搜索结果：Tissue & cell

Meat production and ethical concerns related to animal welfare have led to an increase in research into the creation of conventional meat. These technologies rely on the isolation, multiplication, and controlled differentiation of animal cells, which can potentially reduce negative environmental impact while maintaining comparable nutritional and sensory properties. The aim of this study is to comprehensively analyze and compare selected cell types used in the production of cultured meat, such as fibroblasts, satellite cells, adipocytes, and pluripotent cells: embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). It is important to consider the proliferative capacity, differentiation potential, suitability in scalable bioprocessing systems, and their impact on the structure and sensory properties of muscle tissue. This analysis demonstrates that no single cell type can fully replicate the complex structure of native muscle tissue. Satellite cells are responsible for the formation of muscle fibers, fibroblasts provide support through the synthesis of the extracellular matrix, and adipocytes contribute to the flavor and juiciness of the final product. Pluripotent cells differentiate into all of cell lineages, but their use is associated with regulatory and ethical considerations. This work also addresses key aspects of bioprocess engineering, such as scalability, culture conditions, and the importance of 3D cell culture and cell co-cultures in restoring tissue structure. Furthermore, regulatory, ethical, and economic issues affecting the feasibility of implementing the technology for industrial production are considered. In summary, the data presented indicate that the development of cultured meat requires an integrated approach combining appropriate cell selection, process optimization, and compliance with regulatory and ethical requirements.

In single-cell biology, the main limitation has shifted from data generation to converting sparse, heterogeneous single-cell RNA sequencing (scRNA-seq) datasets into accurate cell types, interpretable multi-omic states, and reproducible conclusions. To address these challenges, we present scParadise, which transforms scRNA-seq data to a new scientific knowledge. scParadise comprises three integrated tools: scAdam, a multi-level cell type annotation tool with unknown cell type identification; scEve, a cross-tissue modality imputation tool; and scNoah, a standardized benchmarking tool. Using scParadise, we corrected annotation mistakes in the Tabula Muris Senis atlas, showing that cells labeled as granulocytes are exclusively neutrophils and that presumably annotated macrophages actually represent a range of different cell types. Moreover, we identify three previously unknown natural killer T (NKT) cell subsets by imputing protein expression across tissues, which include CD56dim CD3+, CD56dim CD3+ CD4+, and CD56dim CD3+ CD8+ cell subsets in human visceral adipose tissue, which we verify by flow cytometry. These new subsets engage in obesity-related tumor necrosis factor-centric crosstalk with myeloid and adipose progenitors, thereby illuminating a new paradigm for immune-stromal interactions that contribute to chronic inflammation and impaired adipogenesis.

Endoplasmic reticulum (ER) stress is central to the onset and progression of metabolic and inflammatory disorders, such as insulin resistance, hepatic steatosis, and cardiovascular dysfunction. The unfolded protein response, triggered by ER stress, induces maladaptive pathways through PERK, IRE1, and ATF6, leading to inflammation, apoptosis, and cellular dysfunction. Targeted ER stress modulation is an attractive therapeutic approach, and recent developments in bioengineering have enabled precise delivery of modulatory agents using cell-penetrating peptides and adipose-derived stem cells. On the one hand, cell-penetrating peptides (CPPs) enable intracellular delivery of therapeutic cargoes such as siRNA, peptides, or small-molecule targeting key ER stress mediators, including CHOP, GRP78, IRE1, and NF-κB. CPP-mediated delivery systems restore ER homeostasis, reduce inflammatory signaling, and improve cellular survival in hepatocytes, pancreatic β-cells, and cardiomyocytes. Simultaneously, adipose tissue-derived stem cells (ADSCs), which are derived from lipo-aspirated fat tissue, induce paracrine effects through the secretion of anti-inflammatory cytokines (i.e., IL-10), growth factors (i.e., VEGF, HGF, TGF-β), and antioxidants that regulate ER stress responses. ADSCs also have adipogenic and endothelial differentiation, playing roles in repairing tissue and metabolic homeostasis. Downregulation of ER stress markers and mitigation of oxidative stress increase their therapeutic efficacy for metabolic disorders. Collectively, this bioengineered synergy of CPPs and ADSCs represents a multifunctional therapeutic platform to target ER stress and its downstream effects. This synergistic approach has translational potential for precision medicine in metabolic pathophysiology, advancing from laboratory innovations to clinical applications.

