Hepatopulmonary syndrome (HPS) is a condition characterized by pulmonary angiogenesis and refractory hypoxemia, often seen in patients with chronic liver disease. Its unclear mechanism means that liver transplantation is the only effective therapy. Agrimoniin, a compound from Pilosa ledeb, shows potential in protecting against liver cirrhosis via anti-angiogenic and anti-glycolytic effects. This study investigates agrimoniin as a potential integrated therapy for HPS-related liver and lung dysfunction. Using transcriptome data and an ICU cohort, we analyzed the role of glycolysis in chronic liver disease progression. HPS rats were established via common bile duct ligation, and serum metabolites were measured. The oxygen consumption rate and extracellular acidification rate were also detected. Rats were treated with agrimoniin (3 mg/kg/day or 8 mg/kg/day) at the early stage of HPS. Our results showed that imbalanced oxidative phosphorylation and glycolysis correlated with chronic liver disease progression and poorer outcomes. Decreased oxygen consumption rate and increased extracellular acidification rate, as well as increased glycolysis, were observed in the HPS group. Agrimoniin treatment improved liver and lung function by inhibiting pathological angiogenesis and glycolysis. Through TCM suite analysis, molecular docking, and dynamics simulations, PGC-1α was identified as a potential target of agrimoniin. Inhibiting PGC-1α blocked agrimoniin's benefits on angiogenesis and glycolysis flux. Thus, agrimoniin may be a potential integrated therapy for HPS by activating PGC-1α to inhibit glycolysis and angiogenesis.
Vasculogenic mimicry (VM) contributes significantly to tumor aggressiveness and resistance to anti-angiogenic therapies. Simultaneous inhibition of both angiogenesis and VM represents a promising strategy to improve therapeutic outcomes in aggressive cancers, such as triple-negative breast cancer (TNBC), which responds poorly to anti-angiogenic therapies. In this study, we identified carvacrol, a natural monoterpenoid phenol widely used as a food additive, as a dual inhibitor of angiogenesis and VM in TNBC. Carvacrol preferentially inhibited angiogenesis in endothelial cells (ECs) and VM in TNBC cells at concentrations that had minimal effects on TNBC cell proliferation. Mechanistically, carvacrol directly bound to the vanilloid-like (VL) site of transient receptor potential melastatin 7 (TRPM7), thereby inhibiting channel activity and attenuating Zn2+ influx. This triggered dephosphorylation of the mammalian target of rapamycin (mTOR) and subsequent proteasomal and lysosomal degradation of key receptor tyrosine kinases (RTKs), including vascular endothelial growth factor receptor 2 (VEGFR2), Tie2, fibroblast growth factor receptor 1 (FGFR1), and insulin-like growth factor 1 receptor (IGF1R) in ECs, as well as FGFR1 and IGF1R in TNBC cells. Genetic knockdown of TRPM7 recapitulated the anti-vascular effects and signaling alterations induced by carvacrol. In vivo, carvacrol effectively suppressed TNBC vascularization and growth in a mouse dorsal skinfold chamber model and an orthotopic xenograft model. Together, these findings suggest that carvacrol preferentially targets angiogenesis and VM in TNBC by suppressing the TRPM7/Zn2+/mTOR/RTKs axis, highlighting it as a promising therapeutic candidate for TNBC and potentially other tumors resistant to anti-angiogenic therapies, while positioning the TRPM7 channel as a novel anti-vascular target for TNBC treatment.
Heme is an essential iron-containing porphyrin of vital importance for all cells, including endothelial cell (EC). Indeed, due to its involvement in several biological processes, including gene transcription regulation, energy production, anabolic processes, heme metabolism is critically required in high-energy-demanding processes like angiogenesis. Over the past decade, growing evidence has identified heme metabolism as a central regulator of the angiogenic process. Hence, targeting heme synthesis and homeostasis could offer valuable therapeutic opportunities to modulate pathological neovascularization, as in ocular neovascularization diseases and cancer, and, potentially, to support neo-vascular growth in conditions characterized by insufficient blood supply as ischemia and stroke.The present review summarizes the literature on heme and angiogenesis, emphasizing the novel functions of heme, beyond its more canonical role as cofactor in hemoproteins and addressing how heme homeostasis can orchestrate a plethora of endothelial functions indispensable for angiogenesis.
