The generation of mature, functional cardiomyocytes from human pluripotent stem cells (hPSCs) remains a major challenge in cardiac regenerative medicine. While fibronectin and Matrigel individually support cardiomyocyte differentiation, their combined potential, particularly when integrated with temporally optimized small-molecule modulation of developmental signaling pathways, has not been systematically investigated.

Biomaterial-associated infections pose a significant challenge, impairing tissue integration and frequently leading to implant failure and revision surgeries. Upon implantation, host cells and bacteria compete for colonizing the implant, in a process known as the "race for the surface," which is critical for the long-term survival of the implant. However, conventional biomaterials commonly fail to simultaneously promote cellular integration and prevent infections. To address this issue, we developed a protease-degradable PEG hydrogel functionalized with the RGD integrin-binding motif to enhance cell adhesion and the antimicrobial peptide hLf1-11 (LF) to provide antibacterial activity. This hydrogel was crosslinked using a protease-sensitive peptide (VPM), enabling enzymatic degradation, and dynamic adaptation to the cellular microenvironment (PEG-RGDLF). Non-bioactive but degradable (PEG-50) and neither bioactive nor degradable (PEG-0) hydrogels were included as controls. PEG-RGDLF hydrogels showed an adequate internal structure, with well-defined porosity, swelling capacity, and protease-mediated degradation rate. PEG-RGDLF improved the adhesion, spreading, proliferation, and ALP activity of human bone marrow mesenchymal stem cells (hBMSCs) and reduced the viability and adhesion of Gram-positive and Gram-negative bacteria, significantly affecting their morphology. Furthermore, co-culture models were established under two clinically relevant scenarios: "pre-infection" and "post-infection". In both settings, PEG-RGDLF hydrogels supported enhanced cellular responses, with hBMSCs displaying an elongated morphology and improved adhesion. In summary, by integrating cell-instructive and antibacterial properties with a controlled degradation mechanism, this multifunctional hydrogel presents a robust platform for implant-based therapies, actively promoting tissue regeneration while preventing infection, thus addressing the persistent challenge of implant-associated infections in regenerative medicine and clinical applications.

Angiogenesis, the newly formed blood vessels from preexistent ones, is essential for the progression and potential resolution of diseases. Here we introduce a view of arteriolar angiogenesis (the growth of new small arteries), and define a concept that molecular signaling balance between pro- and anti-angiogenic signaling determines angiogenic phenotype. We discuss VEGF and CXCL12 signaling pathways in vascular endothelial cells essential for arteriolar angiogenesis, which is potentially regulated by PKD1-mediated Notch1-CD36 signaling, emphasizing the function of arteriolar angiogenesis as a vascular niche/microenvironment under pathological conditions. We delineate implications of arteriolar angiogenesis in cancer stem cell development and anti-angiogenic immunotherapeutic strategies, highlighting anti-angiogenic strategy in combination with immune checkpoint blockade in pancreatic cancers. In summary, this review article seeks to develop the concept of arteriolar angiogenesis and yield insights into developing novel vascular targeting and immune therapies to cure cancers and cardiovascular and neurovascular diseases manifested with abnormal angiogenesis.

Sarcopenia (SP) is characterized by progressive loss of skeletal muscle mass and function, and is a significant health burden in an aging society. Existing therapies have limited effectiveness. While ferroptosis plays a key role in sarcopenia, its regulatory mechanism remains unclear. As a traditional tonifying Chinese medicine, Cistanche deserticola has antioxidant potential due to its active ingredient, echinacoside (ECH); however, its mechanism of action in sarcopenia remains to be elucidated.

Photorhabdus bacteria live in mutualistic relationships with Heterorhabditis nematodes, and together, they act as effective insect pathogens. These bacteria produce a diverse array of lectins, sugar-binding proteins that are believed to play crucial roles in the complex tripartite interaction among Photorhabdus, nematodes, and their insect hosts. One such lectin, Photorhabdus laumondii tumor necrosis factor (TNF)-like lectin (PLTL), identified in Photorhabdus laumondii subsp. laumondii TTO1, exhibits notable sequence similarity to the N-terminal domain of the BC2L-C lectin (BC2L-CN), a TNF-like lectin recognized for its specificity toward fucosylated glycans associated with human embryonic stem cells and certain cancers. Through glycan array analysis and surface plasmon resonance, we identified PLTL's binding preference for branched histo-blood group oligosaccharides. The crystallographic structure of PLTL in complex with the BLeb pentasaccharide reveals a network of direct and water-mediated hydrogen bonds simultaneously stabilizing the Fucα1-2 and Galα1-3 moieties, which define its narrow glycan specificity. A combination of mass spectrometry, protein crystallography, and analytical ultracentrifugation showed a unique hexameric PLTL architecture stabilized by intermolecular disulfide bridges. Our data suggest that PLTL may contribute to the mutualistic relationship between Photorhabdus and its nematode symbiont, Heterorhabditis bacteriophora, rather than playing a role in the interaction with the insect host. This study provides a structural and functional characterization of PLTL, a newly identified member of the TNF-like lectin family. Comparative analysis with BC2L-CN highlights both conserved and distinct structural features, suggesting potential applications in glycan recognition-based diagnostics or biotechnological tools beyond its biological role. Our findings underscore its complex glycan specificity and offer insights into its potential role in Photorhabdus-nematode symbiosis.