Adaptive immune activation in lymph nodes requires rare antigen-specific naïve T cells to locate antigen-bearing dendritic cells within a spatially structured stromal network. Reduced priming efficiency is typically attributed to weak T cell receptor signaling, yet it remains unclear whether failure arises from impaired signaling or from limited access to antigen-bearing dendritic cells during early scanning. We developed COORDINATE, a spatially explicit agent-based model of lymph node microanatomy that integrates fibroblastic reticular cell topology, chemokine-guided migration, and competition for dendritic cell access. We show that stromal architecture and trafficking biases strongly influence which T cells encounter antigen, while competition for limited dendritic cell access can exclude a substantial fraction of cells from forming any productive contact. Consequently, reduced activation can arise from failed clonal recruitment rather than diminished signaling following contact. These results support a view of early T cell priming as an access-limited process and indicate that commonly used endpoint measurements can conflate failure to access antigen with failure to activate. Together, our findings suggest that improving early antigen access, rather than strengthening signaling alone, may represent an alternative strategy to enhance adaptive immune responses.

Triple-negative breast cancer (TNBC) is characterized as the most unfavorable prognosis of the breast cancer subtype. Chemotherapy is currently the primary treatment owing to a persistent lack of effective alternative medicine. To fulfill this unaddressed clinical requirement, we utilized the PGLU-Fc-III-4C MsAb platform to develop a nanobioconjugate trispecific antibody (TsAb; CD3×CD137×CD276) that targeted CD3, CD137, and CD276, aiming to restrict the growth of TNBC tumors (4T1 model) and provide a novel therapeutic strategy. The capacity for binding to target cells and anti-tumor effects of TsAb in vitro were evaluated. In vivo antitumor efficacy and biosafety were further assessed in the 4T1 subcutaneous tumor model. Anti-tumor immune responses induced by TsAb on tumor-infiltrating CD8+ T cells were monitored. The TsAb effectively bound and facilitated interactions between 4T1 tumor cells and T cells, significantly boosting the anti-tumor effect. TsAb promoted the expansion of tumor and splenic T lymphocytes and facilitated the recruitment of splenic and blood T lymphocytes to tumor tissues. Compared with the PGLU-Fc-III-4C-IgG treatment group, the TsAb treatment group had varying degrees of increase in CD8+ tissue-resident memory T cells (TRM), central memory T cells (TCM), and terminal effector memory T cells (TEM) in tumor tissues. The TsAb treatment group exhibited a significant increase of PD-1+ CD8+ T cells and TCF1-Tim-3+ CD8+ terminally exhausted T cells in tumor tissues. The safety profile demonstrated no obvious systemic toxicity. Briefly, TsAb mediated CD8+ T cell activation, proliferation, and terminal differentiation, accompanied by increasing cytokine production to eliminate the tumor. Meanwhile, no obvious systemic toxicity was observed. In general, the CD3×CD137×CD276 nanobioconjugate trispecific antibody provides a promising immunotherapeutic approach via regulating CD8+ T cell immune response for the treatment of triple-negative breast cancer.

