidence of toxicity from DAPs, and there were no tumors or abnormally proliferating cells detected.

Discussion: This study developed a novel method for determining biodistribution and differentiation in vivo, provided a strategy to evaluate the safety of iPSC derived DAPs, and showed their safety in mice. The data provides essential safety data for the clinical translation of DAPs and supports their phase I clinical trials in China and the United States.

Introduction: During embryogenesis, specific morphogen gradients are essential for inducing tissue pattern formation. In two-dimensional (2D) human pluripotent stem cell (hPSC) culture, distinct patterns can emerge in hPSC colonies without external morphogen gradients, implying that critical intrinsic factors may induce spatial organization. However, studying the mechanism is challenging due to the lack of efficient spatial labels.

Methods: We employed the mitochondrial membrane potential (MMP) probe JC-1 to stain and track cells within hPSC colonies. Using this tool, we assessed metabolic patterns under different culture coatings and manipulated pathways using mTOR and ROCK inhibitors.

Results: We identified JC-1 as a durable spatial tracker, revealing a clear metabolic pattern in hPSC colonies, significantly influenced by coating materials (integrin-stimulating matrices vs. E-cadherin). This metabolic pattern correlated with spatial mesodermal cell fate under BMP4 induction. Modulation of the mTOR pathway altered the metabolic pattern and subsequent mesoderm induction.

Conclusion: This study reveals that intrinsic metabolic patterns predispose hPSCs to spatial organization of cell fate and highlights JC-1 as a potent spatial marker for studying tissue patterning mechanisms.

Atherosclerosis (AS) is the primary pathological basis for the disability and mortality rates of global cardiovascular diseases. Its core characteristics are abnormal deposition of blood vessel wall lipids, chronic inflammatory activation, and vascular structural remodeling, which ultimately lead to acute cardiovascular and cerebral vascular events such as coronary heart disease and cerebral infarction. Existing treatment methods, such as statins and interventional interventions, can only delay disease progression and cannot reverse the pathological damage to blood vessels that has already occurred. Stem cells provide a novel strategy for the targeted therapy of AS due to their multi-directional differentiation potential, immune regulatory ability, and tissue repair properties. This review systematically reviews the research progress of stem cells in the treatment of AS in recent years, focusing on the mechanism of the main cell types such as mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and endothelial progenitor cells (EPCs), including regulating lipid metabolism, inhibiting inflammatory reaction, repairing vascular endothelium, and stabilizing atherosclerotic plaque. This study summarizes the key evidence from animal experiments and clinical trials in 2023-2025; analyzes core challenges such as low homing efficiency, short survival time, and the risk of immune rejection of stem cells; and proposes optimization strategies such as gene modification, biomaterial carriers, and combination therapy. Finally, the application prospects of single-cell sequencing, organoid models, and precision delivery systems in promoting the clinical translation of stem cells are discussed, with specific implementation paths being supplemented: single-cell sequencing can analyze the heterogeneity of stem cells in the AS lesion microenvironment (e.g., subtype differentiation differences of MSCs under hypoxic conditions) to screen high-activity stem cell subpopulations; vascular organoids constructed from patient-derived iPSCs can simulate the in vivo lipid deposition-inflammatory microenvironment to evaluate stem cell therapeutic effects; and precision delivery systems can enhance lesion targeting via ligand modification (e.g., anti-VCAM-1 antibody-modified PLGA carriers), thus providing theoretical basis and research directions for the disease modification therapy of AS.

Diabetic cardiomyopathy (DCM) is one of the crucial causes leading to heart failure and adverse outcomes in patients with diabetes mellitus; however, effective strategies targeting its molecular pathological mechanisms and therapies are currently lacking. DCM is primarily characterized by early diastolic dysfunction, cardiomyocyte apoptosis, and fibrosis. Its disease progression is relatively insidious, eventually evolving into heart failure with preserved ejection fraction. The intrinsic metabolic environment of diabetes markedly exacerbates oxidative stress, and the accumulated polyunsaturated fatty acids within cardiomyocytes are highly susceptible to lipid peroxidation, leading to the excessive generation of 4-hydroxy-2-nonenal (4-HNE). The pivotal role of this reactive aldehyde in promoting the progression of DCM has been extensively demonstrated in animal, cellular, and clinical models. However, its subcellular targets and the underlying molecular mechanisms remain inadequately elucidated. Organelles, as central executors of diverse intracellular functions, may serve as potential sites of 4-HNE-induced interference and therapeutic targeting. This article focuses on the central role of 4-HNE in triggering energy depletion, calcium overload, autophagic flux blockade, and ferroptosis through its interactions among mitochondria, endoplasmic reticulum, lysosomes, and other organelles. On the basis of existing evidence, potentially translatable therapeutic avenues include ALDH2 activators, G protein-coupled receptor 40 (GPR40) agonists, mitochondria-targeted antioxidants and ferroptosis inhibitors. The aim is to provide a theoretical foundation and reference for the clinical identification of myocardial injury in DCM, model replication, and the development of targeted intervention strategies.

Colorectal cancer (CRC) is one of the most prevalent malignant neoplasms worldwide, characterized by a high incidence of recurrence and metastasis, which substantially diminishes patient survival rates. This underscores the urgent need to identify novel biomarkers and therapeutic targets. Transcribed ultraconserved regions (T-UCRs), a category of non-coding RNAs with significant evolutionary conservation, are crucial to various biological processes. Recent studies have shown that T-UCRs play a pivotal role in tumorigenesis and tumor progression. A growing body of evidence indicates that T-UCRs significantly influence CRC development by modulating critical mechanisms, including cell proliferation, apoptosis, invasion, and metastasis. This review systematically explores the functions of T-UCRs in tumorigenesis, focusing on their regulatory roles, underlying molecular mechanisms, and potential clinical applications in CRC.