Fatty acid (FA) desaturation is a key determinant of membrane physicochemical properties and influences multiple aspects of cellular viability and stress responses. A substantial body of evidence indicates that certain cancer cells exhibit heightened sensitivity to perturbations in FA desaturation, a feature that is also observed in cells with high differentiation potential. This sensitivity has been linked to changes in membrane composition, endoplasmic reticulum (ER) homeostasis, and signaling pathways. Insights from stem cell systems highlight the cell-type-specific nature of these processes. In particular, trophoblast stem cells (TSCs), which exhibit high monounsaturated fatty acid (MUFA) abundance, display opposite dependencies on MUFAs and express a distinct variant of stearoyl-CoA desaturase (SCD), compared with embryonic stem cells (ESCs), which are characterized by lower MUFA levels, suggesting that optimal MUFA to saturated fatty acid (SFA) ratios are required in a cell-type-specific manner. In this review, we synthesize current knowledge on the molecular and biophysical mechanisms linking FA desaturation to cellular viability, including its effects on membrane fluidity, protein function, and signaling pathways. Where stem cell-specific mechanistic data are limited, we draw on broader cellular systems to inform these mechanisms. We propose a "desaturation window" model, whereby deviations in either direction: excess saturation or insufficient saturation, disrupt membrane homeostasis and compromise cell survival. A clearer understanding of the mechanisms governing cell viability in response to FA desaturation may help explain differential sensitivities to lipid desaturation and inform therapeutic strategies in cancer and regenerative contexts.

Dexamethasone-loaded liposomes composed of DSPC/Chol/PEG (85/10/5 mol%) and dispersed in a 16.25% Poloxamer 407 (P407) hydrogel were developed as a local therapeutic strategy for sound trauma-induced sensorineural hearing loss (SNHL). Physicochemical and rheological characterization demonstrated that the formulation remains injectable at room temperature and undergoes rapid in situ gelation within 8.0 ± 3.8 min in the middle ear cavity at 37°C. Incorporation of liposomes into the 16.25% P407 hydrogel significantly prolonged the in vitro release of encapsulated dexamethasone compared to the free drug solution. Cryogenic transmission electron microscopy (cryo-TEM) revealed multilamellar and multivesicular liposomal vesicles, consistent with sustained release behavior. The formulation was well tolerated by HEI-OC1 cells and cochlear explants and conferred a significant otoprotective effect, as evidenced by preservation of synaptic surface area following kainic acid-induced excitotoxic injury.

Yak milk is recognized for its superior nutritional quality, yet the biological basis underlying its high milk protein content remains poorly understood, particularly regulatory mechanism of small intestine. This study compared the major nutrients and amino acid composition of raw milk among yaks, cattle-yaks and cows, revealing the characteristics of high protein and rich amino acids in yak milk. We annotated 16 major cell types from a total of 27,026 cells by constructing the first single-cell transcriptome atlas of yak small intestine. Among them, intestinal stem cells and tuft cells exhibited strong proliferation and differentiation potential, contributing to the maintenance of efficient protein absorption. Our multi-strategy GWAS framework by integrating genomics and scRNA-seq data further identified candidate genes associated with milk protein content (SCP2, ETV6, ACSS2, and WWOX), which are mainly involved in amino acid utilization and energy regulation. Notably, WWOX was consistently identified across multiple analyses. It may enhance protein absorption efficiency in the small intestine, thereby providing sufficient substrates for milk protein synthesis and ultimately increasing milk protein content in yaks. In summary, these findings demonstrate that functional specialization of the small intestine contributes to enhanced milk protein content in yaks and highlight the importance of integrating phenotypic, cellular, and genetic data to understand complex traits. This work provides a novel perspective on the regulation of milk protein and offers potential targets for genetic improvement of milk quality in yaks and other ruminants.

