Tyrosine kinase inhibitors (TKIs) targeting ABL1 catalytic activity have markedly improved Chronic Myeloid Leukemia (CML) outcomes, inducing unprecedented and durable therapeutic responses. However, while TKIs efficiently target committed leukemic progenitors, they fail to eradicate leukemic stem cells (LSCs), which may drive disease relapse. High BCR::ABL1 transcripts at diagnosis confer a proliferative and survival advantage and are associated with a higher risk of CML progression to the acute phase. Specifically Targeting the ABL Myristoyl Pocket (STAMP) compounds, including asciminib (ASC), provide a novel mechanism to inhibit BCR::ABL1 catalytic activity. ASC is FDA-approved for patients who have failed one or more TKIs, and its efficacy has been evaluated as monotherapy, and in combination with different TKIs, in T315I-positive or advanced-phase CML. We investigated the cytotoxic effects of ASC, alone or with imatinib (IM) or nilotinib (NIL), on committed progenitors and LSCs from CML patients expressing high or low BCR::ABL1 at diagnosis. ASC reduced BCR::ABL1-dependent survival and impaired clonogenicity in committed progenitors with low, but not high, BCR::ABL1 transcripts. ASC also disrupted LSC self-renewal, reducing both frequency and number of Long-Term Culture-Initiating Cells (LTC-ICs). When combined with IM or NIL, ASC restored TKI activity against LTC-ICs expressing high BCR::ABL1 transcripts, with the association of ASC and NIL reducing both LTC-IC division rates and LTC-IC-derived CFUs. These findings suggest that ASC, alone or with NIL, may target LSCs and improve outcomes in patients with high BCR::ABL1 expression at diagnosis.

The limited regenerative capacity of cartilage tissue and the high morbidity associated with injuries and diseases have driven the search for innovative regenerative medicine strategies. The objective of the study was to compare the chondrogenic differentiation of human MSCs in conventional pellet cultures to that of spheroids generated using an innovative microwell system.

Extracellular vesicles (EVs) are potential cell-free therapies for cardiac regeneration. Although adipose-derived stem cells (ADSCs) are easily obtained using minimally invasive procedures, therapeutic effects of hypoxically conditioned ADSC-derived EVs on the heart remain unknown. We aimed to verify whether hypoxic preconditioning enhances the therapeutic efficacy of ADSC-derived EVs.

Osteoarthritis (OA) is the most prevalent chronic degenerative joint disorder worldwide, characterized by progressive cartilage degradation, subchondral bone remodeling, synovial inflammation, and impaired mobility. Growing evidence has established mitochondrial dysfunction-including impaired oxidative phosphorylation (OXPHOS), excessive reactive oxygen species (ROS) generation, disrupted mitochondrial dynamics, and dysregulated mitophagy-as an early and pivotal driver of OA pathogenesis. These bioenergetic failures not only disrupt chondrocyte metabolism but also amplify inflammation, matrix degradation, and cell death. In recent years, mitochondrial transplantation has emerged as a revolutionary therapeutic paradigm, aiming to restore cellular homeostasis by delivering functional mitochondria into damaged chondrocytes. This review systematically summarizes the molecular mechanisms of mitochondrial dysfunction in OA and highlights three major therapeutic strategies: (1) cell-based approaches, particularly mesenchymal stem cell (MSC)-mediated mitochondrial transfer via tunneling nanotubes (TNTs) or extracellular vesicles (EVs); (2) cell-free approaches, utilizing purified mitochondria or MitoEVs for direct transplantation; and (3) engineered mitochondrial transplantation, integrating bioengineering, nanotechnology, and genetic modification to enhance mitochondrial quality, delivery efficiency, and therapeutic persistence. We further discuss opportunities and challenges in clinical translation, including standardization of mitochondrial preparation, optimization of delivery systems, immunological safety, and regulatory classification. Collectively, mitochondrial transplantation represents a disruptive strategy that directly addresses the bioenergetic collapse of chondrocytes and offers a promising avenue for disease-modifying therapy in OA. Future advances in mechanistic elucidation, technological optimization, and multicenter clinical trials will be crucial to transform "mitochondrial medicine" from experimental concept to clinical reality.