The BCR::ABL1 tyrosine kinase inhibitors (TKIs) in CML represent a paradigm for molecularly targeted therapy. However, clinical outcomes - rate/depth of response, treatment-free remission (TFR), progression to blast crisis (BC) - and adverse events vary among patients. While additional somatic mutations have been invoked to explain varying clinical outcomes, we here propose a complementary perspective based on single-cell omics approaches that have enabled unprecedented resolution of the cellular ecosystems, including their composition, interactions, and activity. In treatment-naïve chronic phase (CP) patients, this has revealed differences in the growth-rate of BCR::ABL1+ clones, ratio of TKI-insensitive leukemic stem cells (LSCs) to residual hematopoietic stem cells (HSCs), and immune cell composition - factors that collectively contribute to variability in therapy efficacy. Together these findings suggest that cellular heterogeneity serves as a foundation of clinical outcome in CML. Patients who remain in CP exhibit an erythroid signature in LSCs, while those progressing to BC manifest an inflammatory profile, additional mutations, and expansion of early progenitors. Deep responders with active natural killer, and regulatory T-cells are more likely to sustain TFR. Similarly, the outcomes of donor lymphocyte infusion after allogenic stem cell transplantation are heterogenous and reflect differences in pre-existing T-cell clonotypes, their expansion and interaction with leukemic cells in responders versus non-responders. Here, we summarize key insights from sc-omics in CML and propose an actionable roadmap to further leverage these technologies. This includes mechanistically explaining heterogeneity, predicting therapy response and BC, tracking leukemogenic clones longitudinally, targeting TKI-insensitive LSCs, and restoring hematopoiesis from residual HSCs.

Dental stem cells (DSCs) hold immense potential in regenerative medicine due to their unique properties, including superior proliferative and differentiation capacities, robust immunomodulatory functions, and resilience to aging. However, the aging process profoundly impairs their functionality, diminishing their regenerative potential and limiting their clinical utility. This review provides a systematic examination of the mechanisms underlying DSC aging, focusing on disrupted signaling pathways, metabolic dysregulation, and epigenetic modifications, as well as the regulatory roles of non-coding RNAs and critical proteins. It further investigates the key intrinsic and extrinsic factors driving this process, offering a comprehensive perspective on the interplay between cellular and systemic influences. Building on this foundation, the review explores innovative strategies to mitigate age-related decline in DSCs, emphasizing approaches that target the extracellular matrix, mitochondrial dysfunction, and key molecular pathways. Finally, it addresses the challenges in translating these findings into clinical applications, such as inter-individual variability and systemic influences, and advocates for multidisciplinary approaches to enhance therapeutic outcomes. Collectively, this review provides a critical framework for advancing the clinical translation of DSC-based therapies, with broader implications for regenerative medicine in aging contexts.

In psoriasis, dendritic cells activate T cells, which then release excessive pro-inflammatory cytokines, leading to abnormal growth of keratinocytes in the epidermis. At the same time, anti-inflammatory cytokines attempt to restore balance. In reality, these immune processes are not immediate; they involve biological time gaps due to signal processing, cell communication, and cytokine feedback. Such immune-related delays may play a key role in triggering unstable or oscillatory behavior observed in psoriasis flare-ups. In this study, we present and analyze a mathematical model of psoriasis that explicitly includes two intracellular immune-mediated time delays to demonstrate their biological significance in disease progression. The model captures the interactions among T cells, dendritic cells, keratinocytes, and local mature stem cells. It features two cytokine-mediated feedback loops between T cells and dendritic cells, while stem cells attempt to regulate the immune response through anti-inflammatory signaling. A key challenge is identifying the critical time delays that modulate these interactions. To address this, we introduce two different delays in different interaction terms of the model system. We test the hypothesis that these delays can critically influence the onset and persistence of psoriatic pathology mathematically. Using stability analysis of the interior equilibrium, we determine parametric relations, their ranges, and delay thresholds that give rise to Hopf bifurcations, thereby linking delays to disease and deriving conditions of instability. Our analysis demonstrates that both immune-mediated delays critically influence system stability, with threshold values of [Formula: see text] and [Formula: see text] inducing oscillations through Hopf bifurcations. Further, we apply optimal control strategies on the delayed system using the effects of two biologic agents: TNF-α and IL-17 inhibitors. Incorporation of optimal controls effectively stabilizes the immune response. Numerical simulations support these analytical findings and show that biologic interventions can effectively reduce keratinocyte density. Inclusion of immune-related delays, based on both analytical and numerical results, provides a more realistic understanding of psoriasis dynamics and helps optimize therapeutic approaches for psoriasis management.