Our laboratory and others have shown that programmed cell death receptor-ligand 1 (PD-L1) contributes to the development of shock/sepsis-induced morbidity and mortality, but its role appears to vary across organ/cell type. Here, we leverage the construction of Cre-lox mouse models to produce mice constitutively lacking either PD-L1 gene expression on endothelial cells (ecPD-L1-/-) or neutrophils (pmnPD-L1-/-) to test the hypothesis that endothelial cell as opposed to neutrophil deficiency of PD-L1 differentially contributes to shock/sepsis-induced lung injury/death. Methods: Adult male C57BL/6 (breeder background strain), ecPD-L1-/-, pmnPD-L1-/-, and/or mixed flox (ec and pmn PD-L1-/+ or PD-L1+/+, respectively)-no Cre (Control) mice were subjected to either hemorrhagic (Hem) shock followed 24 h by cecal ligation and puncture (CLP) (Hem/CLP) or sham Hem and sham CLP (Sham). Survival studies were performed, and a separate set of animals were taken at 24 h post-procedure for peripheral blood, bronchoalveolar lavage fluid (BALF), and lung tissue collection. Samples were processed and stained for analysis by flow cytometry, cytokine, chemokine, and angiopoietin ELISAs and indices of organ injury assays. A subset of animals was also examined for changes in lung permeability using Evan's Blue dye exclusion. Fourteen-day mortality in the ecPD-L1-/- mice was lower than in the Hem/CLP Control group, while the mortality rate was increased in the pmnPD-L1-/- vs. Controls. Lung vascular permeability was also markedly decreased in the ecPD-L1-/- Hem/CLP mice, but no such decline was seen in the lungs of pmnPD-L1-/- mice. While Hem/CLP increased the lung tissue, BALF, and blood levels of several cytokine, chemokine, and angiopoietin levels, the concentrations of lung tissue and BALF MCP-1 and blood urea nitrogen markedly declined in the ecPD-L1-/- vs. Control mice. Alternatively, the lung levels of Angiopoietin 2 and BALF MIP-2 and IL-6 concentrations significantly increased in Hem/CLP pmnPD-L1-/- animals. Taken together, these results support the hypothesis we have previously proffered, that expression of PD-L1 on endothelial cells has a morbid impact. However, surprisingly, we have also uncovered a potential immune protective role of PD-L1 expression on neutrophils.

The therapeutic efficacy of stem cell-based treatments depends critically on maintaining high cell viability through the injection process. Mechanical stress induced on cells during passage through injection needles represents a significant source of cell damage that can compromise therapeutic outcomes. This review examines the current understanding of how needle gauge (diameter) and length affect human stem cell viability, exploring the mechanical forces involved, empirical evidence across different stem cell types, and practical implications for clinical protocols. We analyze the competing demands of minimizing tissue trauma through smaller needles while preserving cell viability and provide evidence-based recommendations for optimizing injection parameters across various clinical applications.

Brucellosis is a zoonotic disease caused by Brucella species. Its pathogenesis is closely associated with bacterial evasion of macrophage-mediated killing, induction of a pro-inflammatory cytokine storm, and immune-mediated pathological damage. Accumulating evidence indicates that Codonopsis pilosula polysaccharides (CPPS) inhibit inflammatory signaling, enhance macrophage phagocytosis, and exert immunomodulatory effects across multiple organs. However, the therapeutic potential of CPPS in brucellosis remains largely unexplored. This study aimed to investigate the effects of CPPS on the inflammatory response induced by Brucella outer membrane protein 19 (OMP19). In vivo, CPPS significantly alleviated tissue damage and simultaneously downregulated the expression of high mobility group box 1 protein (HMGB1), E-cadherin, and paxillin. In vitro, CPPS inhibited SYK/FAK/AKT phosphorylation, PKC activation, and WNT-1 signaling pathway transduction. Additionally, CPPS modulated the cytokine profile by downregulating pro-inflammatory cytokines (TNF-α, IL-6) while increasing the level of the anti-inflammatory cytokine IL-10. Furthermore, CPPS decreased the expression levels of E-cadherin and paxillin and reduced the intracellular calcium ion (Ca2+) concentration. ATP2A1 was identified as a key differentially expressed gene through transcriptome sequencing. Knockdown experiments further confirmed that CPPS exerts anti-inflammatory effects by regulating ATP2A1. Collectively, CPPS attenuates the inflammatory response in macrophages induced by OMP19 via regulating ATP2A1 to modulate cell adhesion and calcium signaling.

