Stem Cell Reviews and Reports最新文献

Background: Despite affecting approximately 30% of the population, the pathogenesis of temporomandibular disorders (TMD) remains poorly understood. Conditions such as disc displacement and joint degeneration are often associated with biomechanical dysfunction. Identifying and categorizing biomarkers in the articular disc may enhance our understanding of disease mechanisms and progression, potentially improving diagnostic accuracy and therapeutic outcomes.

Aim: This review examines patterns among immunohistochemical biomarkers in the articular disc, with a focus on internal derangement and disc displacement. It also explores associations with clinical, radiological, and histological findings, defining the functional and stage-specific relevance of each marker.

Methods: A systematic search of major databases and journals identified studies that used immunohistochemical methods and included control groups. Biomarker patterns were analyzed in isolation and in relation to clinical, radiological, and histological findings. Patient demographics were examined to determine their alignment with disease trends. Study selection followed PRISMA guidelines; bias was assessed using the Newcastle-Ottawa Scale.

Results: The review included 511 patients (579 samples) and 132 controls (158 samples). Analysis identified 24 biomarkers, providing valuable insights into their role in inflammatory progression, ECM remodeling, and tissue degeneration. Biomarkers were classified according to functional and stage-specific patterns, facilitating early detection, refining disease staging, and supporting individualized treatment strategies.

Conclusion: Disc biopsy offers unique insights into the joint- and disc-specific mechanisms that drive TMD progression from disc displacement to degenerative findings. However, its clinical use remains limited by its invasive nature, ethical constraints, and the lack of standardized protocols for reliable study design and validated biomarker profiles.

Human Umbilical Cord-derived Mesenchymal Stromal Cells (hUC-MSCs) represent a promising candidate for regenerative medicine, though their therapeutic potential is constrained by replicative senescence. Pyrroloquinoline quinone (PQQ), a redox-active coenzyme, has been reported to protect against cellular aging. However, its precise role and mechanism of action in mitigating replicative senescence of hUC-MSCs remain to be elucidated. This study employed an integrated approach of phenotypic screening and transcriptomic profiling to systematically evaluate the anti-senescence effects of PQQ on replicatively senescent hUC-MSCs. Our results indicated that PQQ treatment enhanced proliferative capacity, reduced senescence-associated β-galactosidase (SA-β-gal) activity, and attenuated G1 phase cell cycle arrest. Moreover, PQQ improved mitochondrial membrane potential, reduced intracellular reactive oxygen species (ROS) accumulation, and attenuated telomere attrition. RNA sequencing analysis suggests that PQQ treatment appears to alleviate senescence-related transcriptional features, which is consistent with the observed phenotypic improvements. Gene Set Enrichment Analysis (GSEA) revealed a significant upregulation of pathways governing cell cycle progression and DNA replication following PQQ intervention. Key Driver Analysis (KDA) further identified regulators within these pathways, including PLK1, MCM5, and CDC6. Subsequent qPCR validation showed that the expression of these genes, which are critical for DNA replication initiation and mitotic progression, was downregulated in senescent cells and increased following PQQ treatment. In conclusion, the effect of PQQ on the replicative senescence of hUC-MSCs may be related to the upregulation of genes associated with the cell cycle and DNA replication.

Polycomb Repressive Complex 1 (PRC1) is a group of epigenetic regulatory complexes critical for mammalian development. Elucidating PRC1 composition and function across cell types and developmental stages is key to understanding the epigenetic regulation of cell fate determination. In this study, we discovered POGZ, a prominent autism spectrum disorder (ASD) risk factor, as a novel component of PRC1.6, forming the PRC1.6-POGZ complex. Functional assays revealed that POGZ elicits transcriptional repression that is dependent on RING1B expression. Analysis of publicly available data showed that POGZ highly colocalizes with RING1B and HP1g, two PRC1.6 components, at genes involved in multiple aspects of transcriptional regulation in embryonic mouse cortical cells. Although Pogz knockout (KO) does not compromise stem cell pluripotency, Pogz ablation in neuronal progenitor cells (NPCs) led to widespread transcriptomic dysregulation with failed activation of key neuronal genes. Finally, we demonstrated that PRC1.6-POGZ regulates neuronal differentiation by repressing bone morphogenetic protein (BMP) signaling. These findings reveal a mechanism by which PRC1 and POGZ coordinate transcription during neuronal differentiation and demonstrate that disrupting this complex impairs BMP signaling, potentially contributing to neurodevelopmental disorders such as ASD.

Background: Glucagon-like peptide-1 receptor agonists, originally developed for managing type 2 diabetes, have gained attention for their weight-reducing and broader biological effects. Among these, their influence on human mesenchymal stem cells remains underexplored, despite the critical role of mesenchymal stem cells in tissue regeneration and secretion of bioactive factors.

Methods: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify and evaluate in vitro studies investigating the effects of glucagon-like peptide-1 receptor agonists and their analogues on human mesenchymal stem cell functions, including proliferation, differentiation, signaling, apoptosis, and tissue-specific applications. Risk of bias was assessed using an adapted Quality Assessment Tool for In Vitro Studies (QUIN) tool.

