Stem Cell Reviews and Reports最新文献

Background: Steroid-induced osteonecrosis of the femoral head (SONFH) is a progressive and refractory orthopedic disorder characterized by deterioration of the subchondral bone microstructure and eventual femoral head collapse, leading to hip joint dysfunction. Current therapeutic strategies offer limited efficacy and fail to reverse the necrotic process, with approximately 70% of patients eventually requiring total hip arthroplasty. Therefore, developing novel treatments capable of halting disease progression and promoting bone repair is crucial for addressing this clinical challenge. Exosomes, bioactive nanovesicles that regulate apoptosis, angiogenesis, and inflammation, represent a promising regenerative modality. In particular, stem cell-derived exosomes are considered to play a key role in the treatment of SONFH by promoting osteogenesis and angiogenesis and modulating inflammatory responses. However, the efficacy and mechanisms underlying exosome-based therapy for SONFH have not been systematically evaluated. A comprehensive synthesis of current evidence is urgently needed to inform future clinical translation.

Purpose: By synthesizing preclinical evidence, this study explored the mechanism and therapeutic potential of stem cell-derived exosomes in SONFH and identified key methodological limitations to provide a roadmap for future research.

Study design: Systematic review and meta-analysis.

Methods: A comprehensive literature search was conducted in PubMed, Web of Science, the Cochrane Library, and Embase for preclinical studies published from database inception until August 2025, with a focus on exosome-based therapy for osteonecrosis of the femoral head. Studies meeting the predefined inclusion criteria were rigorously selected and assessed for methodological quality, and relevant data were extracted. All the statistical analyses were performed via Review Manager (RevMan) version 5.4 software.

Results: A total of 12 studies were included, all of which involved rat models of SONFH. The results of the meta-analysis revealed that exosome intervention significantly increased bone mineral density (BMD), thickness of trabecula, percentage of bone mass, the number of trabecula, vascular length, vascular volume and vascular area and reduced trabecular bone dissociation.

Conclusion: Exosomes rescue SONFH through multiple pathways. By promoting angiogenesis and osteogenesis, they effectively reverse the core pathological process of femoral head necrosis.

Calcific aortic valve disease (CAVD) is a progressive and life-threatening condition characterized by fibrocalcific remodeling of the valve leaflets. Valvular interstitial cells (VICs) are central mediators of calcific aortic valve disease (CAVD), as their osteogenic trans-differentiation drives pathological matrix remodeling and calcium deposition within the valve leaflets. Human-induced pluripotent stem cell-derived valvular interstitial cells (hiVICs) represent a promising patient-specific platform for disease modeling. While primary VICs (pVICs) readily undergo mineralization under osteogenic stimulation, hiVICs fail to calcify in conventional two-dimensional (2D) cultures. Our data suggests that the inability of hiVICs to calcify in 2D culture is related to FOXO1 (Forkhead box protein O1) activity, which suppresses the osteogenic transcriptional program by inhibiting RUNX2 (Runt-related transcription factor 2). To address this limitation, we then developed a three-dimensional tissue ring construct using hiVICs. When cultured in osteogenic medium, these constructs exhibited robust calcification, as confirmed by Alizarin Red and Von Kossa staining. FOXO1 was also identified as a mediator of calcification in the tissue ring constructs. Metformin treatment restored FOXO1 expression and inhibited calcification, while AS1842856, a selective FOXO1 inhibitor, exacerbated tissue construct mineralization and led to a near-complete tissue collapse. In summary, we establish a functional 3D hiVIC-based model of CAVD enabling mechanistic investigation and pharmacological screening and identify FOXO1 as a critical regulator of osteogenic transition.