IL-17, a pleiotropic cytokine, activates downstream signaling pathways through the IL-17 receptor (IL-17R), influencing the expression and regulation of inflammatory mediators, growth factors, and matrix metalloproteinases, thereby modulating various biological processes. Recent studies have shown that IL-17 exhibits dynamic biphasic effects during tissue repair: in the acute phase, it accelerates tissue repair by promoting epithelial regeneration, angiogenesis, and the recruitment of reparative immune cells, whereas in the chronic phase, excessive activation leads to uncontrolled inflammation and fibrosis progression. This "double-edged sword" effect shows significant heterogeneity across different tissues, including the skin, lungs, and intestines. Despite the widely recognized dual roles of IL-17, the field still lacks a holistic perspective that systematically explains how this duality is regulated across different tissue environments. This review outlines recent advances in IL-17's functional dichotomy and identifies cellular origin, injury phase, and local microenvironment as critical regulatory determinants. We aim to elucidate under what circumstances and why IL-17 promotes tissue repair rather than exacerbates fibrosis, and discuss the implications of these insights for developing therapeutic strategies tailored to distinct clinical scenarios.

Decitabine (DEC) is rapidly deaminated by cytidine deaminase (CDA); tetrahydrouridine (THU), a CDA inhibitor, reduces degradation and increases DEC exposure. This is clinically relevant in sickle cell disease (SCD), where DEC increases foetal haemoglobin in erythrocytes.The effect of THU pre-treatment on the tissue distribution of radiolabelled decitabine ([14C]-DEC) was studied in mouse by quantitative whole-body autoradiography and area under the concentration curve (AUC) as exposure metric.The decitabine-related exposure was highest in haematolymphoid tissues, particularly the bone marrow, followed by gastrointestinal tissues across all dosing groups, with up to 115‑ and 18‑fold higher levels than in blood, respectively.Furthermore, THU pre-treatment increased the exposure in haematolymphoid tissues, gastrointestinal tract, and reproductive organs by up to 4.8-, 6.2-, and 5.3-fold, respectively.In conclusion, THU pre-treatment enhances decitabine-related exposure in target tissues like bone marrow, supporting pre-dosing of THU prior to DEC treatment of SCD.

This study aims to identify potential biomarkers for diabetic retinopathy (DR) by focusing on genes associated with mesenchymal stem cell-derived exosomes (MSCs-Exo). By integrating DR transcriptome data with the protein dataset of MSCs-Exo, we utilized a comprehensive array of bioinformatics techniques, including weighted gene coexpression network analysis, Mfuzz clustering, and machine learning algorithms such as least absolute shrinkage and selection operator regression and random forest to pinpoint key genes. Functional mechanisms were explored through functional enrichment analysis, immune infiltration, and single-cell RNA sequencing. The immunohistochemistry and Western blotting were used for validation on DR mice models. Our comprehensive analysis identified 16 hub genes associated with MSCs-Exo. Through the application of interpretable machine learning techniques, YBX1 and PSMA7 were further identified as central genes within this network. A predictive diagnostic model for DR was developed and validated using receiver operating characteristic curve analysis, which demonstrated modest diagnostic efficacy, as indicated by an area under the curve exceeding 0.7. Importantly, experimental validation showed that the protein expression levels of YBX1 and PSMA7 were significantly reduced in the retinal tissues of DR mice compared with the control group (P < 0.05). Functional enrichment analysis suggested that YBX1 and PSMA7 are involved in critical biological processes, specifically the regulation of protein and amino acid metabolism. In addition, immune infiltration results show that they are significantly associated with the immune dysregulation of DR, especially in CD4T memory cells. Single-cell analysis also supported the above finding. These findings suggest that YBX1 and PSMA7, derived from MSCs-Exo, may serve as potential biomarkers for DR. Further studies are needed to confirm their clinical utility and therapeutic relevance.

