Angiogenesis is a complex physiological process. In recent years, the immune regulation of angiogenesis has received increasing attention, and innate immune cells, which are centred on macrophages, are thought to play important roles in vascular neogenesis and development. Various innate immune cells can act on the vasculature through a variety of mechanisms, with commonalities as well as differences and synergistic effects, which are crucial for the progression of vascular lesions. In recent years, monotherapy with antiangiogenic drugs has encountered therapeutic bottlenecks because of the short-term effect of 'vascular normalization'. The combination treatment of antiangiogenic therapy and immunotherapy breaks the traditional treatment pattern. While it has a remarkable curative effect and survival benefits, it also faces many challenges. This review focuses on innate immune cells and mainly introduces the regulatory mechanisms of monocytes, macrophages, natural killer (NK) cells, dendritic cells (DCs) and neutrophils in vascular lesions. The purpose of this paper was to elucidate the underlying mechanisms of angiogenesis and development and the current research status of innate immune cells in regulating vascular lesions in different states. This review provides a theoretical basis for addressing aberrant angiogenesis in disease processes or finding new antiangiogenic immune targets in inflammation and tumor.

The vasculature plays a critical role in homeostasis and health as well as in the development and progression of a wide range of diseases, including cancer, cardiovascular diseases, metabolic diseases (and their complications), chronic inflammatory diseases, ophthalmic diseases, and neurodegenerative diseases. As such, the growth of the vasculature mediates normal development and physiology, as well as disease, when pathologically induced vessels are morphologically and functionally altered owing to an imbalance of angiogenesis-stimulating and angiogenesis-inhibiting factors. This review offers an overview of the angiogenic process and discusses recent findings that provide additional interesting nuances to this process, including the roles of intussusception and angiovasculogenesis, which may hold promise for future therapeutic interventions. In addition, we review the methodology, including those of in vitro and in vivo assays, which has helped build the vast amount of knowledge on angiogenesis available today and identify important remaining knowledge gaps that should be bridged through future research.

Vascular endothelial growth factor (VEGF) signaling is a critical regulator of vasculogenesis, angiogenesis, and lymphangiogenesis, processes that are vital for the development of vascular and lymphatic systems, tissue repair, and the maintenance of homeostasis. VEGF ligands and their receptors orchestrate endothelial cell proliferation, migration, and survival, playing a pivotal role in dynamic vascular remodeling. Dysregulated VEGF signaling drives diverse pathological conditions, including tumor angiogenesis, cardiovascular diseases, and ocular disorders. Excessive VEGF activity promotes tumor growth, invasion, and metastasis, while insufficient signaling contributes to impaired wound healing and ischemic diseases. VEGF-targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors, have revolutionized the treatment of diseases involving pathological angiogenesis, offering significant clinical benefits in oncology and ophthalmology. These therapies inhibit angiogenesis and slow disease progression, but they often face challenges such as therapeutic resistance, suboptimal efficacy, and adverse effects. To further explore these issues, this review provides a comprehensive overview of VEGF ligands and receptors, elucidating their molecular mechanisms and regulatory networks. It evaluates the latest progress in VEGF-targeted therapies and examines strategies to address current challenges, such as resistance mechanisms. Moreover, the discussion includes emerging therapeutic strategies such as innovative drug delivery systems and combination therapies, highlighting the continuous efforts to improve the effectiveness and safety of VEGF-targeted treatments. This review highlights the translational potential of recent discoveries in VEGF biology for improving patient outcomes.

Abnormal tongue development is a craniofacial deformity that affects dental-maxillofacial esthetics and function. Recent evidence has identified macrophages as multi-functional immune cells crucial for heart and brain development. However, it is still unknown whether macrophages affect tongue development. Therefore, this study aims to assess the distribution, phenotype, and roles of macrophages in the developing tongue.

In this study, immunohistochemical (IHC) and multiplex immunofluorescence (mIF) staining were conducted on C57BL/6 mice at embryonic day (E) 13.5, E14.5, E16.5, and E18.5 to analyze the distribution and phenotype of macrophages. Hematoxylin-Eosin (HE), IHC, IF, and mIF staining were also performed on embryonic CX3 CR1-CreERT2; Rosa-DTA conditional macrophage-depleted mice to investigate the effects on fetal tongue development and elucidate mechanisms from myogenesis, vascularization, and cell apoptosis. Statistical significance between the two groups was determined using unpaired two-tailed Student's t-tests. For comparisons involving three or more groups, one-way analysis of variance (ANOVA) followed by Tukey's multiple comparison tests was utilized. A significance level of P < 0.05 was set for statistical significance.

Macrophages were present in the developing tongue from E13.5 to E18.5, with a majority being of the M2 phenotype. Depletion of macrophages resulted in abnormal tongue morphology, decreased tongue height, width, and size, as well as reduced and disorganized muscle fibers. Depletion of macrophages also increased apoptosis. Vascular morphogenesis was impacted, with reductions in the luminal and vascular wall cross-sectional areas of the lingual artery. Vascular endothelial cells were reduced and disorganized with decreased expression of VEGFA and TGF-β1. Moreover, macrophages were located near vascular endothelial cells and secreted pro-angiogenic factors, suggesting their involvement in promoting vascularization.

Our findings indicate that macrophages play crucial roles in fetal tongue development by affecting myogenesis, cell apoptosis, and vascular growth.

