Integrins are transmembrane glycoproteins that act as essential adhesion receptors, allowing cells to communicate with the extracellular matrix (ECM). This interaction not only helps cells regulate adhesion, but also transmits signals that guide a variety of cellular processes. Once bound to the ECM, integrins play an important role in the cell differentiation, migration, proliferation, and survival, thereby maintaining tissue homeostasis. However, when integrin signaling becomes dysregulated, it is often associated with tumor development and progression. Abnormal integrin activity promotes uncontrolled cell growth, resistance to apoptosis, and the promotion of angiogenesis in tumors. They also provide resistance to therapies by disrupting growth suppressors. Due to their documented role in the process of tumorigenesis, integrins have become an interesting target for anticancer therapy. In this review, we discuss the function and structure of integrins, emphasizing how altered signaling in integrins consequently leads to cancer formation, progression, and metastasis. In addition, we review existing therapies that target integrins, discuss their limitations, and look at the future of integrin-based therapies. This review deepens our understanding of integrins, their role in cancer, and their possible role as a cancer biomarker.

Restoration of vascular structure and function is pivotal for neurological recovery following spinal cord injury (SCI), yet repairing the blood-spinal cord barrier (BSCB) remains a significant challenge. In this study, we demonstrate that exosomes (Exos) derived from endothelialized human umbilical cord mesenchymal stem cells (E‑UCMSCs) markedly enhance angiogenesis, improve vascular function, and promote neurological recovery. Human umbilical cord mesenchymal stem cells were induced to differentiate into endothelial‑like cells, and RNA‑sequencing revealed upregulation of genes associated with angiogenesis and vascular barrier integrity, alongside activation of relevant signaling pathways. In a co‑culture system, E‑UCMSC‑derived Exos significantly enhanced bEnd.3 cell migration and BSCB stability. To enable targeted delivery to neovasculature, Exos were engineered with RGD peptides (RGD‑E‑UCMSC‑Exos) via lentiviral modification. In vivo, these modified Exos preferentially localized to neovascular endothelial cells, promoted angiogenesis, reinforced BSCB integrity, and improved neurological outcomes in SCI mouse models. Proteomic profiling identified key angiogenic and barrier‑stabilizing factors carried by RGD‑E‑UCMSC‑Exos, including MMP2, FLT1, TIMP1, GAS6, CTHRC1, and NEO1, which likely mediate their therapeutic effects. Collectively, these findings provide novel mechanistic insights and establish a novel strong preclinical foundation for exosome‑based therapies in SCI.

Stem cell therapy has been utilized in the treatment of periodontitis. Recent studies have demonstrated that treatment with apoptotic mesenchymal stem cells (MSCs) exhibits immunomodulatory effects comparable to those of living MSCs. However, the effect of type 2 diabetes mellitus (T2DM) on the efficacy of apoptotic MSCs therapy for periodontitis remains poorly understood. In this study, a ligature-induced experimental periodontitis model was established in wild-type (WT) and db/db mice, followed by the injection of exogenous apoptotic periodontal ligament stem cells (PDLSCs). The results revealed suboptimal therapeutic outcomes with apoptotic PDLSCs in db/db mice. It was observed that the progression of periodontitis was associated with a reduction in the expression of developmental endothelial locus-1 (DEL-1) in experimental periodontitis model. Additionally, the expression of DEL-1 was partially restored during the resolution phase of inflammation. T2DM mice exhibited exacerbated alveolar bone loss and suppressed regeneration, accompanied by the inhibition of DEL-1 expression. In co-culture experiments, impaired macrophage efferocytosis of apoptotic PDLSCs was ameliorated by the addition of exogenous DEL-1 under lipopolysaccharide and high glucose conditions. Moreover, the co-administration of exogenous DEL-1 enhanced the therapeutic efficacy of exogenous apoptotic PDLSCs in db/db mice. In conclusion, diminished DEL-1 expression and impaired macrophage efferocytosis constrain the therapeutic potential of exogenous apoptotic PDLSCs in periodontitis with T2DM. The diminished therapeutic efficacy may be alleviated by the combination of exogenous DEL-1 and apoptotic PDLSCs, offering novel insights into potential therapeutic strategies for periodontitis with T2DM.

Mesenchymal stromal cells (MSCs) of various origins promote regeneration through paracrine signaling, immune modulation, and angiogenesis support. Premature ovarian failure (POF) is an excellent model to study coordinated ovarian and uterine repair, as cytotoxic injury simultaneously depletes ovarian follicles and impairs uterine receptors, resulting in infertility.