Gold nanoparticles (AuNPs) are widely applied in nanomedicine, cellular and tissue biology, nanoscopy, photothermal therapy, and a range of diagnostic and clinical technologies. Among them, gold nanostars (AuNSs) have emerged as particularly promising due to their highly tunable optical and chemical properties. However, like other nanostructures, the stability of AuNSs remains a key challenge, especially within complex cellular microenvironments. Here, wide-field hyperspectral microscopy is evaluated for the real-time characterization of the morphology-dependent stability of AuNS formulations in immune-cell microenvironments. A computationally efficient image processing pipeline extracts statistical features from reflectance images, enabling the real-time analysis of hyperspectral data. UMAP-based visualization of spectral data revealed distinct, time- and formulation-dependent spectral shifts, with smaller seed volume formulations (larger overall diameter) for AuNSs exhibiting rapid destabilization and aggregation in THP-1 cells. In contrast, larger seed volume formulations (smaller overall diameter) for AuNS demonstrated enhanced colloidal stability and spectral uniformity. Compared to conventional ensemble measurements, hyperspectral reflectance measurements provided a rapid and resource-efficient approach that enabled macroscale imaging while retaining the spectral detail necessary to resolve AuNS transformations. Overall, the hyperspectral microscopy techniques presented here provide a label-free, high-throughput platform for evaluating AuNS stability and biocompatibility, with strong potential to guide the rational design of AuNSs for immunotherapeutic and diagnostic applications.

Musculoskeletal tissue regeneration remains a major clinical challenge due to the limited intrinsic healing capacity of cartilage, bone and interface tissues, as well as the complexity of recreating their hierarchical structure and mechanical properties. In recent years, costal cartilage (CC) has emerged as a promising and versatile resource for regenerative applications, owing to its hyaline cartilage composition, biological plasticity and relative surgical accessibility. This systematic review aims to critically evaluate in vivo and clinical evidence published over the last decade regarding the use of CC-derived cells and matrices for musculoskeletal tissue regeneration. A systematic search of PubMed, Scopus and Web of Science databases was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, identifying 26 eligible studies, including 18 in vivo and 8 clinical investigations. CC was employed either as a source of costal chondrocytes or cartilage-derived stem cells, or as decellularized or particulate extracellular matrix scaffolds. Preclinical studies demonstrated consistent regenerative potential across cartilage, osteochondral, bone and enthesis models, with outcomes showing hyaline-like tissue formation, improved biomechanical properties, enhanced integration with host tissue and coordinated chondrogenic and osteogenic responses. Clinical studies, primarily focused on cartilage and osteochondral defects, reported significant improvements in patient-reported outcomes, imaging-based repair quality and functional recovery, with follow-up periods extending up to 5 years and a favourable safety profile. Cell-based CC approaches showed robust biological efficacy but were associated with greater regulatory and translational complexity due to substantial manipulation requirements. In contrast, matrix-based CC strategies offered a more readily translatable option, leveraging the intrinsic bioactivity of the extracellular matrix while reducing regulatory burden. CC could be considered a highly promising and adaptable platform for musculoskeletal regeneration. However, heterogeneity in study design, limited sample sizes and variable methodological quality highlight the need for standardized protocols and well-designed, long-term randomized clinical trials to definitively establish clinical indications and optimize therapeutic strategies. N/A.