The complex interplay between the immune and cardiovascular systems during development, homeostasis and regeneration represents a rapidly evolving field in cardiac biology. Single cell technologies, spatial mapping and computational analysis have revolutionised our understanding of the diversity and functional specialisation of immune cells within the heart. From the earliest stages of cardiogenesis, where primitive macrophages guide heart tube formation, to the complex choreography of inflammation and its resolution during regeneration, immune cells emerge as central orchestrators of cardiac fate. Translating these fundamental insights into clinical applications represents a major challenge and opportunity for the field. In this Review, we decode the immunological blueprint of heart development and regeneration to transform cardiovascular disease treatment and unlock the regenerative capacity of the human heart.

The high metabolic demand of retinal neurons requires a precisely regulated vascular system that can deliver rapid changes in blood flow in response to neural need. In the retina, this is achieved via the action of a coordinated group of cells that form the neurovascular unit. While cells such as pericytes, Müller cells, and astrocytes have long been linked to neurovascular coupling, more recently the resident microglial population have also been implicated. In the healthy retina, microglia make extensive contact with blood vessels, as well as neuronal synapses, and are important in vascular patterning during development. Work in the brain and retina has recently indicated that microglia can directly regulate the local vasculature. In the retina, the fractalkine-Cx3cr1 signalling axis has been shown to induce local capillary constriction within the superficial vascular plexus via a mechanism involving components of the renin-angiotensin system. Furthermore, aberrant microglial induced vasoconstriction may be at the centre of early vascular reactivity changes observed in those with diabetes. This review summarizes the recent emerging evidence that microglia play multiple roles in retinal homeostasis especially in regulating the vasculature. We highlight what is known about the role of microglia under normal circumstances, and then build on this to discuss how microglia contribute to early vascular compromise during diabetes. Further understanding of the mechanisms of microglial-vascular regulation may allow alternate treatment strategies to be devised to reduce vascular pathology in diseases such as diabetic retinopathy.

Endothelial cells (ECs) are critical drivers of tumour progression, and their angiogenic process has been widely studied. However, the post-angiogenic transition of tip endothelial cells after sprouting remains insufficiently characterised. In this study, we utilised single-cell RNA sequencing analyses to identify a novel EC transition signature associated with endothelial permeability, migration, metabolism, and vascular maturation. Within the transition pathway, we discovered a critical EC subpopulation, termed tip-to-capillary ECs (TC-ECs), that was enriched in tumour tissues. Comparative analyses of TC-ECs with tip and capillary ECs revealed distinct differences in pathway activity, cellular communication, and transcription factor activity. The EC transition signature demonstrated substantial prognostic significance, validated across multiple cancer cohorts from TCGA data, particularly in bladder cancer. Subsequently, we constructed a robust prognostic model for bladder cancer by integrating the EC transition signature with multiple machine-learning techniques. Compared with 31 existing models across the TCGA-BLCA, GSE32894, GSE32548, and GSE70691 cohorts, our model exhibited superior predictive performance. Stratification analysis identified significant differences between different risk groups regarding pathway activity, cellular infiltration, and therapeutic sensitivity. In conclusion, our comprehensive investigation identified a novel EC transition signature and developed a prognostic model for patient stratification, offering new insights into endothelial heterogeneity, angiogenesis regulation, and precision medicine.

Microglia are the resident immune cells of the central nervous system. Unlike other glial cells-such as astrocytes and oligodendrocytes-which originate from neural stem cells alongside neurons, microglia derive from erythromyeloid progenitors that emerge in the yolk sac during early embryonic development. Once they reach the brain, microglia expand their population through proliferation during development. A growing body of research has revealed that microglia play diverse roles throughout life, both in physiological and pathological contexts. With recent advancements in single-cell transcriptomics, it has become increasingly evident that microglia exhibit substantial heterogeneity in their gene expression patterns. While various functions and subtypes of microglia are being uncovered, the mechanisms underlying their diversity remain largely unknown. Two key hypotheses may explain how microglial diversity arises. One possibility is that their diversity is influenced by the different colonization routes they take before settling in the brain. Alternatively, microglia may acquire distinct properties in response to their local environment. This review explores both possibilities, with a particular focus on the first hypothesis, drawing on recent findings that highlight the multiple routes microglia utilize to colonize the brain. It discusses how these processes contribute to the establishment of microglial diversity during brain development.

Understanding the timing of fetal brain vulnerability to inflammatory changes in pregnancy complications is crucial for predicting neurodevelopmental risks. Beyond the placenta, the developing brain's vascular system is believed to form a secondary defense, the blood-brain barrier (BBB), which restricts harmful substances that could disrupt neurodevelopment. However, the precise timing and mechanisms underlying BBB development are poorly understood. In this study, we examined the spatiotemporal expression of key BBB components and fetal brain vascularization in mice from gestational days (GD) 10 to 18. Fetal brain sections were immunostained to identify BBB components, including CD31, Factor VIII, NG2, and claudin-5. Our results showed that endothelial precursor cells form the primitive vascular network in a caudal-to-rostral gradient by GD10, with pericyte recruitment stabilizing vessels by GD12 in a lateral-to-medial gradient that aligns with neurogenesis, despite some regional exceptions. However, Factor VIII was not detected until GD15, and claudin-5 until GD18, suggesting a significant delay in endothelial maturation and tight junction formation. These findings highlight the critical timing of structural developments in the fetal brain vasculature and its vulnerability to placental diseases, laying the groundwork for future research on the impact of placental disorders on fetal brain development and potential therapeutic interventions.