Extracellular vesicles (EVs) mediate intercellular communication by transferring microRNAs (miRNAs) that regulate gene expression post-transcriptionally. EVs derived from mesenchymal stem/stromal cells (MSCs) have been widely investigated, and many studies have reported the presence of miRNAs within these vesicles. However, a comprehensive analysis comparing datasets to identify miRNA functional patterns has not yet been conducted. To address this gap, we compiled and analyzed published data on miRNAs in MSCs-derived EVs to uncover common features and explore regulatory roles. A literature search was performed to identify in vitro studies involving human MSCs that provided detailed methodologies for EVs concentration and miRNA characterization. Selected miRNA datasets were used for downstream bioinformatic analyses. Validated miRNA-target gene interactions were retrieved using MultiMiR R package. Functional enrichment analyses were performed using Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways to investigate potential biological roles of the identified genes. We curated 461 studies reporting miRNAs in MSCs-derived EVs. The most studied cells were adipose-derived (ADSCs), bone marrow-derived (BMMSCs), and umbilical cord-derived MSCs (UCMSCs), with BMMSCs contributing the highest number of unique miRNAs. hsa-miR-21-5p was the most frequently reported miRNA. For ADSCs, BMMSCs, and UCMSCs, the most frequently targeted genes were ZZZ3, ZZZ3, and PTEN, respectively. Notably, ZZZ3, a chromatin regulator, was prominent in all three cells. GO analysis revealed biological process enrichment in axonogenesis, while KEGG analysis highlighted significant involvement of neutrophil extracellular trap formation and aminoacyl-tRNA biosynthesis. This study provides an integration of miRNA data from human MSCs-derived extracellular vesicles.

Neurodevelopmental and neurodegenerative diseases involve critical abnormalities in pathogenesis. Even though there exists copious drugs and treatments, still a need for an effective model for absolute replication of disease pathophysiology and therapeutic drug discovery. This comprehensive systematic review amasses methods and approaches for developing neuronal models for neurological diseases using hPSCs/iPSCs. Abundant culturing methods, growth factors, modulators and toxins were utilised to induce the disease and were appraised. Research articles were traced from Google Scholar, PubMed/NIH, and Science Direct. Publications using hPSCs/iPSCs as differentiated neuronal disease models were screened using PRISMA guidelines, with designed inclusion and exclusion criteria. This protocol highlights the procedures for developing 2D and 3D neuronal models derived from hPSCs/iPSCs. 2D neuronal models include NPCs, NSCs, and neural rosettes, neurons, while 3D methods rely on embryoid bodies, neurospheres, spheroids and organoids due to the enhanced differentiation, survival and maturation of hPSCs/iPSCs. These processes include varied factors for culturing. Growth factors like GDNF, BDNF, cAMP, ascorbic acid, TGF-β, and Dual-SMAD inhibition. Post-analytical techniques like MEA, H&E, TEM, microscopy, immunoassays, and electrophysiology ensures the structural and functional endorsements. These models offer researchers a reliable platform to investigate the disease physiopathology and drug design for neurological disorders.

It has been widely accepted for many years that the essential components of the complement cascade (ComC), including C3 and C5 proteins, are produced solely in the liver and released into circulation after synthesis. However, recent evidence shows that complement components are also expressed in other cell types, including human cardiomyocytes. Moreover, a new regulatory loop was identified in lymphocytes that regulates immune responses and metabolism, named the "Complosome." Following this significant discovery, the Complosome has been shown to play a role in the trafficking and metabolism of hematopoietic stem/progenitor cells (HSPCs) and is expressed in several types of bone marrow (BM) resident stem cells. ComC has been studied in various models of tissue and organ injury and regeneration. However, most of these studies did not distinguish between the role of systemic, liver-derived circulating complement in the blood and the complement expressed as a "Complosome" inside cells. Since Complosome is expressed in several types of stem cells that could influence the clinical outcome of myocardial infarction (MI), this distinction is important because intracellular components of the ComC may have beneficial roles in cell survival, growth, differentiation, and trafficking of stem and progenitor cells. We report herein the systemic activation of the Complosome in the heart and hematopoietic tissues in a murine model of myocardial infarction (MI).