Cytokeratin-positive interstitial reticulum cell (CIRC) tumor, a subtype of fibroblastic reticular cell tumor (FRCT), is an extremely rare primary neoplasm of lymph nodes and soft tissue, with limited understanding of its clinicopathological and molecular features. This case is the first identification of human leukocyte antigen loss of heterozygosity (HLA LOH) in CIRC tumor, which provides novel insights into immune evasion mechanisms and potential therapeutic implications. A 67-year-old female presented with a local recurrence seven years after initial resection of a CIRC tumor on her right shoulder. Physical examination revealed a firm, poorly mobile subcutaneous mass (12cm&#xd7;8cm). Imaging confirmed a right parascapular mass with bone destruction. Histologically, the recurrent tumor consisted of spindle and epithelioid cells arranged in storiform and sheet-like patterns, with extensive necrosis and a mitotic count of 3 per 10 high-power fields. Immunohistochemically, tumor cells diffusely expressed cytokeratins, vimentin, CD68, CD163, and EMA, with focal expression of SMA, S-100, calponin, and CD3, but were negative for CD21, CD35, CD1a, ALK, and HHV8. The Ki-67 index was 25%. Whole-exome sequencing identified 30 single-nucleotide variants and 7 indels (variant allele frequencies 2.17%-12.6%), copy number gains on chromosomes 7, 11, and 14, and microsatellite stability. Notably, two HLA LOH events affecting HLA-B39:01:01:01 and HLA-C07:02:01:01 were detected. No disease progression was observed during follow-up. This is the first report of HLA LOH in FRCT/CIRC tumor. The key take-away lesson is that HLA LOH represents a potential immune evasion mechanism, which may render single-agent immune checkpoint inhibitors ineffective and thus guide alternative immunotherapeutic strategies. Chromosomal instability appears to be a prominent genomic feature of FRCT. These findings expand the molecular landscape of this rare tumor and underscore the value of comprehensive genomic profiling in guiding individualized treatment.

Hepatocellular carcinoma (HCC) is associated with gut microbiota dysbiosis, yet specific oncogenic mechanisms remain elusive. We identified Enterococcus faecalis (EF) as significantly enriched in human liver tumours, where its abundance correlates with disease severity. Both live EF and its conditioned medium promoted HCC cell proliferation, protein translation and tumourigenesis. Mechanistically, EF-derived extracellular vesicles (EF-EVs) deliver the bacterial GTPase Obg to activate the host mTOR pathway and drive tumour progression. EF-Obg contains a Ras-like G domain homologous to the mTOR regulator Rheb and binds mTOR via a conserved G1 motif. CRISPR interference-mediated knockdown of obg in EF abolished mTOR activation and tumourigenic capacity in vivo. Clinically, high EF-Obg expression in HCC tissues correlates with mTOR hyperactivation and reduced patient survival. The mTOR inhibitor Everolimus effectively suppressed tumour growth in an EF-colonied orthotopic model, highlighting its therapeutic potential for HCC patients with high EF burden. Collectively, this work establishes a causal link between tumour-resident E. faecalis and hepatocarcinogenesis, revealing EF-Obg as a cross-kingdom activator of mTOR and providing a rationale for microbiota-guided personalised therapy in HCC.

Primary diffuse large B-cell lymphoma (DLBCL) of the skeletal muscle is an extremely rare subtype of extranodal non-Hodgkin lymphoma, and primary DLBCL of the rectus abdominis muscle is even rarer with few reports in the literature. Due to the lack of specific clinical manifestations and imaging features, it is easily misdiagnosed, leading to delayed treatment. We herein report an 85-year-old female patient who presented with a painful mass in the right lower abdominal wall. Preoperative contrast-enhanced computed tomography (CT) showed an irregular soft-tissue mass in the right abdominal wall with unclear boundaries abutting adjacent small-bowel loops. Tumour markers were within normal limits; complete blood count, lactate dehydrogenase, &#x3b2;2-microglobulin and peripheral-blood flow cytometry were unremarkable, and contrast-enhanced CT of the chest and brain magnetic resonance imaging (MRI) revealed no other lesions. Tumour markers were within normal limits. Contrast-enhanced ultrasound suggested a hypervascular malignant lesion. The diagnosis of a presumed primary DLBCL of the rectus abdominis muscle (non-germinal centre B-cell-like subtype) was confirmed by ultrasound-guided needle biopsy and immunohistochemistry. The patient received 4 cycles of an attenuated R-THP-COP regimen (rituximab, pirarubicin [tetrahydropyranyl adriamycin, THP, substituted for doxorubicin to reduce cardiotoxicity], cyclophosphamide, vincristine and prednisone). Partial response was achieved after 2 cycles, and complete radiological response on contrast-enhanced CT was obtained after 4 cycles. The patient remained free of reported abdominal symptoms during telephone follow-up (no further imaging surveillance was performed) and died of cerebral haemorrhage 3 years later, from a cause unrelated to the lymphoma. Primary muscular DLBCL is highly aggressive and easily misdiagnosed. Pathological biopsy combined with immunohistochemistry is the gold standard for diagnosis. In this single elderly patient, an attenuated R-THP-COP regimen was well tolerated and produced a sustained complete clinical response, suggesting that an individualised, biopsy-guided, chemotherapy-based approach may be a reasonable option for similarly localised disease in elderly patients; this observation, however, requires confirmation in larger series. This case enriches the clinical data of this rare disease and provides a reference for clinical diagnosis and treatment.