The interplay between the nervous and immune systems is well documented in the context of adult physiology and disease. Recent advances in understanding immune cell development have highlighted a significant interaction between neural lineage cells and microglia, the resident brain macrophages, during developmental stages. Throughout development, particularly from the embryonic to postnatal stages, diverse neural lineage cells are sequentially generated, undergo fate determination, migrate dynamically to their appropriate locations while maturing, and establish connections with their surroundings to form neural circuits. Previous studies have demonstrated that microglia contribute to this highly orchestrated process, ensuring the proper organization of brain structure. These findings underscore the need to further investigate how microglia behave and function within a broader framework of neurodevelopment. Importantly, recent epidemiological studies have suggested that maternal immune activation (MIA), triggered by various factors, such as viral or bacterial infections, environmental stressors, or other external influences, can affect neurogenesis and neural circuit formation, increasing the risk of neurodevelopmental disorders (NDDs) in offspring. Notably, many studies have revealed that fetal microglia undergo significant changes in response to MIA. Given their essential roles in neurogenesis and vascular development, inappropriate activation or disruption of microglial function may impair these critical processes, potentially leading to abnormal neurodevelopment. This review highlights recent advances in rodent models and human studies that have shed light on the behaviors and multifaceted roles of microglia during brain development, with a particular focus on the embryonic stage. Furthermore, drawing on insights from rodent MIA models, this review explores how MIA disrupts microglial function and how such disturbances may impair brain development, ultimately contributing to the onset of NDDs.

Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness in older adults. Its pathogenesis involves multiple factors, including aging, environmental influences, genetic predisposition, oxidative stress, metabolic dysfunction, and immune dysregulation. Currently, AMD treatment focuses primarily on wet AMD, managed through repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) therapies. While anti-VEGF agents represent a major breakthrough in wet AMD care, repeated injections may lead to incomplete responses or resistance in some patients, and carry a risk of progressive fibrosis. Artemisinin (ART) and its derivatives, originally developed as antimalarial drugs, exhibit a broad spectrum of pleiotropic activities beyond their established use, including anti-inflammatory, anti-angiogenic, antioxidant, anti-fibrotic, mitochondrial regulatory, lipid metabolic, and immunosuppressive effects. These properties position ART as a promising therapeutic candidate for AMD. A growing interest in ART-based therapies for AMD has emerged in recent years, with numerous studies demonstrating their potential benefits. However, no comprehensive review has systematically summarized the specific roles of ART and its derivatives in AMD pathogenesis and treatment. This paper aims to fill the knowledge gap by synthesizing the therapeutic efficacy and molecular mechanisms of ART and its derivatives in AMD, thereby providing a foundation for future investigations.

The lower urinary tract is comprised of the bladder and urethra and develops from the cloaca, a transient endoderm-derived structure formed from the caudal hindgut. After cloacal septation to form the urogenital sinus and anorectal tract, the bladder gradually develops from the anterior portion of the urogenital sinus while the urethra elongates distally into the genital tubercle. The bladder is a target for regenerative and reconstructive therapies but engineering an impermeable bladder epithelial lining has proven challenging. Urethral epithelial function, including its role as an active immune barrier, is poorly studied and neglected in regenerative therapy. A deeper understanding of epithelial patterning of the urogenital sinus by the surrounding mesenchyme, also accounting for sex-specific differences, can inform regenerative therapies. In this study, we identified spatially distinct genes in the epithelial and mesenchymal compartments of the developing mouse bladder and urethra that could be potential drivers of patterning in the lower urinary tract. Our data revealed spatially restricted domains of transcription factor expression in the epithelium that corresponded with bladder or urethra-specific differentiation. Additionally, we identified the genes Wnt2, Klf4 and Pitx2 that localize to the mesenchyme of the developing bladder and could be potential drivers of bladder differentiation. Our data revealed an increase in the expression of several chemokine genes including Cx3cl1 and Cxcl14 in the developing urethral epithelium that correlated with an increase in epithelial-associated macrophages in the urethra. A survey of sex-specific differences in epithelial and mesenchymal compartments revealed several differentially expressed genes between the male and female urethra but few sex-specific differences in bladder. By comparing spatially distinct gene expression in the developing lower urinary tract, our study provides insights into the divergent differentiation trajectories of the fetal bladder and urethra that establish their adult functions.

Background: Peripheral artery disease is associated with significant morbidity and mortality. Mechanical revascularization strategies are a mainstay of treatment but are often limited by the anatomic complexity of atherosclerotic lesions. Therapeutic angiogenesis has fallen short of being impactful due to fundamental gaps in our understanding of postdevelopmental angiogenesis. Methods: Using a preclinical model of peripheral artery disease involving acute vascular injury by femoral artery ligation along with cellular and molecular studies of VEGF-A expression, we sought to further understand the early role of macrophages in inflammatory angiogenesis and arteriogenesis. Results: Macrophage depletion studies revealed that the optimal levels of tissue VEGF-A expression, endothelial cell recruitment, and blood flow recovery were dependent on early macrophage recruitment. Proangiogenic VEGF-A expression was highest in macrophages polarized towards an inflammatory phenotype. Myeloid VEGF-A-deletion, while having no impact on the potent inflammatory cytokine, IL-1β, led to reductions in ischemic tissue VEGF-A, endothelial cell recruitment, and blood flow recovery due to impaired angiogenesis and arteriogenesis. Transplant of inflammatory polarized macrophages rescued the myeloid VEGF-A-deletion phenotype, leading to full blood flow recovery. Conclusions: Macrophages are a necessary and sufficient source of tissue VEGF-A during inflammatory-driven angiogenesis and arteriogenesis in response to vascular injury. Although further study is needed, cell-based therapeutic angiogenesis strategies involving the polarization of macrophages toward an inflammatory state, in order to produce high levels of proangiogenic VEGF-A, may be quite effective for improving revascularization in the context of PAD.