Cryopreserved porcine skin (CPS) is widely applied in skin grafting for burns. In this study, we aimed to investigate the effects and underlying mechanisms of CPS on burn wound healing. Cryopreserved porcine skins were acquired. Guinea pig burn models were established and grafted with thawed-CPS. Human umbilical vein endothelial cells (HUVECs) were cultured in CPS-conditioned medium. Histological structure was assessed by hematoxylin-eosin (HE) staining. Protein levels were detected using enzyme-linked immunosorbent assay (ELISA), western blot, and immunohistochemistry. HUVECs proliferation was evaluated by 5-ethynyl-2'-deoxyuridine (EdU) assay. The invasion and migration of HUVECs were analyzed via Transwell assay. Tube formation was also assessed. CPS maintained its structural integrity and cellular viability, with lower antigenicity compared with fresh porcine skin. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-1 alpha (IL-1α) secreted by CPS were detected in the CPS-grafted burned tissue. Moreover, CPS grafting accelerated wound healing and angiogenesis in burned guinea pigs. In vitro, CPS-conditioned medium enhanced the proliferation, invasion, migration, and tube formation of HUVECs, as well as activated the JAK2/STAT3 pathway. Neutralizing antibodies against GM-CSF and IL-1α synergistically reversed the pro-angiogenic effects of CPS in vivo and in vitro. Additionally, JAK2 inhibitor AG490 abolished the enhanced proliferation, invasion, migration, and tube formation of HUVECs induced by CPS-conditioned medium. We confirmed that CPS-secreted GM-CSF and IL-1α promoted angiogenesis in burn tissue by activating the JAK2/STAT3 pathway, thereby revealing an active therapeutic role of CPS for burn wound healing and offering theoretical support for its clinical application.
Breast cancer remains one of the leading causes of cancer-related mortality amongst women worldwide, with rising incidence rates paralleling the global obesity epidemic. Obesity has been increasingly recognised as a risk factor for breast cancer, yet the molecular mechanisms underlying the association remain poorly understood. This review explores the role of angiogenesis as the central mechanism linking obesity to breast cancer progression. Angiogenesis is essential for both adipose tissue expansion and tumour growth. It is dysregulated in obesity and breast cancer, resulting in the formation of abnormal vasculature that perpetuates hypoxia and malignancy. Obesity contributes to this process through hypertrophic adipose tissue, altered adipokine profiles and elevated expression of proangiogenic factors, such as VEGF. These changes create a tumour microenvironment conducive to cancer progression, treatment resistance and poor clinical outcomes. Emerging evidence also implicates endothelial cells, pericytes and lipid metabolism in this interaction, suggesting novel therapeutic targets.
During cardiac development, the myocardium expands in response to physiological demands to achieve proper cardiac morphology and functional contractility, while simultaneously integrating with the developing coronary vasculature. However, the mechanisms governing this ordered expansion remain poorly understood. Here, we found that regional hypoxia drives local tissue thickening, which in turn exacerbates a hypoxic microenvironment. We demonstrate that epicardial hypoxia serves as a central regulatory mechanism, coordinating both coronary angiogenesis and myocardial expansion during juvenile zebrafish heart development. This mechanism activates discrete spatial patterns of epicardial gene expression, including vegfaa, loxl2a, and col12a1b. Through live and fixed imaging, we find that cardiomyocytes and endothelial cells exhibit coordinated expansion patterns through third-party epicardial signals that are required for both coronary development and myocardial expansion. Using cxcr4aum20 mutants lacking functional coronary vessels, we show that coronary vessels provide negative feedback on epicardial hypoxia, while positively responding to the same hypoxic cues that drive myocardial expansion. Disruption of this negative feedback leads to increased myocardial stiffness through dysregulated extracellular matrix crosslinking as observed in pathological conditions such as cardiomyopathies. These findings establish the role of regional epicardial hypoxia within a fundamental regulatory network that drives appropriate regional tissue growth with integrated vascular supply during cardiac morphogenesis.
We employed nanoparticle (NP) platforms to enhance the delivery of both erythropoietin receptor (EpoR) plasmids (pEpoR) and the antisense of pEpoR (pRopE) to induce angiogenesis in ischemic tissues of peripheral arterial disease (PAD). Poly (lactic-co-glycolic acid) (PLGA) NPs loaded with these plasmids were successfully fabricated and characterized. In migration assays, pEpoR/pRopE NPs exhibited a synergistic effect, significantly outperforming pEpoR NPs alone (by 3.7-fold) and pRopE NPs alone (by 2.3-fold). Furthermore, the dual-plasmid NPs significantly enhanced cell survival and facilitated tube formation compared to the VEGF-treated group. In a PAD animal model, pEpoR/pRopE NPs improved blood perfusion in ischemic limbs by 3.8-fold and increased capillary densities in the gastrocnemius muscle by 4.7-fold compared to the VEGF group. In conclusion, pEpoR/pRopE NPs successfully transfected ischemic cells, enhancing both blood perfusion and capillary densities in ischemic tissues, highlighting their therapeutic potential for PAD treatment.