Results: Thirty-eight eligible studies were identified. Glucagon-like-peptide-1 receptor agonist, like native glucagon-like peptide-1, Exendin-4, and Liraglutide, exert context-, dose-, and timing-dependent effects on human mesenchymal stem cells. They modulate proliferation and overall promote osteogenesis while inhibiting adipogenesis. Key pathways, including Wnt/β-catenin, bone morphogenetic protein 2/Smad, phosphoinositide 3-kinase/Akt and protein kinase A, play a role in this. Furthermore, these agents modulate inflammation, reduce apoptosis, and improve stem cell functions even under diabetic or inflammatory conditions. Exendin-4 facilitated tenogenic and insulin-producing cell differentiation, particularly in engineered scaffolds or genetically engineered human mesenchymal stem cells.

Conclusion: Glucagon-like peptide-1 receptor agonists modulate key pathways in human mesenchymal stem cells to influence survival, differentiation, and metabolic function, suggesting promising therapeutic potential beyond glycemic control. However, heterogeneous experimental designs and limited translational data necessitate further standardized and in vivo research to define clinical applications.

Metastasis and therapy resistance are main clinical challenges of pancreatic ductal adenocarcinoma (PDAC) still limiting patient`s prognosis. Both are dependent on tumor cell plasticity, which allows rapid adaptation of tumor cells to changing microenvironmental conditions. Epithelial-Mesenchymal-Transition (EMT), a process by which carcinoma cells acquire invasive abilities, is associated with a gain of cancer stem cell (CSC) properties. Different CSC phenotypes were described in PDAC, whereby high levels of the CSC marker Nestin was identified in CSC clones of mesenchymal Panc1 cells, while CSC clones of epithelial Panc89 cells were characterized by a high SOX2 expression. To investigate the functional impact of these CSC markers in PDAC cells with different EMT phenotypes, expression of either CSC marker was silenced in heterogenous (parental) and CSC PDAC populations to analyze their impact on essential malignancy associated properties.SiRNA-mediated knockdown (KD) of NES and/or SOX2 in Panc1 and Panc89 cell variants (parental and CSC population), respectively, was successfully achieved. Decreased NES expression in Panc1 cell variants and decreased SOX2 expression in Panc89 cell variants significantly inhibited self-renewing properties, however, only marginally impacted cell growth, EMT marker expression, migration and invasion properties as well as response to chemotherapy. Overall, our data indicate that Nestin and SOX2 are crucial mediators of self-renewal capabilities of mesenchymal and epithelial PDAC cell variants, respectively, but that further factors are required for the maintenance of other malignancy associated properties.

The persistence and drug resistance of leukemic stem cells (LSCs) are major challenges in the treatment of acute myeloid leukemia (AML). Ferroptosis, a novel form of programmed cell death, has emerged as a promising strategy for eradicating LSCs. This review provides a systematic analysis of LSC ferroptosis resistance and explores the interplay between iron metabolism, lipid peroxidation, and antioxidant defense mechanisms. We propose a novel predictive model based on single-cell multiomics data that integrates iron homeostasis regulators (TfR1, GPX4, and FTH1) to assess the susceptibility of LSCs to ferroptosis. A key innovation of this study was the in-depth exploration of LSC ferroptotic heterogeneity and its interaction with the tumor microenvironment, shedding light on new approaches for precision AML therapy. Based on these findings, we introduced an innovative treatment paradigm combining ferroptosis inducers (e.g., erastin, RSL3) with immunotherapies (such as PD-L1 inhibitors and CAR-T cell therapy) to enhance LSC clearance and minimize measurable residual disease (MRD). This review fills a critical knowledge gap in the study of ferroptosis in LSCs, providing a theoretical foundation and translational insights for future AML treatment strategies.

Background & aims: Human induced pluripotent stem cell (hiPSC)-derived hepatic endoderm (HE) is a potential treatment for liver diseases, but its heterogeneity poses challenges. Hepatic specification, the conversion of hiPSC-derived endoderm (DE) into HE, is critical for HE induction. Caudal homeobox transcription factor 2 (CDX2) regulates multiple signalling pathways during embryonic development and directs organogenesis. While CDX2 is a key regulator of organ development, its role during hepatic specification remains unclear.

Methods: HE markers were detected using western blotting (WB) and immunofluorescence (IF). The CDX2 regulatory axis was identified using mRNA-seq and bioinformatics analysis. During hepatic specification, the relative pathways PI3K-AKT, WNT, epithelial‒mesenchymal transition (EMT) and extracellular matrix (ECM) were confirmed using WB. Hepatocyte-like functions were evaluated based on glycogen content, indocyanine green (ICG) uptake and albumin levels. The therapeutic efficacy of HE cells was evaluated in a mouse liver injury model.

Results: Overexpression of CDX2 resulted in enhanced expression and function of HE markers during hepatic specification. mRNA-seq and bioinformatics analysis revealed differentially expressed genes following CDX2 overexpression that target the PI3K-AKT and WNT pathways, which was confirmed by WB. Furthermore, the results showed that EMT and the ECM degradation were suppressed by CDX2 overexpression (p < 0.05). In addition, SB-3CT, an matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) inhibitor, effectively promoted the formation of HE cells derived from hiPSC-DEs. Functionally, hepatocyte-like cells derived from HE cells through CDX2 overexpression presented increased glycogen levels, ICG uptake and albumin production. On the other hand, liver functions and acute injuries were significantly ameliorated when CDX2-modulated HE cells were transplanted into a mouse model.

Conclusions: CDX2 promotes HE formation through inhibition of the PI3K-Akt and Wnt/β-catenin pathways, as well as suppression of EMT and ECM degradation. Moreover, transplantation of CDX2-modulated HE cells represents an effective therapeutic approach for liver injury treatment.