Osteosarcoma, a primary malignant bone tumor commonly found in adolescents, is highly aggressive, with a high rate of disability and mortality. It has a profound negative impact on both the physical and psychological well-being of patients. The standard treatment approach, comprising surgery and chemotherapy, has seen little improvement in patient outcomes over the past several decades. Once relapse or metastasis occurs, prognosis worsens significantly. Therefore, there is an urgent need to explore new therapeutic approaches. In recent years, the successful application of immunotherapy in certain cancers has demonstrated its potential in the field of cancer treatment. Macrophages are the predominant components of the immune microenvironment in osteosarcoma and represent critical targets for immunotherapy. Macrophages exhibit dual characteristics; while they play a key role in maintaining tumor-promoting properties within the microenvironment, such as inflammation, angiogenesis, and immune suppression, they also possess antitumor potential as part of the innate immune system. A deeper understanding of macrophages and their relationship with osteosarcoma is essential for the development of novel therapeutic strategies.

Cancer immunotherapy is a well-established therapeutic approach for various types of cancer. However, its clinical utility is usually limited by cardiovascular adverse events. Immune Checkpoint Inhibitors (ICIs) can induce diverse forms of cardiotoxicity, with myocarditis being the most fatal complication. The underlying mechanism of its occurrence remains elusive. Therefore, this study aims to elucidate the impact of programmed death-1 (PD-1) inhibitor on myocarditis development in mice. Myeloid-epithelial-reproductive tyrosine kinase (MerTK) receptors, located on the surface of macrophages, play a pivotal role in phagocytic regulation. We established a mouse model of autoimmune myocarditis by injecting 6-week-old normal male BALB/c mice with PD-1 inhibitor and cardiac troponin I peptide fragments, which resulted in elevated levels of serum soluble MerTK (SolMer) and reduced numbers of MerTK-CD68 double-positive macrophages, accompanied by cardiac injury in mice. In vitro, PD-1 inhibitor promotes a disintegrin and metalloproteinase17 (ADAM17)-mediated shed of the MerTK, forming SolMer, through MKK3/P38 MAPK pathway, leading to downregulation of MerTK expression on the macrophage surface. This results in the inhibition of efferocytosis and impairment of tissue repair function, ultimately contributing to myocarditis development. TAPI-0 inhibited the activity of ADAM17, while SB203580 inhibited the phosphorylation of P38 MAPK. Both inhibitors effectively restored the inhibition of efferocytosis induced by the PD-1 inhibitor. In vitro, when the PD-1 receptor on the surface of RAW264.7 macrophages was knocked down and then stimulated with a PD-1 inhibitor, no further significant alterations in the pathway were elicited. In conclusion, the PD-1 inhibitor induces the shedding of MerTK in macrophages by binding to the PD-1 receptor on the surface of macrophages and activating the MKK3/P38 MAPK/ADAM17 pathway, leading to impaired efferocytosis. Elucidation of this molecular mechanism holds promise for improved prognosis and therapeutic strategies in cancer patients.

The neuroretinal vascular system is comprised of three interconnected layers. The initial superficial vascular plexus formation is guided by astrocytes around birth in mice. The formation of the deep and intermediate vascular plexuses occurs in the second postnatal week and is driven by Müller-cell-derived angiogenic signaling. Previously, we reported that microglia play an important role in regulating astrocyte density during superficial vascular plexus formation. Here, we investigated the role of microglia in regulating Müller-cell-dependent inner retinal vascular development.

In this study, we depleted microglia during retinal development using Csf1R antagonist (PLX5622). We characterized the developmental progression of inner retinal vascular growth, effect of microglial depletion on inner retinal vascular growth and Müller cell marker expressions by immunostaining. Differential expressions of genes in the control and microglia depleted groups were analyzed by mRNA-seq and qPCR. Unpaired t-test was performed to determine the statistical differences between groups.

This study show that microglia interact with Müller cells and the growing inner retinal vasculature. Depletion of microglia resulted in reduced inner retinal vascular layers densities and decreased Vegfa isoforms transcript levels. RNA-seq analysis further revealed that microglial depletion significantly reduced specific Müller cell maturation markers including glutamine synthetase, responsible for glutamine biosynthesis, necessary for angiogenesis.

Our study reveals an important role for microglia in facilitating inner retinal angiogenesis and Müller cell maturation.

Bladder cancer (BCa) is a prevalent malignancy characterized by a poor prognosis. Numerous studies have increasingly recognized the role of M2 macrophages in cancer progression. Consequently, our objective is to investigate hub genes in BCa associated with M2 macrophages, assessing their prognostic significance and exploring potential regulatory mechanisms.

We performed a comprehensive bioinformatics analysis using data from urine proteomics, the Gene Expression Omnibus (GEO) database, and The Cancer Genome Atlas (TCGA) database, in conjunction with machine learning methods such as LASSO and SVM to identify intersections of differentially expressed genes (DEGs). Subsequently, the role of hub genes in BCa was validated in vitro and in vivo using CCK-8 assay, wound healing assay, immunofluorescence assay, transwell assay, immunohistochemistry, and xenograft tumor model. Finally, we investigated the correlation between hub genes and M2 macrophage immune infiltration using the TIMER database.