Hydrogels are promising platforms for the controlled release of drugs, biologics, and living cells, but conventional statically crosslinked networks face important translational limitations, including poor injectability, brittle mechanical behavior, and an inability to recapitulate the time-dependent mechanics of native tissues. Dynamic bonding provides a powerful strategy to overcome these limitations while expanding the design space for controlled release. Non-covalent interactions, including hydrogen bonding, host-guest complexation, metal-ligand coordination, and electrostatics, as well as dynamic covalent chemistries such as imines, hydrazones, oximes, and boronate esters, reversibly break and reform under physiological conditions to generate viscoelastic hydrogels with tunable self-healing, stress relaxation, and energy dissipation. In this review, we describe how the thermodynamics and kinetics of dynamic bonds govern hydrogel injectability, toughness, and viscoelastic behavior, and how these same bond parameters regulate therapeutic cargo transport through affinity-mediated retention of small molecules and dynamic mesh gating of macromolecular cargo. We discuss strategies for programming the release of small-molecule drugs, proteins, nucleic acids, and cells, including stimuli-responsive systems triggered by pH, glucose, enzymes, or competing oligonucleotides. We then examine how dynamic bond exchange shapes the behavior of both delivered therapeutic cells and infiltrating immune cells by controlling matrix viscoelasticity, ligand presentation, and foreign body responses. We highlight applications in adoptive cell therapy, mesenchymal stem cell delivery, and sustained-release vaccine depots, and conclude by outlining the translational challenges, design rules, and key knowledge gaps that must be addressed to advance dynamically crosslinked hydrogels as next-generation controlled-release materials.

Histone proteolysis is an understudied phenomenon in which the N-terminal tails of histones are irreversibly cleaved by intracellular proteases. During development, histone post-translational modifications (PTMs) are known to orchestrate gene expression patterns that ultimately drive cell fate decisions. Therefore, deciphering the mechanisms of histone proteolysis is necessary to enhance the understanding of cellular differentiation. Here we show that histone H2A is cleaved by the lysosomal protease Cathepsin L during mouse ESC differentiation. Using quantitative mass spectrometry (MS), we identified L23 to be the primary cleavage site that gives rise to the main clipped form of H2A (cH2A), which reaches a maximum level of ∼1% of total H2A after four days of ESC differentiation. Using ChIP-seq, we found that preventing proteolysis leads to an increase in acetylated H2A at promoter regions in differentiated ES cells. We also identified novel readers of different acetylated forms of H2A in pluripotent ES cells, such as members of the PBAF remodeling complex, and show that H2A proteolysis abolishes this recognition. Analysis of the histone H3 PTM profiles of full-length (FL) H2A and cH2A containing nucleosomes demonstrate that cH2A is associated with marks found on active genes, consistent with ChIP-seq experiments. cH2A containing nucleosomes also are less stable or turned over at faster rates than nucleosomes containing FL H2A. Altogether, our data suggests that proteolysis serves as an efficient mechanism to silence pluripotency genes and destabilize the nucleosome core particle.

Cell manipulation is an important technique in biomedical research, yet existing micromanipulation tools still face challenges in force-control precision, multiscale adaptability, and biocompatibility. To address these limitations, this paper presents an electromagnetically actuated single-cell microgripper system for controlled cell manipulation. The system integrates a 3D-printed gripper, an electromagnetic gripping actuator, a motorized stage, and a control system. The gripper opening can be adjusted to accommodate cells of different sizes over a wide range from 10 to 500 μm, while the gripping force can be regulated by tuning the voltage applied to the electromagnetic coil. In addition, the microgripper incorporates a liquid-retention structure, which allows cells to be reliably transferred out of the culture medium while maintaining a hydrated microenvironment. Experimental results demonstrate that the electromagnetically actuated microgripper system enables controlled alignment of polystyrene microspheres with varying diameters, controlled deformation of oocytes, and capture, transfer, and release of living stem cells while preserving cell viability. With its simple structure and straightforward operation, the system exhibits promising potential for applications in the field of single-cell biomedical research.

Prolonged immobility and exposure to microgravity during spaceflight negatively affect male reproductive organs. Various interventional strategies have been employed to mitigate testicular pathology in immobile and/or physically inactive men. However, an effective therapy remains elusive. The experimental rodent model of simulated microgravity (SM), is widely used to study the pathogenesis of male infertility during prolonged bed rest and spaceflight.

MiR-224-5p has been proven to play an important role in regulating cell differentiation. This study aimed to clarify the regulatory role and mechanism of miR-224-5p in the osteogenic differentiation of human dental pulp stem cells (hDPSCs), thereby laying a theoretical foundation for subsequent jaw defect repair.

Primary glomerular disease, particularly IgA Nephropathy (IgAN), is one of the leading causes of kidney disease burden. IgAN is characterized by IgA deposition in the mesangial area; this is a typical pathological feature that leads to nephritis symptoms. Though the cause is unknown, the quadripartite attack theory is generally accepted. There are many reasons, but the biggest is an imbalance in the immune system. Recently, some studies have shown that mesenchymal stem cells (MSCs) can regulate IgA production and clearance by controlling B cells, T cells, and mucosal epithelial cells. Currently, the standard treatment for IgAN primarily relies on supportive care and immunosuppression, but these approaches are ineffective and have serious side effects. In contrast, stem cell therapy is a promising option and shows great promise in diagnosing and treating various kidney diseases. This review provides an update on recent advances in IgAN using stem cell therapy, including disease mechanisms, treatment pathways, clinical trials, case reports, safety concerns, current challenges, and prospects.