Intrauterine adhesions (IUA) arise from inflammation-driven fibrotic remodeling that limits endometrial repair. Mesenchymal stem cells (MSCs) and MSC-derived exosomes are promising, but direct comparisons by tissue source and delivery route are limited. To compare umbilical cord (UC) and adipose-derived MSCs versus their exosomes and to assess local intrauterine versus intravenous (IV) UC-exosome delivery in a rat IUA model. Thirty-five female Sprague-Dawley rats were randomized (n = 5/group) to negative control, positive control (ethanol-IUA), and five treatment arms (local UC-MSC, UC-Exo, Adipose-MSC, Adipose-Exo, and IV UC-Exo). IUA was induced with 0.3 mL 95% ethanol; treatments were administered 2 weeks later. Two weeks after treatment, uterine tissues underwent H&E/Masson's trichrome evaluation, epithelial and wall thickness measurements, and blinded 0-3 scoring of inflammation, vascular proliferation, and fibrosis. Positive controls showed severe fibrosis and luminal narrowing. All treated groups demonstrated improved architecture and reduced collagen deposition versus positive controls. Epithelial thickness was higher in treated groups but did not differentiate treatment arms; only negative vs. positive controls differed (p < 0.001). Uterine wall thickness increased in all treatment groups versus positive controls (overall p < 0.006), and local and IV UC-Exo groups were similar. Remodeling scores (inflammation/fibrosis) separated groups more clearly, with the most favorable combined profile in the Adipose-Exo group. MSC-based interventions (especially exosomes) attenuated inflammatory-fibrotic remodeling in this rat IUA model. Tissue source and product type influenced the repair profile while IV exosome delivery produced remodeling effects comparable to local administration.

Triple-negative breast cancer (TNBC) is a very aggressive form of breast cancer and Black American (BA) women face disproportionately higher mortality rates than White American (WA) women. The molecular mechanism behind this disparate clinical outcome remains poorly understood. We find that BA TNBC patients exhibit higher protein expression of KRT17 compared to WA TNBC and non-TNBC patients and correlates to poor distant metastasis-free survival. Mechanistic studies in metastatic mouse TNBC tumors with higher Krt17 demonstrates higher Wnt signaling targets, cancer stem cells (CSCs), which positively correlates to several metastasis signatures, supporting clinical data. Consistently, KRT17high BA patient tumors display higher activated Wnt signaling. Furthermore, Krt17 regulates Wnt signaling to drive recruitment of γδ T-cells in both mouse and human samples, which can be reversed by targeting Wnt signaling, identifying the Krt17-Wnt signaling axis as a critical driver of clinical disparities and a novel targetable vulnerability for BA TNBC patients.

Secondary primary malignancies (SPMs), new histologically distinct cancers that develop in patients with a history of primary tumors, represent a critical long-term adverse event in cancer survivorship. Although epidemiological studies have suggested associations between certain primary tumors and SPMs, systematic validation of their causal relationships is lacking. A Mendelian randomization analysis was employed to investigate the causal links between primary tumors and SPMs. This study systematically examined cancers spanning eight major human organ systems using data from two large European prospective cohorts: UK Biobank (31 cancer types) and FinnGen (28 cancer types). A meta-analysis of the two cohorts revealed that gastric cancer (GC) had a significant causal relationship with an increased risk of secondary esophageal cancer (odds ratio [OR] = 1.29, 95% confidence interval [95% CI]: 1.13-1.46, P < 0.001) and rectal cancer (OR = 1.13, 95% CI: 1.07-1.21, P < 0.001). Further, a single-cell sequencing analysis identified PLK1+ cancer stem cells as potential drivers of this causal relationship. Our findings provide important genetic evidence of the causal links between GC and specific SPMs, which may inform the optimization of precise follow-up strategies for GC survivors.

YAP1 signaling is essential for development but its specific roles in early embryogenesis remain poorly understood. To shed light on this, we analyze YAP1's role in regulating the pluripotency of the mammalian epiblast, using scRNAseq approaches. Conditional deletion of Yap1 in the mouse epiblast (Sox2-Cre) alters the expression of signaling genes, including Nodal, Wnt3, and Fgf8. Accordingly, Yap1 loss leads to enhanced differentiation of the epiblast toward primitive streak lineages, as evidenced by the upregulation of T/Brachyury and Eomes genes. A proximity labeling assay in human pluripotent stem cells, followed by biochemical assays and molecular modeling predictions, reveals that YAP1 cooperates with QSER1 protein to regulate lineage genes. Our analysis shows that YAP1:TEAD4 enhancers recruit QSER1 to prevent RNA Polymerase II recruitment. QSER1 depletion, similar to YAP1, increases NODAL gene expression and leads to hyperactive NODAL signaling during human embryonic stem cells differentiation. Overall, our findings define a role of YAP1 in the epiblast in vivo and uncover an interplay with QSER1 controlling the activity of developmental signaling pathways in pluripotent cells.