Chitinase 3 like 1 (CHI3L1) emerged as a pivotal gene linked to M2 macrophages in BCa. Notably, CHI3L1 was associated with a poor prognosis for BCa, with elevated expression correlating to more advanced histologic and pathologic stages in BCa patients. The findings suggest that inhibiting CHI3L1 can effectively impede the proliferation, migration, and invasion of BCa cells and synergistically increase the inhibitory effect of gemcitabine (GEM) on cell activity. Meanwhile, the downregulation of CHI3L1 was accompanied by inhibition of the PI3K-AKT signaling pathway. Additionally, CHI3L1 demonstrated a significant association with M2 macrophage infiltration in the BCa tumor microenvironment (TME).

The present study suggests that CHI3L1 may promote bladder cancer progression through the PI3K-Akt signaling pathway and is associated with M2 macrophage infiltration.

Atherosclerosis (AS) is a chronic inflammatory vascular disease closely tied to cellular metabolism. Recent genome-wide association study data have suggested the significant roles of endothelial cells, smooth muscle cells, and macrophages in the regression and exacerbation of AS. However, the impact of cellular crosstalk and cellular metabolic derangements on disease progression in AS is vaguely understood. In this review, we analyze the roles of the three cell types in AS. We also summarize the crosstalk between the two of them, and the associated molecules and consequences involved. In addition, we emphasize potential therapeutic targets and highlight the importance of the three-cell co-culture model and extracellular vesicles in AS-related research, providing ideas for future studies.

Wound healing is a dynamic, multi-stage process essential for restoring skin integrity. Dysregulated wound healing is often linked to impaired macrophage function, particularly in individuals with chronic underlying conditions. Macrophages, as key regulators of wound healing, exhibit significant phenotypic diversity, ranging from the pro-healing M2 phenotype to the pro-inflammatory M1 phenotype. Imbalances in the M1/M2 ratio or hyperactivation of the M1 phenotype can delay the normal healing. Consequently, strategies aimed at suppressing the M1 phenotype or promoting the shift of local skin macrophages toward the M2 phenotype can potentially treat chronic non-healing wounds. This manuscript provides an overview of macrophages' role in normal and pathological wound-healing processes. It examines various therapeutic approaches targeting M2 macrophages, such as ex vivo-activated macrophage therapy, immunopharmacological strategies, and biomaterial-directed macrophage polarization. However, it also highlights that M2 macrophage therapies and immunopharmacological interventions may have drawbacks, including rapid phenotypic changes, adverse effects on other skin cells, biotoxicity, and concerns related to biocompatibility, stability, and drug degradation. Therefore, there is a need for more targeted macrophage-based therapies that ensure optimal biosafety, allowing for effective reprogramming of dysregulated macrophages and improved therapeutic outcomes. Recent advances in nano-biomaterials have demonstrated promising regenerative potential compared to traditional treatments. This review discusses the progress of biomaterial-assisted macrophage targeting in chronic wound repair and addresses the challenges faced in its clinical application. Additionally, it explores novel design concepts for combinational therapies, such as incorporating regenerative particles like exosomes into dressing materials or encapsulating them in microneedling systems to enhance wound healing rates.

Current biomedical titanium alloys have been repurposed from other industries, which has contributed to several biologically driven implant failure mechanisms. This review highlights the added value that may be gained by building an appreciation of implant biological responses at the onset of alloy design. Specifically, the fundamental mechanisms associated with immune response, angiogenesis, osseointegration and the potential threat of infection are discussed, including how elemental selection can modulate these pivotal systems. With a view to expedite inclusion of these interactions in alloy design criteria, methods to analyze these performance characteristics are also summarized. While machine learning techniques are being increasingly used to unearth complex relationships between alloying elements and material properties, much is still unknown about the correlation between composition and some bio-related properties. To bridge this gap, high-throughput methods are also reviewed to validate biological response along with cutting edge manufacturing approaches that may support rapid discovery. Taken together, this review encourages the alloy development community to rethink their approach to enable a new generation of biomedical implants intrinsically designed for a life in the body, including functionality to tackle biological challenges thereby offering improved patient outcomes.

Macrophages play an important role in the development of vascular diseases, with their homeostasis closely linked to metabolic reprogramming. This study aims to explore the role of circular RNA-mediated epigenetic remodeling in maintaining macrophage homeostasis during diabetes-induced microvascular dysfunction. We identified a circular RNA, circRNA-sperm antigen with calponin homology and coiled-coil domains 1 (cSPECC1), which is significantly up-regulated in diabetic retinas and in macrophages under diabetic stress. cSPECC1 knockdown in macrophages attenuates M1 macrophage polarization and disrupts macrophage-endothelial crosstalk in vitro. cSPECC1 knockdown in macrophages mitigates diabetes-induced retinal inflammation and ameliorates retinal vascular dysfunction. Mechanistically, cSPECC1 regulates GPX2 expression by recruiting eIF4A3, enhancing GPX2 mRNA stability and altering arachidonic acid metabolism. The metabolic intermediate 12-HETE has emerged as a key mediator, regulating both macrophage homeostasis and the crosstalk between macrophages and endothelial cells. Exogenous 12-HETE supplementation interrupts the anti-angiogenic effects of cSPECC1 knockdown. Collectively, circSPECC1 emerges as a novel regulator of macrophage-mediated vascular integrity and inflammation. Targeting the metabolic reprogramming of macrophages presents a promising therapeutic strategy for mitigating diabetes-induced vascular dysfunction.