HECT and RCC1-like domain-containing protein 1 (HERC1), a large E3 ubiquitin ligase, has been implicated in neural development and genome stability, but its role in cancer remains unclear. This study identifies HERC1 as a critical regulator of cancer stemness, metastasis, and chemoresistance in head and neck squamous cell carcinoma (HNSCC). CD44⁺ HNSCC organoids with shRNA-mediated HERC1 knockdown were assessed for stemness, EMT, and IL-6/STAT3/HERC1 signaling using molecular assays, CAF co-culture, xenografts, and tissue immunohistochemistry. High HERC1 expression in TCGA-HNSCC datasets was associated with enrichment of stemness signatures. HERC1 knockdown in CD44⁺ cells reduced Sox2, and Slug expression, suppressed EMT, and impaired metastatic potential in Transwell assays and in vivo models. CD44⁺ cells formed organoids in a HERC1-dependent manner. CAF co-culture showed that IL-6 promoted organoid invasiveness through STAT3 activation and HERC1 upregulation. Mechanistic validation revealed that HERC1 modulation altered p-STAT3, p-ERK, CD44, and Slug levels, and STAT3 inhibition reduced HERC1 expression, defining a p-STAT3-HERC1-p-ERK axis. IL-6 neutralization or HERC1 inhibition sensitized organoids to 5-fluorouracil and cisplatin, and combined HERC1 knockdown with 5-FU markedly reduced tumor growth and increased apoptosis. Tissue arrays confirmed elevated HERC1 and pathway markers in advanced HNSCC. These findings define an p-STAT3-HERC1-p-ERK signaling axis that promotes cancer stemness and chemoresistance through CD44+ tumor-stromal crosstalk. Targeting HERC1 may offer a promising strategy to eliminate cancer stem-like cells in HNSCC.

Neutrophils rapidly accumulate in the heart after myocardial infarction (MI), yet bone marrow granulopoiesis peaks later, suggesting an alternative early source. Here we show in male mice that the first wave of neutrophils recruited to the ischemic heart arises from the vascular marginated pool rather than newly generated cells in the bone marrow or spleen. Using hematopoietic stem cell ablation, flow cytometry and proteomic analyses, we find that early MI-induced neutrophilia displays hallmarks of stress-induced demargination, a process in which adherent neutrophils are rapidly released into circulation. Pharmacological or genetic inhibition of norepinephrine synthesis or β-adrenergic receptor signaling in male mice suppresses neutrophil demargination and limits cardiac infiltration. Although sustained β-adrenergic blockade does not improve long-term outcomes, transient inhibition enhances cardiac remodeling and function. These findings identify stress-induced demargination as the dominant source of early post-MI neutrophils and suggest that temporally targeted β2-adrenergic modulation may help restrain acute inflammatory injury.

Small cell lung cancer (SCLC) patients frequently experience a remarkable response to first-line therapy. Follow up maintenance treatments aim to control residual tumor cells, but generally fail due to cross-resistance, inefficient targeting of tumor vulnerabilities, or dose-limiting toxicity, resulting in relapse and disease progression. Here we show that SCLC cells, similar to their cells of origin, pulmonary neuroendocrine cells, exhibit low activity in pathways protecting against reactive oxygen species (ROS). When exposed to a thioredoxin reductase 1 (TXNRD1) inhibitor, these cells quickly exhaust their ROS-scavenging capacity, regardless of their molecular subtype or resistance to first-line therapy. Importantly, unlike non-cancerous cells, SCLC cells cannot adapt to drug-induced ROS stress due to the suppression of ROS defense mechanisms by multiple layers of gene regulation. By exploiting this difference in oxidative stress management, we safely increase the therapeutic dose of TXNRD1 inhibitors in vivo by pharmacological activation of the NRF2 stress response pathway. This results in improved tumor control without added toxicity to healthy tissues. These findings underscore the therapeutic potential of TXNRD1 inhibitors for maintenance therapy in SCLC.