[This corrects the article DOI: 10.1016/j.mtbio.2026.102976.].
[This corrects the article DOI: 10.1016/j.mtbio.2024.101361.].
Chronic diabetic wounds remain a major clinical challenge owing to impaired angiogenesis, persistent inflammation and cellular dysfunction. In this study, we developed a bioadhesive composite hydrogel scaffold (gelatin methacryloyl/alginate methacrylate [GA]) fabricated using digital light processing three-dimensional (3D) bioprinting, in which human adipose-derived mesenchymal stem cells (ADSCs) or their conditioned medium (CM) was incorporated to generate 3D skin constructs, and compared the paracrine effects on skin regeneration. We characterized the microstructures of GA-ADSC and GA-CM scaffolds; profiled CM proteins and systematically compared the effects of GA-ADSCs and GA-CM on fibroblast proliferation, migration, angiogenesis and macrophage polarization in vitro. Their therapeutic efficacy was further evaluated in diabetic mouse wound models, including analyses of collagen deposition, angiogenesis and fibrosis markers. Furthermore, proteomic analysis was performed to understand the underlying mechanisms. In vitro, both GA-ADSCs and GA-CM promoted fibroblast proliferation, migration, angiogenesis and macrophage M2 polarization. Moreover, they accelerated wound closure in diabetic mice by enhancing collagen deposition and neovascularization (CD31) and suppressing α-smooth muscle actin and transforming growth factor-β1 expression. Notably, GA-ADSCs showed prolonged cell viability and exhibited stronger immunomodulatory and antifibrotic effects than GA-CM. Proteomic analysis revealed distinct mechanistic differences: GA-ADSCs markedly activated Toll-like receptor signaling, necroptosis and extracellular matrix remodeling pathways, suggesting their key roles in immune regulation and metabolic reprogramming. In contrast, GA-CM primarily activated the Hippo signaling pathway, consistent with its role in growth factor-mediated tissue repair. Furthermore, we compared the differentially regulated proteins between ADSCs and CM in diabetic wounds and showed that ADSCs significantly modulated RGL2, RSPH9 and CRTC3, which are associated with enhanced cellular function and energy metabolism. These findings provide mechanistic insights into ADSC- and CM-mediated effects and support the development of bioinspired stem cell-based therapeutic strategies for chronic diabetic wound repair.
Cerebrovascular diseases are a major cause of morbidity/mortality worldwide, yet more than 30% of strokes remain of undetermined origin. Rare cerebrovascular diseases (rCVDs) contribute to this burden but are often underdiagnosed due to limited awareness, clinical heterogeneity, and fragmented diagnostic access. The ALIGNED project was established to address these gaps through a nationwide multidisciplinary network. ALIGNED was aimed to improve clinical/molecular characterization of rCVDs through standardized data collection, assess level of care of rCVDs by an online/on-site survey and reduce the geographical gap across Italy, by a virtual model of rCVDs care. In the first phase we conducted a survey to evaluate the availability of diagnostic/therapeutic pathways. Preliminary molecular profiling (i.e., transcriptomic/proteomic analyses) has been carried out on middle-cerebral artery and plasma samples from Moyamoya angiopathy (MMA) patients. Fourty-nine centers adhered to the project. Initially, we collected a cohort of 308 subjects with rCVDs: CADASIL (162), COL4A1/A2-related disease (9), Sneddon syndrome (25), Fabry disease (32), and MMA (80). Web-based survey and site visits provided a representative overview of national capabilities in rCVD diagnosis and care. Transcriptomic analysis showed a peculiar expression profile of angiogenesis growth factors/inhibitors in MMA cerebral vessels. Plasma proteomic profiles of MMA patients highlighted circulating proteins expressed in dysfunctional angiogenesis. Preliminary data suggested a substantial variability in the quality of rCVDs management and in the availability of diagnostic tools across Italy. Thus, mapping Italian expertise and facilities emerged as a crucial target for pinpointing gaps, improving resource allocation, standardizing rCVD care to guarantee equitable access for patients.