With the widespread application of pesticides, water pollution problems are becoming more and more serious, which is very likely to cause harm to fish. Lower vertebrates, including fish, have the ability to repair damaged tissues. The spread of pesticides in the water may affect their regeneration process after injury, leading to their death, thereby affecting the survival rate of the population. Therefore, we used zebrafish as a model animal to evaluate the effect of the pesticide pyrazosulfuron-ethyl on caudal fin regeneration in zebrafish larvae. We exposed zebrafish larvae to 0, 5, 15, and 25 mg/L pyrazosulfuron-ethyl at 3 days after caudal fin amputation. It was found that exposure to pyrazosulfuron-ethyl significantly inhibited caudal fin regeneration and affected the behavior of zebrafish larvae. After exposure to pyrazosulfuron-ethyl, proliferating cells decreased and apoptotic cells increased in the caudal fin of zebrafish larvae. Pyrazosulfuron-ethyl exposure resulted in the decreased number of neutrophils and macrophages, and the downregulation of immune related gene expression levels during caudal fin. Using LPS to activate inflammation can effectively rescue the fin regeneration defects induced by pyrazosulfuron-ethyl. However, inhibiting the Notch signaling pathway and inhibiting reactive oxygen cannot rescue the fin regeneration defects induced by pyrazosulfuron-ethyl. Our results indicate that pyrazosulfuron-ethyl can inhibit zebrafish caudal fin regeneration by reducing the number of innate immune cells and affecting the normal process of inflammation, thereby inhibiting caudal fin regeneration. This study expands our understanding of the potential effects of the pesticide pyrazosulfuron-ethyl on injured fish, highlights the link between the immune system and the regeneration process, and demonstrates the potential application of fin regeneration in risk assessments of environmental toxicology to assess drug toxicity.

Vascular calcification (VC) is a crucial risk factor for the high morbidity and mortality associated with cardiovascular and cerebrovascular diseases. With the global population aging, the incidence of VC is escalating annually. However, due to its silent clinical process, VC often results in irreversible clinical outcomes. Inflammation is a core element in the VC process, and macrophages are the major inflammatory cells. Due to their diverse origins, microenvironments, and polarization states, macrophages exhibit significant heterogeneity, exerting strong effects on the occurrence, development, and even the regression of VC. In this review, we summarize the origin, distribution, classification, and surface markers of macrophages. Simultaneously, we explore the mechanisms by which macrophages maintain homeostasis or regulate inflammation, including the macrophage-mediated regulation of VC through the release of inflammatory factors, osteogenic genes, extracellular vesicles, and alterations in efferocytosis. Finally, we discuss research targeting inflammation and macrophages to develop novel therapeutic regimens for preventing and treating VC.

Immuno-fibrotic networks and their protein mediators, such as cytokines and chemokines, have increasingly been appreciated for their critical role in cardiac healing and fibrosis during cardiomyopathy. Immune activation, trafficking, and extravasation are tightly regulated to ensure a targeted and effective response against non-self antigens/pathogens while preserving tolerance towards self-antigens and coordinate fibrotic responses for efficient scar formation, a distinction that is severely compromised during chronic diseases. It is clear that immune cells are not only the critical regulators of post-infarct healing and scarring but are also the key players in regulating fibroblast activation during left-ventricular (LV) remodeling. Incomplete resolution coupled with sustained low-grade inflammation during dilated cardiomyopathy precipitates a "frustrated" immune cell response resulting in unconstrained pro-fibrotic and pro-hypertrophic signaling to induce maladaptive structural and functional changes in the myocardium. The aims of this review are to (i) briefly summarize the role of key immune cells that regulate wound healing during MI and fibrosis during LV remodeling; (ii) underscore phenotypic diversities in immune cells and their subsets to underscore their role in regulating fibrotic responses, and, last but not the least, (iii) highlight gaps in our understanding that restrict the translation of immuno-modulatory therapies from the preclinical models to heart failure patients.

Brain vasculature formation begins with vessel invasion from the perineural vascular plexus, which expands through vessel sprouting and growth. Recent studies have indicated the existence of oligodendrocyte-vascular crosstalk during development. However, the relationship between oligodendrocyte progenitor cells (OPCs) and the ordered spatiotemporal vascularization of the neocortex has not been elucidated. Our findings suggest that OPCs play a complex role in the vessel density of the embryonic and postnatal neocortex. Analyses of normal human and mouse embryonic cerebral cortex show that vascularization and OPC distribution are tightly controlled in a spatially and temporally restricted manner, exhibiting a positive correlation. Loss of OPCs at both embryonic and postnatal stages led to a reduction in vascular density, suggesting that OPC populations play a role in vascular density. Nonetheless, dynamic observation on cultured brain slices and staining of tissue sections indicate that OPC migration is unassociated with the proximity to blood vessels, primarily occurring along radial glial cell processes. Additionally, in vitro experiments demonstrate that OPC secretions promote vascular endothelial cell (VEC) growth. Together, these observations suggest that vessel density is influenced by OPC secretions.