Raman spectroscopy enables label-free identification of biological tissues, but its clinical application remains limited due to low-throughput measurements. Here, we developed a spatially multiplexed random-access Raman probe that enables simultaneous spectral acquisition from arbitrarily selected locations in vivo. Parallel acquisition of up to 1718 spectra in a single exposure has been enabled by using a custom fiber bundle in combination with a spatial light modulator. In vivo measurement of a peripheral nerve in the abdominal cavity of an anesthetized canine demonstrated the feasibility of the developed system for intraoperative tissue identification within 5 s. We further performed discriminant analysis of multipoint spectra from nerve and non-nerve regions in rats, which achieved 92.5% accuracy and sensitivity for nerve discrimination. The developed system provides a basis for efficient and accurate navigation in surgery.

Critical limb ischemia (CLI) remains refractory to current revascularization strategies due to its complex pathology. Here, we report an injectable alginate hydrogel that orchestrates a dual-pathway regenerative cascade by simultaneously reprogramming the immune microenvironment and activating direct tissue repair. The system is rationally designed by integrating two functional modules: (i) immunomodulatory carbon dots (PNS-AA@CQDs-COS) that selectively target M1 macrophages and drive them to the M2 phenotype, and (ii) intrinsically bioactive cross-linkers (Zn2+/l-Arg) that serve as sustained-release pro-regenerative signals. Critically, this dual-component architecture enables a synergistic interplay&#x2500;while the carbon dots establish an anti-inflammatory microenvironment (path 1), the liberated Zn2+ and l-Arg directly activate endothelial cells and muscle satellite cells, thereby initiating coordinated vascular and myogenic regeneration (path 2). In vitro, the hydrogel significantly amplified reparative crosstalk within macrophage-endothelial/myogenic cells' cocultures. In a murine CLI model, a single injection of the hydrogel resulted in durable recovery of hindlimb perfusion (80.4% by day 14), improved motor function, and enhanced tissue repair. Mechanistic studies revealed that these benefits stem from microenvironment remodeling (M2 polarization and IL-10 upregulation) and modulation of key signaling pathways&#x2500;suppressing NF-&#x3ba;B while potentiating PI3K/Akt/eNOS. This work presents a material-based strategy that couples immunomodulation with direct cellular activation, offering a synergistic therapeutic platform for CLI and potentially other ischemic diseases.

Immune signaling has emerged as a central regulator of cardiac biology, extending far beyond its traditionally recognized roles in pathology. From embryogenesis to adulthood, immune cells orchestrate key processes, including coronary vasculature formation, cardiomyocyte maturation, mitochondrial homeostasis, and extracellular matrix (ECM) remodeling. In the setting of myocardial injury, immune responses unfold in tightly choreographed phases, initially clearing necrotic debris and later facilitating scar formation and, in certain contexts, promoting tissue regeneration. Recent advances in single-cell and spatial transcriptomics have revealed the remarkable heterogeneity and plasticity of immune cell populations in the heart, highlighting their metabolic and phenotypic adaptability across developmental and disease contexts. Alongside these biological insights, therapeutic interest has grown in targeting specific immune pathways to modulate inflammation, enhance repair, and restore cardiac function. This review integrates discoveries from developmental immunology, cardiac injury models, and regenerative medicine to illustrate how the immune system underpins cardiac resilience and plasticity. By synthesizing molecular, cellular, and systems-level data, we present a cohesive view of cardioimmune interactions that opens new avenues for precision therapies aimed at heart repair and regeneration.