The management of bronchial asthma has evolved from a one-size-fits-all approach to the era of precision medicine, which is guided by intrinsic phenotypes. This article systematically reviews the mechanisms of action of current targeted biologics (targeting pathways such as IgE, IL-5/IL-5R, IL-4/IL-13, and TSLP), the efficacy and safety data derived from pivotal clinical trials, and the biomarker systems that guide clinical decision-making, further elaborating on how to implement tailored individualized therapy based on patient-specific characteristics. However, existing biologics still face challenges including the need for long-term administration and the inability to reverse disease progression. Therefore, this article focuses on the transformative prospects of next-generation therapeutic modalities. Cell therapy represents the most promising breakthrough, with its core shifting from "passive suppression" to "active regulation and remodeling". This is mainly reflected in three cutting-edge areas: cellular reprogramming (e.g., converting pathogenic Th2 cells into homing-competent regulatory T cells), engineering modification (e.g., designing CAR-NK cells with dual functions of targeted clearance and immune regulation), and multifunctional immune/repair modulation (e.g., utilizing mesenchymal stem cells and their exosomes to suppress immune abnormalities at the source and promote tissue repair). Collectively, these strategies drive a fundamental shift in treatment goals from symptom control to the induction of long-term immune tolerance and even functional cure. In conclusion, the future management of asthma will be a dynamically evolving individualized integrated system. By deeply integrating targeted biologics, intelligent advanced cell therapies, and continuously optimized precision management strategies, we are expected to ultimately establish a multi-level, closed-loop diagnosis and treatment pathway for each patient, laying the foundation for achieving long-term high-quality remission.

Postmenopausal osteoporosis (PMO) develops as a result of pathological cross-tissue interactions. However, current experimental paradigms are constrained by their single-tissue focus, hindering efforts to discover systemwide regulatory genes.

Due to toxicity, high costs, and potential side effects of standard treatments of rheumatoid arthritis (RA) including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and disease-modifying antirheumatic drugs (DMARDs), natural products and advanced drug delivery systems, such as nanoparticles and mesenchymal stem cell (MSC)-derived exosomes (EXO), have garnered interest due to their ability to target inflammation and oxidative damage, with enhanced precision and reduced side effects, offering a promising approach for RA management.

Epithelial stem cells in the interfollicular epidermis (IFE) and hair follicle (HF) play key roles in maintaining and regenerating the skin barrier by balancing self-renewal and differentiation. These fate decisions are governed by transcriptional and epigenetic mechanisms that respond to context-dependent signals from the skin microenvironment. In the IFE, basal stem cell divisions follow a stable pattern but rely on tightly regulated transcription factors and chromatin states to ensure proper epidermal maintenance. In contrast, HF stem cells exhibit a higher degree of plasticity that allows for rapid adaptation to changing environments, including IFE regeneration following injury. While this plasticity is critical for epidermal integrity, it can also drive disease onset if transcriptional programs become disrupted. This review provides a comprehensive analysis of how transcriptional and epigenetic regulators guide stem cell fate decisions required in the IFE and HF that promote epidermal homeostasis. We also explore how these programs are altered in various pathological contexts in the skin. By comparing differentiation mechanisms in the IFE and HF compartments, we highlight how dynamic control of gene expression sustains skin homeostasis.

Regeneration of tubular dentine structure is key to its biological function, and the polarity of odontoblasts is crucial for this, but the mechanism is unclear. On the basis of differential gene expression data comparing odontoblasts and donor-matched osteoblasts, we hypothesized that forkhead box Q1 (Foxq1), a key regulator in embryonic development, plays a significant role in the differentiation of polarized odontoblasts. This study aimed to investigate the role of Foxq1 in odontoblast polarization and tubular-dentine formation, and to explore its relationship with Wingless-type family member 5A (Wnt5a) signalling.

Umbilical cord blood (UCB) is a rich source of hematopoietic stem and progenitor cells for regenerative medicine. This study characterized the cellular composition of UCB from twin pregnancies to identify blood type concordance (BTC)-related differences.

Restless legs syndrome (RLS) is a sensorimotor disorder marked by an uncontrollable urge to move the legs. A pathophysiological hallmark of RLS is brain iron deficiency. The endothelial cells (ECs) of the blood-brain barrier (BBB) are responsible for regulating brain iron uptake. Our objective is to determine if brain iron uptake is altered in ECs in RLS.

Chemotherapy-induced premature ovarian failure (POF) is a major cause of infertility, with limited treatment options. Mesenchymal stem cell-derived exosomes (MSC-Exos) have therapeutic potential. This study investigated whether preconditioning MSCs with the antioxidant flavonoid isorhamnetin (ISO) enhances the efficacy of their exosomes (ISO-MSC-Exos) against POF.

Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder characterized by increased platelet destruction and impaired megakaryopoiesis within a dysregulated bone marrow niche. Conventional therapies often achieve only transient platelet recovery, failing to restore immune tolerance, thereby underscoring the need for mechanism-based therapeutic strategies. Mesenchymal stem cells (MSCs) have emerged as promising candidates due to their ability to modulate immune responses and repair the hematopoietic microenvironment. This review synthesizes current evidence regarding the biological properties, immunomodulatory mechanisms, and therapeutic applications of MSCs in ITP, emphasizing intrinsic abnormalities of patient-derived MSCs and the corrective potential of exogenous MSCs from distinct tissue sources. It further integrates emerging insights into MSC functional heterogeneity, optimization of culture conditions, priming strategies, and cellular engineering approaches that may enhance therapeutic efficacy and safety. By highlighting the interplay between immune tolerance restoration and bone marrow niche remodeling, this review provides a translational framework that links mechanistic understanding to the future clinical development of MSC-based therapies for ITP.

Prime editing (PE) enables precise genetic modifications using canonical prime editing guide RNA (pegRNA), with the reverse transcription template and primer binding site (RTT-PBS) attached to the 3' ends of CRISPR-Cas guide RNAs. Although PE ribonucleoprotein (RNP) delivery holds great therapeutic potential, its weak genomic editing capability limits therapeutic applications. Here we present structure-guided engineering of the PE complex using non-canonical pegRNAs (npegRNAs), with the RTT-PBS integrated within the single guide RNA loops, to improve PE efficiency. This approach demonstrates enhanced precise editing rates across various genomic sites and cell types, and improves therapeutic gene correction in a tyrosinaemia mouse model. Cas9-associated npegRNAs are more resistant to exonuclease degradation, probably enhancing the PE complex's targeting efficiency in living cells. Using PE RNP delivery, npegRNAs achieve increased average editing yields of 26.8-fold over canonical pegRNAs and 5.9-fold over engineered pegRNAs (epegRNAs). Furthermore, npegRNA-mediated RNPs increased the efficiency of installing disease-relevant mutations up to 123-fold in human cell lines, including Jurkat T cells and induced pluripotent stem cells. Collectively, our findings demonstrate a robust PE strategy and highlight the potential of npegRNAs for therapeutic PE applications.

Bivalent histone modifications, marked by the coexistence of activating and repressive histone marks, define a distinctive chromatin state with key roles in developmental gene regulation. However, the specific sequence features that distinguish bivalent chromatin regions remain unclear. Here we show that genome-wide profiling of H3K4me3, H3K27me3, and H3K9me3 in mouse embryonic stem cells revealed that bivalent domains have higher GC content and stronger evolutionary conservation than monovalent regions. Genes marked by bivalency were enriched in developmental signaling pathways, including Hippo, MAPK, and TGF-β. Using machine learning models trained on k-mer sequence features, we accurately distinguished bivalent from monovalent regions. Feature analysis identified informative motifs such as TCTGAA and TCACAG, associated with pluripotency transcription factors including OCT4, SOX2, ESRRB, and TCFCP2l1. Deep learning models further improved predictive accuracy and uncovered motifs enriched at the boundaries of bivalent peaks, suggesting positional specificity. These findings reveal that bivalent chromatin states are encoded by distinct sequence features.

Endocrine therapy resistance remains a major challenge in the treatment of advanced estrogen receptor positive (ER+) breast cancer. This can be driven by acquired mutations in the estrogen receptor gene (ESR1), such as Y537S or D538G, that results in constitutive estrogen-independent ER activity. Progesterone receptors (PR) are important modifiers of ER activity, in part via direct binding. We previously showed that PR mediates expansion of cancer stem-like cell (CSC) populations. In this study, we sought to define whether PR function changes in the context of ESR1 mutations. PR readily interacted with wild type (WT), but not Y537S or D538G ERs. RNA-seq and ChIP-seq studies demonstrated that ER+ breast cancer models expressing Y537S ER exhibited a distinct response to progesterone. CSC populations were enhanced in Y537S ER+ cells compared to WT ER+ cells. PR knockdown demonstrated that this property required PR expression but was unresponsive to antiprogestins. Moreover, we identified PR-dependent transcriptional programs such as the unfolded protein response (UPR) that can be leveraged to target CSCs in Y537S ESR1-mutant breast cancer. Our findings demonstrate an interplay between PR and mutant ER function and provide insight into PR-driven pathways that can be exploited as potential therapeutic avenues in ER+ breast cancer.