The safety of multi-dose mesenchymal stem cell (MSC) regimens has seldom been systematically investigated. The PRIME-HFrEF (Prospective Randomized Controlled Study of Multiple Intravenous Infusions of Umbilical Cord-derived MSCs in Patients with Heart Failure and Reduced Ejection Fraction) trial was a single-center, randomized, placebo-controlled, investigator-initiated study (ClinicalTrials.gov identifier: NCT04992832) that enrolled 40 patients. The trial aimed to evaluate the safety of three intravenous infusions of Umbilical Cord-derived MSCs (UC-MSCs) administered at six-week intervals in patients with heart failure and reduced ejection fraction (HFrEF), while also collecting exploratory efficacy data. The primary safety endpoint was the incidence of serious adverse events (SAEs), and the primary efficacy endpoint was the change (Δ) in left ventricular ejection fraction (LVEF). Secondary efficacy endpoints included changes in right ventricular (RV) end-systolic and end-diastolic volumes (ESV and EDV). Thirty-nine patients completed 12 study visits over a 360-day follow-up period or until death. The incidence of SAEs did not differ significantly between treatment groups. However, UC-MSC-treated patients exhibited elevated D-dimer levels, suggesting a treatment-associated increase in coagulability. D-dimer levels were negatively correlated with LVEF, and no significant difference in ΔLVEF was observed between groups. In contrast, the improvement in ΔRVESV was significantly greater in the UC-MSC group than in placebo-treated patients (P = 0.033). In summary, multi-dose UC-MSC infusions were safely administered to patients with HFrEF and were associated with improvements in RV volumes. However, these benefits were accompanied by transient increases in coagulability, which may have attenuated potential improvements in left ventricular contractile function.

Primary human hepatocyte (PHH)-derived organoids form grape-like clusters with proliferative capacity, hepatocyte functionality, and multipolar polarity, serving as valuable models for liver biology and therapeutics. However, deriving comparable organoids from human embryonic stem cells (hESCs) remains difficult. Here, we established a defined system to differentiate hESC-derived hepatoblast organoids into hepatocyte organoids (heporgs) with two morphologies: spheroid-like (S-heporgs) and grape-like (G-heporgs). S-heporgs predominated but displayed senescence and apoptosis, generating an inflammatory niche that facilitated G-heporg emergence. G-heporgs exhibited mature hepatocyte markers, binucleation, proliferative activity, and multipolar structures with branched bile canaliculi, closely resembling PHH-derived organoids. Transcriptomic and functional analyses identified IGF2-driven PI3K-AKT activation as essential for G-heporg formation, while YAP signaling supported their long-term expansion. IGF2 supplementation combined with YAP agonist treatment enabled stable G-heporg propagation for over 60 days. These expandable G-heporgs demonstrated regenerative competence and faithfully recapitulated hepatocyte polarity and functional bile canalicular networks, as evidenced by ATP7B copper-dependent translocation and drug-induced cholestasis assays. Our findings establish hESC-derived G-heporgs as expandable, functional counterparts to PHH-derived organoids, providing a robust platform for studying hepatocyte polarity, metabolite trafficking, and liver disease modeling.

Preeclampsia, a life-threatening hypertensive disorder of pregnancy, is a leading cause of maternal and perinatal morbidity and mortality. Its early-onset form (EO-PE), requiring delivery before 34 weeks of gestation, is particularly severe and closely linked to defective trophoblast differentiation. Here, we identify BRCA1-associated protein 1 (BAP1) and its cofactors ASXL2 and ASXL3 as upregulated in EO-PE placentas. Enforced BAP1 expression in human trophoblast stem cells reinforced epithelial identity, enhanced adhesion, and impaired both extravillous trophoblast differentiation and syncytiotrophoblast formation. Integrated transcriptomic and proteomic analyses revealed suppression of lineage-specific pathways alongside maintenance of progenitor-like and pro-inflammatory signatures. In trophoblast organoids, an excess of BAP1 disrupted syncytial maturation and induced interferon-driven pathways overlapping with EO-PE transcriptomes. Together, these findings establish BAP1 as a key regulator of human trophoblast differentiation and implicate its dysregulation in the pathogenesis of EO-PE, providing mechanistic insight into the cellular basis of placental dysfunction.

Although p53 plays a vital role in tumor suppression, the molecular programs underlying its tumor suppressor function remain incompletely understood. Recent work coupling genetically engineered mouse models and single-cell RNA sequencing has illuminated new aspects of p53 function in governing cell state changes. During both lung adenocarcinoma suppression and lung injury repair, p53 acts in a plastic transitional cell state to drive alveolar type 1 cell differentiation, while p53 deficiency causes transitional cell persistence and cancer progression or tissue damage. New insights into p53 function in injury repair in other tissues have also emerged, including in injury-induced intestinal revival stem cells. These studies underscore the importance of p53 in specific plastic states, where it coordinately enforces differentiation and restrains lineage infidelity during tissue healing and cancer suppression.