Patient-specific, human-based cellular models integrating a biomimetic blood-brain barrier, immune, and myelinated neuron components are critically needed to enable accelerated, translationally relevant discovery of neurological disease mechanisms and interventions. To construct a human cell-based model that includes these features and all six major brain cell types needed to mimic disease and dissect pathological mechanisms, we have constructed, characterized, and utilized a multicellular integrated brain (miBrain) immuno-glial-neurovascular model by engineering a brain-inspired 3D hydrogel and identifying conditions to coculture these six brain cell types, all differentiated from patient induced pluripotent stem cells. miBrains recapitulate in vivo-like hallmarks inclusive of neuronal activity, functional connectivity, barrier function, myelin-producing oligodendrocyte engagement with neurons, multicellular interactions, and transcriptomic profiles. We implemented the model to study Alzheimer's Disease pathologies associated with APOE4 genetic risk. APOE4 miBrains differentially exhibit amyloid aggregation, tau phosphorylation, and astrocytic glial fibrillary acidic protein. Unlike the coemergent fate specification of glia and neurons in other organoid approaches, miBrains integrate independently differentiated cell types, a feature we harnessed to identify that APOE4 in astrocytes promotes neuronal tau pathogenesis and dysregulation through crosstalk with microglia.

Human adipose-derived stem cells (hADSCs) exhibit antibacterial properties, but their effectiveness against bacteria resistant to LL-37- a natural human antimicrobial peptide important in the immune defense- is not fully understood. Some bacteria have evolved mechanisms to evade the antimicrobial effects of LL-37. We aimed to investigate the antibacterial efficacy of hADSCs against Pseudomonas aeruginosa, Proteus mirabilis, and methicillin-resistant Staphylococcus aureus (MRSA), focusing on the antimicrobial peptide LL-37. hADSCs were isolated from human adipose tissue, identified by flow cytometry and differentiation assays, and divided into three groups: unstimulated, stimulated with interferon-gamma (IFN-γ; 100 ng/mL) or Escherichia coli (300 CFU). LL-37 gene expression was measured by qPCR after 6 hours in the E. coli stimulated group. LL-37 peptide levels were quantified by ELISA in conditioned media from unstimulated, IFN-γ stimulated cells, both before and after incubation with pathogens (300 CFU). Antibacterial activity was assessed by colony counting incubation following incubation of conditioned media with bacteria. Conditioned media from both unstimulated and stimulated hADSCs significantly inhibited growth of all three pathogens (P < 0.05), with highest efficacy against P. aeruginosa (86.4% inhibition), followed by MRSA (74%) and P. mirabilis (63%). LL-37 gene expression increased after bacterial stimulation, and also LL-37 concentrations increased in conditioned media but significantly decreased after bacterial exposure (P < 0.05). Despite this reduction, antibacterial activity persisted. hADSC-conditioned media exert potent antibacterial effects against LL-37-resistant pathogens, even when LL-37 levels are reduced after bacterial exposure. These findings support the therapeutic potential of hADSC secretomes, particularly for infections caused by bacteria capable of reducing LL-37 levels.

Connective tissue disease-associated interstitial lung disease (CTD-ILD) is a subtype of ILD that arises due to autoimmune disorders. Unlike other ILDs, CTD-ILD is strongly linked to genetic predisposition, environmental factors, and dysfunction of the immune system. The primary pathogenesis involves immune cells erroneously attacking lung tissues in the context of autoimmune diseases; however, the precise pathogenic mechanisms remain elusive. As core driving factor of autoimmune diseases, immune cells play a pivotal role in the development of CTD-ILD. Neutrophils, key components of the innate immune system, are responsible for defending against infections and are critical in orchestrating immune responses. Notably, neutrophils can combat infections through phagocytosis or by releasing neutrophil extracellular traps (NETs).Recent studies have revealed significant dynamic changes in the quantity and function of neutrophils during the progression of CTD-ILD, highlighting their crucial role in this process. This review not only summarises the clinical manifestations of ILD associated with autoimmune diseases but also investigates the role of neutrophils in autoimmune diseases and inflammation, offering insights into the development of novel therapeutic strategies targeting abnormal neutrophil activity in CTD-ILD.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by the rapid proliferation of immature myeloid cells and poor clinical outcomes. Despite conventional treatments such as chemotherapy and hematopoietic stem cell transplantation, relapse and resistance remain major challenges. Epigenetic alterations-particularly dysregulated DNA methylation and microRNA (miRNA) expression- are crucial in AML pathogenesis.