Diverse macrophage populations inhabit the rodent and human central nervous system (CNS), including microglia in the parenchyma and border-associated macrophages (BAMs) in the meninges, choroid plexus, and perivascular spaces. These innate immune phagocytes are essential in brain development and maintaining homeostasis, but they also play diverse roles in neurological diseases. In this review, we highlight the emerging roles of CNS macrophages in regulating vascular function in health and disease. We discuss that, in addition to microglia, BAMs, including perivascular macrophages, play roles in supporting vascular integrity and maintaining blood flow. We highlight recent advancements in understanding how these macrophages are implicated in protecting against vascular dysfunction and modulating the progression of cerebrovascular diseases, as seen in vessel-associated neurodegeneration.

Prenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs. How the maternal as well as the fetal immune system affect human neurodevelopment and contribute to NDDs remains unclear. An important reason for this knowledge gap is the fact that the impact of exposure to prenatal risk factors has been challenging to study in the human context. Here, we characterized a model of cerebral organoids (CO) with integrated microglia (COiMg). These organoids express typical microglial markers and respond to inflammatory stimuli. The presence of microglia influences cerebral organoid development, including cell density and neural differentiation, and regulates the expression of several ciliated and mesenchymal cell markers. Moreover, COiMg and organoids without microglia show similar but also distinct responses to inflammatory stimuli. Additionally, IFN-γ induced significant transcriptional and structural changes in the cerebral organoids, that appear to be regulated by the presence of microglia. Specifically, interferon-gamma (IFN-γ) was found to alter the expression of genes linked to autism. This model provides a valuable tool to study how inflammatory perturbations and microglial presence affect neurodevelopmental processes.

The germinal matrix harbors neurogenic niches in the subpallium of the prenatal human brain that produce abundant GABAergic neurons. In preterm infants, the germinal matrix is particularly vulnerable to developing hemorrhage, which disrupts neurogenesis and causes severe neurodevelopmental sequelae. However, the disease mechanisms that promote germinal matrix hemorrhage remain unclear. Here, we review recent advances using single-cell transcriptomics to uncover novel mechanisms that govern neurogenesis and angiogenesis in the germinal matrix of the prenatal human brain. These approaches also reveal the critical role of immune-vascular interaction that promotes vascular morphogenesis in the germinal matrix and how proinflammatory factors from activated neutrophils and monocytes can disrupt this process, leading to hemorrhage. Collectively, these results reveal fundamental disease mechanisms and therapeutic interventions for germinal matrix hemorrhage.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide, with limited effective therapeutic options currently available. Recent research has highlighted the pivotal role of mitochondrial dysfunction in the pathophysiology of TBI, making mitochondria an attractive target for therapeutic intervention. This review comprehensively examines advancements in mitochondrial-targeted therapies for TBI, bridging the gap from basic research to clinical applications. We discuss the underlying mechanisms of mitochondrial damage in TBI, including oxidative stress, impaired bioenergetics, mitochondrial dynamics, and apoptotic pathways. Furthermore, we highlight the complex interplay between mitochondrial dysfunction, inflammation, and blood-brain barrier (BBB) integrity, elucidating how these interactions exacerbate injury and impede recovery. We also evaluate various preclinical studies exploring pharmacological agents, gene therapy, and novel drug delivery systems designed to protect and restore mitochondrial function. Clinical trials and their outcomes are assessed to evaluate the translational potential of mitochondrial-targeted therapies in TBI. By integrating findings from bench to bedside, this review emphasizes promising therapeutic avenues and addresses remaining challenges. It also provides guidance for future research to pave the way for innovative treatments that improve patient outcomes in TBI.

In recent years, neural organoids derived from human pluripotent stem cells (hPSCs) have offered a transformative pre-clinical platform for understanding central nervous system (CNS) development, disease, drug effects, and toxicology. CNS vasculature plays an important role in all these scenarios; however, most published studies describe CNS organoids that lack a functional vasculature or demonstrate rudimentary incorporation of endothelial cells or blood vessel networks. Here, we review the existing knowledge of vascularization during the development of different CNS regions, including the brain, spinal cord, and retina, and compare it to vascularized CNS organoid models. We highlight several areas of contrast where further bioengineering innovation is needed and discuss potential applications of vascularized neural organoids in modeling human CNS development, physiology, and disease.

The response rates to immunotherapy vary widely depending on the type of cancer and the specific treatment used and can be disappointingly low for many solid tumors. Fortunately, due to their complementary mechanisms of action, immunotherapy and anti-angiogenic therapy have synergistic effects in cancer treatment. By normalizing the tumor vasculature, anti-angiogenic therapy can improve blood flow and oxygenation to facilitate better immune cell infiltration into the tumor and enhance the effectiveness of immunotherapy. It also reduces immunosuppressive factors and enhances immune activation, to create a more favorable environment for immune cells to attack the tumor. Their combination leverages the strengths of both therapies to enhance anti-tumor effects and improve patient outcomes. This review discusses the vasculature-immunity crosstalk in the tumor microenvironment and summarizes the latest advances in combining anti-angiogenic therapy and immune checkpoint inhibitors to treat digestive system tumors.

Microglia, a widely dispersed cohort of immune cells in the retina, are intricately involved in a diverse range of pivotal biological processes, including inflammation, vascular development, complement activation, antigen presentation, and phagocytosis. Within the retinal milieu, microglia are crucial for the clearance of dead cells and cellular debris, release of anti-inflammatory agents, and orchestration of vascular network remodeling to maintain homeostasis. In addition, microglia are key mediators of neuroinflammation. Triggered by oxidative stress, elevated intraocular pressure, genetic anomalies, and immune dysregulation, microglia release numerous inflammatory cytokines, contributing to the pathogenesis of various retinal disorders. Recent studies on the ontogeny and broad functions of microglia in the retina have elucidated their characteristics during retinal development, homeostasis, and disease. Furthermore, therapeutic strategies that target microglia and their effector cytokines have been developed and shown positive results for some retinal diseases. Therefore, we systematically review the microglial ontogeny in the retina, elucidate their dual roles in retinal homeostasis and disease pathogenesis, and demonstrate microglia-based targeted therapeutic strategies for retinal diseases.