Diabetes mellitus severely impairs wound healing, in part due to persistent inflammation, impaired angiogenesis, and dysregulated cellular responses. Sirtuin-1 (Sirt1), an NAD+-dependent deacetylase, has emerged as a promising therapeutic target for restoring regenerative capacity in diabetic wounds. However, effective and localized gene delivery remains a major challenge. Here, we report an injectable thermoresponsive poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) hydrogel as a localized delivery platform for lentiviruses encoding Sirt1 (LV-Sirt1) to promote sustained gene expression and tissue regeneration in diabetic full-thickness dermal wounds. Encapsulation of LV-Sirt1 within PPCN enabled in situ gelation and significantly accelerated wound closure compared with hydrogel or virus alone. Histological analyses revealed enhanced re-epithelialization, increased granulation tissue formation, and improved epidermal barrier restoration. Immunofluorescence staining demonstrated elevated fibroblast activity, reduced inflammatory response, and a facilitated polarization of macrophage from a pro-inflammatory M1 phenotype toward a regenerative M2 phenotype. Transcriptomic analysis further revealed that Sirt1 modulates key genes associated with immune regulation (Spp1, Ccl24, Ggt1), epithelial migration (Krt8), vascular stabilization (Aspn, Plscr4), and nerve regeneration (Nefm). Collectively, these results demonstrate that thermoresponsive PPCN hydrogels enable effective localized lentiviral gene delivery, and that sustained Sirt1 expression promotes angiogenesis, immune modulation, and tissue regeneration in diabetic wounds. This platform provides a promising strategy for controlled gene therapy in chronic wound management and other regenerative applications.
Fibroblasts play indispensable roles in orchestrating revascularization and angiogenesis of endothelial cells. However, it remains elusive the specific conditions under which the influence of fibroblasts becomes important in modulating angiogenic formation. Here, we extend a previously established microfluidic co-culture system to enable precise manipulation of the density of human lung fibroblasts (HLF) and their distance to human umbilical vein endothelial cells (HUVECs) in a wide range within fibrin hydrogels. Using live cell imaging and image analysis, we quantify the effects of fibroblast density, HLF- HUVEC cell-cell distance, and culturing time on cell migration, morphology, microvasculature, and endothelial sprouting. We find that, for fibroblasts to have a significant positive impact in the angiogenesis of endothelial cells, the fibroblast density should be no less than ~ 3×10 6 cells/ml and the cell-cell distance should be no greater than ~ 2 mm. The experimental findings can be captured by a minimal model accounting for the concentration profile of pro-angiogenic factors secreted by fibroblasts. Our results provide insights into the remodeling of vasculature and the guidance for engineering vascularized tissue mimics.
The combination of antiangiogenic therapy with immune checkpoint blockade has demonstrated significant clinical benefits in various cancers, however, the precise mechanisms of action on the immune system are not fully understood. In particular, the early intratumoral immune responses induced by angiogenesis inhibition remain unclear. Using preclinical models of colorectal cancer, we examined the immune changes elicited by combined vascular endothelial growth factor receptor-2 (VEGFR-2) and programmed cell death protein-1 (PD-1) blockade. Our findings reveal that CD8 T cells respond directly and early to VEGFR-2 inhibition, preceding the acquisition of overt cytotoxic function. Shortly after treatment, intratumoral CD8 T cells expanded and produced interleukin-10 (IL-10). Unexpectedly, this CD8 T cell-derived IL-10 promoted the recruitment of natural killer (NK) cells into tumors. Recruited NK cells subsequently gained effector activity and produced granulocyte-macrophage colony-stimulating factor, which supported macrophage maturation and the induction of CXCL11. This sequence of events enhanced secondary CD8 T-cell infiltration and sustained antitumor immune activity. Disruption of IL-10 signaling or NK-cell function eliminated the therapeutic benefit of combined VEGFR-2 and PD-1 blockade, whereas regulatory T-cell depletion further improved tumor control. Together, these findings identify an unanticipated role for CD8 T cell-derived IL-10 in coordinating early innate and adaptive immune responses following angiogenesis inhibition and define an immune program initiated by VEGFR-2 blockade that is required for therapeutic efficacy in two preclinical colorectal cancer models.