Chromatin regulation of transcriptional enhancers plays a central role in cell fate specification and differentiation. However, how the coordinated activity of transcription factors and chromatin-modifying enzymes regulates enhancers in neural stem cells and dictates subsequent stages of neuronal differentiation and migration is not well understood. The histone methyltransferase PRDM16 is expressed in neural stem cells of the developing mouse and human cerebral cortex, and is essential for determining the position of upper-layer cortical neurons. Here, we report that PRDM16 interacts with C-terminal binding protein 1 (CtBP1) and CtBP2 to control the transcriptional programs of cortical neurogenesis and regulate upper-layer neuron migration. PRDM16 and CtBP1/2 co-regulate enhancers by interacting with histone deacetylase 1 (HDAC1), HDAC2 and lysine-specific demethylase 1 (LSD1). In addition, our results suggest that the CCCTC-binding factor CTCF plays a key role in recruiting CtBP1/2 to cortical enhancers. These findings underscore that reduced interactions between PRDM16 and ubiquitous chromatin regulators may contribute to neurodevelopmental deficits in individuals with PRDM16 haploinsufficiency.

Amphibians display a remarkable capacity for tissue regeneration, with some able to regrow entire limbs. In mammals, while tissues such as skin, bones and skeletal muscles are capable of repair following injury, true multilineage regeneration is rare and restricted to the distal region of the digit tip. Although the mechanisms governing successful tissue repair and regeneration are still coming to light, it is now appreciated that innervation by local nerves is a necessary component of the regenerative microenvironment. In this Review, we examine the current state of the literature that identifies the role of axon-derived signals, Schwann cells and nerve-derived mesenchymal cells as direct and indirect supporters of tissue repair and regeneration. We will also discuss how these cells function under pathological conditions or situations of aberrant tissue repair. Altogether, these findings underscore the significance of elucidating the role of the peripheral nervous system in tissue homeostasis and repair, with potential implications for the development of targeted therapeutic interventions and regenerative medicine strategies.

B-cell maturation antigen (BCMA) directed chimeric antigen receptor T-cell therapy (CAR-T) has transformed the treatment of relapsed/refractory multiple myeloma (RRMM), yet relapse is still common for most patients. A variety of different salvage treatment strategies have been studied in the last several years to address several resistance mechanisms that lead to relapse after BCMA CAR-T. To date, there are no clear guidelines regarding treatment sequencing strategies for salvage therapy. This review will investigate the current landscape of available salvage therapies and data supporting their use, as well as possible treatment sequencing strategies to maximize clinical outcomes in this difficult-to-treat population.

Recanalization intervention has improved patient outcomes in ischemic stroke, but severe ischemia-reperfusion injury remains a major challenge, necessitating effective pharmacotherapy to reverse neuronal damage and recover neurofunctions. Traditional neuroprotection strategies aim to inhibit neuronal death, and are still insufficient to recover long-term neurological dysfunctions. In this work, it is found that carbon monoxide (CO) as a neuromodulator exerts a new role in promoting neurogenesis via the crosstalk between brain endothelial cells and neural stem cells, which is beyond its recognized roles in anti-inflammation and anti-oxidation. This reveals a new possibility to address the above challenge. Furthermore, this work develops a biomimetic and reactive oxygen species-activated CO nanogenerator to effectively penetrate blood-brain barrier, arrive in stroke-affected regions, and release CO in a controlled manner for an innovative dual-channel therapy strategy via co-driving neuroprotection and neurogenesis. This strategy further demonstrates its therapeutic effects on reversing brain injury and recovering neurofunctions in a mouse ischemic stroke model. This work reveals an important new role of CO, and further offers an advanced pharmacotherapy for long-term neurological dysfunctions in ischemic stroke.