Chronic limb-threatening ischemia (CLTI), the most advanced form of peripheral arterial disease (PAD), is the comorbidity primarily responsible for major lower-limb amputations, particularly for diabetic patients. Autologous cell therapy has been the focus of efforts over the past 20 years to create non-interventional therapeutic options for no-option CLTI to improve limb perfusion and wound healing. Among the different available techniques, peripheral blood mononuclear cells (PBMNC) appear to be the most promising autologous cell therapy due to physio-pathological considerations and clinical evidence, which will be discussed in this review. A meta-analysis of six clinical studies, including 256 diabetic patients treated with naive, fresh PBMNC produced via a selective filtration point-of-care device, was conducted. PBMNC was associated with a mean yearly amputation rate of 15.7%, a mean healing rate of 62%, and a time to healing of 208.6 ± 136.5 days. Moreover, an increase in TcPO2 and a reduction in pain were observed. All-cause mortality, with a mean rate of 22.2% and a yearly mortality rate of 18.8%, was reported. No serious adverse events were reported. Finally, some practical and financial considerations are provided, which point to the therapy's recommendation as the first line of treatment for this particular and crucial patient group.

Roundabout (ROBO) 1 and 2 are transmembrane receptors that bind secreted SLIT ligands through their extracellular domains (ECDs) and signal through their cytoplasmic domains to modulate the cytoskeleton and regulate cell migration, adhesion, and proliferation. SLIT-ROBO signaling regulates pathological ocular neovascularization, which is a major cause of vision loss worldwide, but pharmacological tools to prevent SLIT-ROBO signaling are lacking. Here, we developed human monoclonal antibodies (mAbs) against the ROBO1 and ROBO2 ECDs. One antibody that inhibited in vitro SLIT2 signaling through ROBO1 and ROBO2 (anti-ROBO1/2) also reduced ocular neovascularization in oxygen-induced retinopathy (OIR) and laser-induced corneal neovascularization (CNV) mouse models in vivo. Single-cell RNA sequencing of OIR retinas revealed that antibody treatment affected several cell types relevant to physiological and pathological angiogenesis, including endothelial cells, pericytes, and a heterogeneous population of myeloid cells. mAb treatment improved blood-retina barrier integrity and prevented pathological pericyte activation in OIR. SLIT-ROBO signaling inhibition prevented pathological activation of myeloid cells and increased neuroprotective myeloid populations normally seen in the developing retina. Microglia/infiltrating macrophage-specific ablation of Robo1 and Robo2 or knockout of the downstream effector phosphatidylinositol 3-kinase (Pik3cg) encoding PI3Kγ in both OIR and CNV models phenocopied anti-ROBO1/2 treatment, further demonstrating the key role of myeloid cells as drivers of ocular neovascular diseases. ROBO1/2 blocking antibodies may thus provide a promising strategy to combat inflammation in blinding eye diseases.

Organogenesis is a complex process that relies on a dynamic interplay between extrinsic factors originating from the microenvironment and tissue-specific intrinsic factors. For pancreatic endocrine cells, the local niche consists of acinar and ductal cells as well as neuronal, immune, endothelial, and stromal cells. Hematopoietic cells have been detected in human pancreas as early as 6 post-conception weeks, but whether they play a role during human endocrinogenesis remains unknown. To investigate this, we performed single-nucleus RNA sequencing (snRNA-seq) of the second-trimester human pancreas and identified a wide range of hematopoietic cells, including two distinct subsets of tissue-resident macrophages. Leveraging this discovery, we developed a co-culture system of human embryonic stem cell-derived endocrine-macrophage organoids to model their interaction in vitro. Here, we show that macrophages support the differentiation and viability of endocrine cells in vitro and enhance tissue engraftment, highlighting their potential role in tissue engineering strategies for diabetes.

Human prenatal skin is populated by innate immune cells, including macrophages, but whether they act solely in immunity or have additional functions in morphogenesis is unclear. Here we assembled a comprehensive multi-omics reference atlas of prenatal human skin (7-17 post-conception weeks), combining single-cell and spatial transcriptomics data, to characterize the microanatomical tissue niches of the skin. This atlas revealed that crosstalk between non-immune and immune cells underpins the formation of hair follicles, is implicated in scarless wound healing and is crucial for skin angiogenesis. We systematically compared a hair-bearing skin organoid (SkO) model derived from human embryonic stem cells and induced pluripotent stem cells to prenatal and adult skin1. The SkO model closely recapitulated in vivo skin epidermal and dermal cell types during hair follicle development and expression of genes implicated in the pathogenesis of genetic hair and skin disorders. However, the SkO model lacked immune cells and had markedly reduced endothelial cell heterogeneity and quantity. Our in vivo prenatal skin cell atlas indicated that macrophages and macrophage-derived growth factors have a role in driving endothelial development. Indeed, vascular network remodelling was enhanced following transfer of autologous macrophages derived from induced pluripotent stem cells into SkO cultures. Innate immune cells are therefore key players in skin morphogenesis beyond their conventional role in immunity, a function they achieve through crosstalk with non-immune cells.