Tissue engineering seeks to develop biomimetic substitutes for damaged tissues using natural or synthetic materials functionalized with cells or biologically active compounds. Understanding how cell-scaffold interactions influence cellular behavior is critical for optimizing tissue engineering strategies. Polylactic acid (PLA), a biodegradable and biocompatible polymer approved by the U.S. FDA, is commonly used for scaffolds fabrication. Mesenchymal stromal cells (MSCs) are widely utilized in regenerative medicine due to their capacity to differentiate into mesodermal lineages and their secretomes, which exhibit robust paracrine activity. To date, few studies have investigated how scaffold characteristics, such as materials and/or architecture, modulate secretome composition using integrated multi-omics approaches. An untargeted metabolomics workflow combined with label-free proteomics was employed to analyze ASC-derived secretomes, obtained from adipose tissue-derived MSCs (ASCs) cultured in PLA-discs and PLA-scaffolds, as well as on conventional 2D polystyrene (PS) culture surfaces. A similar proteomic distribution was observed when secretomes from PLA-discs and PLA-scaffolds were compared. On the other hand, significant changes in the proteomic profile were observed between PLA-discs and 2D-PS secretomes. Proteins belonging to carbohydrate metabolism, cell motility, vasculature development, and oxidative stress response, among others, were increased in PLA-discs. The metabolomic profile shows significant differences, with metabolites related to glucose metabolism, such as pyruvate and lactic acid, increased in PLA secretomes. Our multi-omic approach demonstrates that the PLA constructs introduced here can modulate the secretome of ASCs, inducing significant changes in its composition, highlighting the influence of culture format on the secretory capacity of ASCs.

All cells within an organism share identical genetic material, yet epigenetic mechanisms determine stem cell fate by precisely regulating transcriptional programs. Histone acetylation is a key epigenetic modification that establishes an open chromatin structure, which is recognized by proteins involved in modulating chromatin dynamics essential for stem cell functions. Bromodomain (BrD)-containing proteins specifically recognize acetylated lysines on histones and act as critical epigenetic regulators within larger protein complexes. This review comprehensively describes the BrD protein family, highlighting their structural classifications and diverse functions, and explores their critical roles in regulating stem cell pluripotency and differentiation, and their implications in cancer development. Dysregulated BrD proteins can drive cancer by increasing stem cell-like features and tumor heterogeneity, making them a potential target for cancer treatment. Furthermore, this review emphasizes BrD inhibitors as promising therapeutic targets capable of targeting cancer stem cells and potentially mitigating cancer progression. Understanding the detailed functions and regulatory pathways of BrD proteins may open new avenues for improved cancer stem cell-targeted therapies.

Objective: The global shortage of platelets presents a significant challenge in healthcare. Although human induced pluripotent stem cells (hiPSCs) offer a renewable source for ex vivo platelet production, the current approach remains constrained by heterogeneity, low yield, and high costs. This study introduces an optimized differentiation scheme (ODS) to improve ex vivo platelet differentiation from hiPSCs.

Methods: A systematically optimized culture protocol was developed, incorporating: (1) a higher initial dose of embryoid body (EB) cells, (2) refining culture medium, (3) substitution of cytokines with small molecules, and (4) enhancement of megakaryocyte (MK) polyploidization via small-molecule supplementation. Feasibility and effectiveness were evaluated using microscopy, cell counting, flow cytometry, Wright-Giemsa staining, immunofluorescence (IF), and transmission electron microscopy (TEM).

Results: Increasing the initial EB cell count significantly promoted megakaryocyte production and accelerated the process. A serum-free medium supplemented with human platelet lysate (HPL) was favorable for megakaryocyte generation. Small molecules 740Y-P and butyzamide effectively substituted SCF and TPO for differentiation, while the combination of blebbistatin and 616452 enhanced megakaryocyte maturation. Mature megakaryocytes continuously generated functional platelets that, upon thrombin activation, facilitated fibrin clot formation and contraction in vitro. This method shortened differentiation to 19 days, enhanced output to 1.42 CD41⁺ megakaryocytes and 14.9 platelets per iPSC, and reduced costs by 58.3%.

Conclusion: We have established a cost-effective strategy for platelet production via hiPSC differentiation, with potential applications in cell therapy and gene editing.