Meningiomas are the most common primary central nervous system tumors, arising from arachnoid cap cells and typically following a benign clinical course. However, a minority of cases-particularly higher-grade meningiomas-exhibit aggressive behavior, including local invasion, recurrence, and, in rare instances, extracranial metastasis. Metastatic meningioma, defined as dissemination beyond the cranial and spinal compartments, remains exceptionally uncommon, with reported incidence ranging from 0.1% to 0.76%. Common metastatic sites include the lungs, bone, liver, and lymph nodes, although virtually any organ may be involved. Proposed mechanisms of spread include hematogenous dissemination via venous sinuses, cerebrospinal fluid seeding in high-grade variants, and possibly lymphatic dissemination. Imaging features that suggest metastatic potential include irregular margins, heterogeneous enhancement, prominent peritumoral edema, and bone destruction. Advanced modalities, such as gallium 68 DOTA-Tyr3-octreotide PET/CT and fluorine 18 fluorodeoxyglucose PET, play an increasing role in detecting and characterizing both known and occult metastatic lesions. Molecular alterations, including TERT promoter mutations, CDKN2A/B deletions, and somatostatin receptor 2 overexpression, are increasingly recognized as important markers for risk stratification and targeted therapy selection. Management requires a multimodal approach, including surgery, radiation therapy, and emerging systemic options such as peptide receptor radionuclide therapy and immune checkpoint inhibitors. Given the rarity and clinical complexity of this entity, radiologists must maintain a high index of suspicion, particularly while evaluating in high-grade or recurrent meningiomas. Keywords: Meninges, Brain/Brain Stem, Neuro-oncology, Molecular Imaging, Metastatic Meningioma, DOTATATE, High-Grade Meningioma, Somatostatin Receptor Imaging, SSTR, Peptide Receptor Radionuclide Therapy © RSNA, 2025.

This study presents an examination of whether the double overexpression of ZNF746 and cellular prion protein (PrPC) genes in rat adipose-derived mesenchymal stromal cells (ADMSCs) (ie, MSCDGe-OVE) offered enhanced protection to the livers of rats against ischemia‒reperfusion (IR) injury. The in vitro results revealed that compared with those of rat ADMSCs, cell activities (viability/proliferation/growth/cell cycle process) were significantly upregulated by the overexpression of either gene in rat ADMSCs and were further significantly increased by MSCDGe-OVE, whereas the expression of biomarkers of oxidative stress/ROS/apoptosis/fibrosis/autophagy decreased with increasing cell viability among the groups (all P < 0.001). Male adult SD rats (n = 50) were equally categorized into groups 1 (sham-operated-control), 2 (IR), 3 (IR-MSCOVE-PrPC), 4 (IR-MSCOVE- ZNF746), and 5 (IR-MSCDGe-OVE), and livers were harvested by day 3. By day 3, the number of circulatory inflammatory/immune cells, protein expression of oxidative stress/apoptotic/fibrotic/mitochondrial damage/autophagic biomarkers, and cellular levels of DNA damage/fibrosis/inflammation in the liver parenchyma were lowest in group 1, highest in group 2 and significantly lower in groups 3/4 than in group 5 (all P < 0.0001). Liver fibrosis detected by ultrasound and the liver injury score displayed identical patterns of circulatory levels of immune cells among the groups (all P < 0.0001). Upstream and downstream inflammatory and cell-stress signaling pathways were identified as playing crucial roles in acute liver IR injury. In conclusion, MSCDGe-OVE enhanced cell proliferation and growth and ameliorated IR-induced liver damage.

Stress urinary incontinence (SUI) is characterized by the involuntary leakage of urine from the urethra due to increased abdominal pressure. The complex pathophysiological mechanisms underlying SUI have driven the development of diverse therapeutic strategies. Current treatment options encompass both conservative and surgical interventions, with surgical approaches generally often regarded as the most effective option approach for severe cases. However, many surgical techniques carry significant risks of complications. In this context, urethral injection therapy, primarily based on stem cell-mediated regenerative approaches, has emerged as a minimally invasive alternative. Stem cell therapies leverage their multipotent differentiation capacity and paracrine signaling pathways to directly target the pathophysiological contributors to SUI, including urethral sphincter dysfunction, neuromuscular junction degeneration, and imbalances in elastin and collagen homeostasis. This narrative review provides a critical evaluation of current stem cell-mediated regenerative strategies for SUI, focusing on cellular mechanisms and the therapeutic effects driven by paracrine signaling. Recent clinical advances, unresolved scientific controversies, and innovative combinatorial delivery systems incorporating targeted therapeutic approaches are analyzed. Despite challenges remain, such as determining the optimal stem cell dosage and improving in vivo survival rates, ongoing research offers valuable insights into the development of cell-free bioactive derivatives, advanced combination delivery systems, and precise molecularly targeted therapies.