Regulatory circuits driving regional cell fate specification and lineage restriction decisions are not fully understood. The molecular mechanisms by which Hedgehog signaling controls lineage segregation in the posterior foregut remain unclear. Here, we employed bulk and single-cell transcriptomics, microscopy, physiology, and genetic cell tracing in differentiating human induced pluripotent stem cells and mouse transgenic models to uncover an essential autoregulatory loop between Hnf1a and Hedgehog signaling. Hnf1a abrogation initiates a domino effect leading to a drift in foregut cell specification toward duodenal cell identity instead of pancreatic fate. This was replicated in vivo in mice. We show that a common dominant negative Hnf1a mutation disrupts GLI3 processing by cilium proteins in the posterior foregut, thus impeding its own upregulation in response to Hedgehog signaling inhibition. In the context of this defective loop, we identified a network of deregulated selector genes responsible for the lineage segregation changes. These may be relevant for changes in the liver, pancreas, and gut seen in patients with mutations in HNF1A.

Perinatal exposure to different photoperiods can lead to differences in behaviour and sleep during adulthood. Information about acute photoperiod is first processed in the brain through the suprachiasmatic nuclei (SCN), the primary brain nuclei responsible for circadian rhythms. In these nuclei, the photoperiodic information is coded and related to the excitatory/inhibitory (E/I) balance of GABA. We investigated in mice, whether behavioural effects of perinatal photoperiod (PNP) in adulthood are represented in a difference in the E/I balance in SCN cells. We exposed males and females to a short or long PNP from conception until weaning, followed by an intermediate photoperiod for 4 weeks. Subsequently, we measured neuronal calcium responses in response to GABA in SCN brain slices. We compared the E/I ratio of the neuronal calcium responses, response type distribution and the baseline intracellular calcium concentration ([Ca2+]i) between the two groups. Mice from the long and short PNP had a similar E/I ratio and distribution of response types. There was no significant difference in [Ca2+]ibetween the PNPgroups, but the cell response type was correlated with baseline [Ca2+]i. On average, baseline [Ca2+]iof inhibitory cells was higher than that of excitatory cells. PNP does not seem to affect GABAergic E/I balance of calcium responses in the SCN in the long-term. This means that previously found behavioural differences in adult mice caused by PNP are probably not mediated through SCN E/I balance. It is possible that the observed long-term differences stem from changes in other brain nuclei or systems.

Cracked teeth syndrome is a common tooth hard tissue injury, often combined with pulp and/or periodontal symptoms.This study aimed to investigate the clinical characteristics and progression patterns of such teeth and to identify independent factors influencing the one-year success rate of early intervention, providing a theoretical basis for precise treatment strategies.

Hematopoietic stem cell (HSC)-targeted gene editing holds significant potential for treating hereditary hematopoietic disorders, yet the efficient and safe delivery of gene editing tools into HSCs remains a critical challenge. Lipid nanoparticles (LNPs) have emerged as a promising platform for nucleic acid delivery; however, achieving high transfection efficiency in HSCs remains challenging. In this study, we developed HSC-targeted LNPs by integrating Bayesian optimization with our functional amino lipids. The optimized LNPs exhibited markedly improved transfection efficiency while preserving cell viability, surpassing earlier formulations. Using these LNPs, we achieved ex vivo TP53 gene editing in cord blood (CB) CD34⁺ cells with up to 40% on-target editing efficiency. Additionally, one LNP demonstrated efficient RNA delivery into primary human monocytic leukemia cells. These results highlight the potential of machine learning-guided LNP design for advancing HSC-targeted therapies and underscore the promise of LNP-based gene editing platforms to treat hereditary and malignant hematopoietic disorders.

This study aimed to evaluate the effect of blue light therapy on tumor behavior and cancer stem cells properties in oral squamous cell carcinoma (OSCC).

The UKBi015-B-6 human induced pluripotent stem cell (hiPSC) line was generated by targeted insertion of a doxycycline-inducible TRE3G expression cassette encoding the ultrasensitive genetically encoded fluorescent voltage indicator rEstus into the AAVS1 locus. This hiPSC line enables controlled, reversible induction of rEstus expression to non-invasively monitor membrane potential dynamics in a human cellular background. The resulting platform allows high-throughput optical electrophysiology across diverse hiPSC-derived lineages, including cardiomyocytes, neurons, and non-excitable cells, thereby facilitating drug screening, developmental studies, and quantitative analysis of bioelectrical signaling under standardized, human-relevant conditions.

Genetically engineering human pluripotent stem cell (hPSC)-derived islets is a promising strategy for improving transplantation for diabetes cell therapy; however, genetic perturbations that modulate transplantation outcomes have yet to be systematically explored.