Adult hippocampal neurogenesis declines with aging and in neurological disorders, leading to cognitive impairment. We previously showed that inducing Plagl2 and antagonizing Dyrk1a (iPaD) rejuvenates aged neural stem cells (NSCs), enhancing neurogenesis and cognition in aged mice. Here, we found that NSC-specific iPaD treatment activates neurogenesis, reduces amyloid-β deposition, and improves cognition in Alzheimer's disease model mice. Transcriptomic analysis revealed widespread changes in gene expression in the hippocampus after iPaD treatment. The upregulated genes include those associated with astrocyte and microglial activation involved in amyloid-β clearance, while several genes upregulated in Alzheimer's disease are downregulated. Among the latter genes, knockdown of Prkag2 in the hippocampus most effectively enhances neurogenesis and reduces amyloid-β accumulation. Notably, both iPaD treatment and Prkag2 knockdown activate AMP-activated protein kinase signaling, upregulating genes involved in autophagy and cellular homeostasis. These results suggest that Prkag2 may represent a promising therapeutic target for neurodegenerative diseases, including Alzheimer's disease.

The evolution and development of eyes are fundamental problems in biology, and numerous genetic and age-related degenerative eye diseases are still poorly understood. Planarians are flatworms that are able to fully regenerate functional eyes following injury, presenting a powerful model to study essential attributes of eye biology and regeneration. We performed single-cell eye transcriptomic analyses and large-scale RNA interference screening to define a hierarchical sequence of steps in eye regeneration and the genes that control each step in this process: from progenitor specification to differentiation into mature photoreceptors and melanin-pigmented optic cup cells, rhabdomere and dorsal projection formation in photoreceptors, eye morphogenesis (a self-organizing process where eyes trap progenitors and promote their differentiation), and interactions with the surrounding extracellular environment to produce a transparent region for light transmission. This hierarchical program defines roles for many conserved genes and establishes a framework for the regeneration of an entire organ.

Neurological disorders represent a major and growing global health challenge due to complex central nervous system pathology and limited drug penetration across the blood - brain barrier. Conventional therapies are largely symptomatic and often fail to achieve sufficient brain bioavailability or disease modification. Biomimetic nanocarriers have emerged as a promising strategy to improve brain targeting and therapeutic efficacy.

Bone tissue engineering has advanced with the development of biomaterials that not only provide structural support but also modulate biological responses for enhanced tissue regeneration. In this study, we developed a cytokine-functionalized Zn-incorporated titanium scaffold (IL4/IL13@SM@pTi-Zn) to improve bone regeneration through immune modulation and osteogenesis. The scaffold exhibited excellent biocompatibility and significantly promoted osteogenic differentiation of mouse bone marrow mesenchymal stem cells. Quantitative polymerase chain reaction analysis showed that the expression of key osteogenic genes was markedly upregulated, with alkaline phosphatase, COL1A1, Runx2, and OPN increasing by 148%, 198%, 250%, and 245%, respectively, compared with the unmodified pTi group. In addition, the scaffold effectively reduced pro-inflammatory marker expression and intracellular reactive oxygen species accumulation, indicating favorable immunomodulatory and antioxidant effects. In vivo evaluation in a rabbit femoral condyle defect model further demonstrated enhanced bone regeneration. Micro-CT analysis revealed that bone volume fraction (BV/TV) increased by 14.8% at 4 weeks and 18.3% at 8 weeks, while trabecular thickness (Tb.Th) increased by 21.3% and 22.2%, respectively, compared to the control group. Collectively, these findings demonstrate that IL4/IL13@SM@pTi-Zn enhances bone repair through the synergistic promotion of osteogenesis and immune regulation, highlighting its potential as a promising biomaterial for bone defect repair.

Malignant tumors currently pose a significant threat to global health. Tumor progression is jointly regulated by genetic mutations and the mechanical properties of the tumor microenvironment (TME), including increased tissue stiffness, elevated fluid pressure, and mechanical compression experienced by circulating tumor cells (CTCs) within microvessels. These mechanical signals are transmitted through mechanosensitive pathways, with the Piezo channel family (Piezo1/Piezo2) serving as a core mediator.With their propeller-like trimeric structure, Piezo channels sense membrane tension, mediate calcium influx, and activate downstream signaling pathways (e.g., MAPK, PI3K/AKT/mTOR, YAP/TAZ), thereby regulating tumor cell proliferation, migration, immune microenvironment remodeling, and cancer stem cell-like transformation. Its expression exhibits tissue specificity and correlates with tumor staging, invasiveness, and pro gnosis.