Endometriosis is a chronic inflammatory disease characterized by the presence of endometrial-like tissue outside the uterine cavity, affecting up to 10% of women of reproductive age. Despite extensive research, its pathogenesis remains incompletely understood, and clinically useful non-invasive diagnostic tools are still lacking. Increasing evidence identifies hypoxia as a key microenvironmental factor promoting lesion establishment and persistence. Cellular responses to hypoxia are mediated by hypoxia-inducible factor 1 alpha (HIF-1α), which coordinates transcriptional programs involved in angiogenesis, inflammation, estrogen biosynthesis, extracellular matrix remodeling, and cell survival. A critical consequence of this hypoxia-driven signaling is the dysregulation of cell adhesion molecules (CAMs), which directly facilitates ectopic implantation and lesion progression. Adhesion-related molecules implicated in endometriosis include integrins, selectins, cadherins (E-cadherin, N-cadherin, CDH12, T-cadherin), claudins, intercellular adhesion molecules (ICAMs), matrix metalloproteinases (MMPs), and anthrax toxin receptor 2 (ANTXR2). Altered expression and activity of these molecules enhance attachment to the peritoneum, immune cell recruitment, angiogenesis, and extracellular matrix remodeling, thereby sustaining chronic inflammation and lesion growth. Beyond their pathogenetic role, CAMs are increasingly recognized as clinically relevant diagnostic and therapeutic targets in endometriosis. Within this group, P-selectin emerges as a particularly promising candidate, as its association with disease-related inflammatory activity supports its potential utility as a non-invasive biomarker and as a therapeutic target, exemplified by preclinical studies using the monoclonal antibody inclacumab. In parallel, growing evidence supports the diagnostic relevance of other adhesion-related molecules, including N-cadherin, ICAM-1, and MMP-9. Furthermore, therapeutic strategies targeting adhesion-related pathways - either directly or through modulation of hypoxia-responsive signaling - have demonstrated promising results in preclinical studies. This review highlights cell adhesion molecules as central effectors of hypoxia-driven mechanisms in endometriosis and underscores their relevance for the development of mechanism-based diagnostic and therapeutic approaches, complementing existing hormonal and symptomatic treatments.
To investigate the effects of a novel total nutritional composition on the healing of full-thickness skin defects in rats. Ninety SPF male Wistar rats aged 8-12 weeks were randomly divided into 5 groups, with 18 rats in each group: normal group (group A), model group (group B), equal-energy standard nutrition preparation group (group C), equal-protein component group (group D), and nutritional composition group (group E). Except group A, full-thickness skin defects of 1.5 cm in diameter were established on the back of rats in the other four groups. On the basis of conventional feeding, rats received intragastric administration of sterile water or corresponding nutritional preparations twice a day for 14 consecutive days. General wound appearance was observed and wound healing rate was calculated at 0, 7, 10, and 14 days after injury. Six rats per group were sacrificed at 7, 10, and 14 days after injury to collect wound tissues. HE and Masson trichrome staining were performed to observe histopathological changes. Immunohistochemical staining was used to detect CD31-positive microvessel density. At 7, 10, and 14 days after injury, wound healing rates in groups C, D, and E were significantly higher than those in group B, and group E was significantly higher than group D ( P<0.05). No significant difference was detected between group C and group E at all time points ( P>0.05). Histological results showed that group E had the least necrotic tissue, mildest inflammatory infiltration, richest neovascularization, widest re-epithelialization range, as well as the densest and most regularly arranged collagen deposition, with better repair effects than groups C and D. CD31 immunohistochemistry indicated that microvessel densities in groups B-E were significantly higher than that in group A ( P<0.05). Microvessel density in groups C, D, and E was significantly higher than that in group B, and groups C and E were significantly higher than group D ( P<0.05). There was no significant difference between group C and group E ( P>0.05). The novel total nutritional composition can relieve wound inflammation, promote collagen deposition and angiogenesis, and accelerate skin wound healing. It possesses better repair efficacy than equal-protein formula, comparable therapeutic effect with equal-energy nutritional preparation, and shows obvious advantages in early wound healing. 探讨一种新型全营养组合物对大鼠全层皮肤缺损创面愈合的促进作用。. 将90只8～12周龄SPF级雄性Wistar大鼠随机分为正常组（A组）、模型组（B组）、阳性对照1组（等能量标准营养制剂，C组）、阳性对照2组（等蛋白质组件，D组）和新型全营养组合物组（E组），每组18只。除A组外，其余4组大鼠背部制备直径1.5 cm全层皮肤缺损创面。5组在标准饲养基础上，分别灌胃灭菌水或相应营养制剂，每日干预2次，连续14 d。于伤后0、7、10、14 d观察创面大体情况并计算创面愈合率；伤后7、10、14 d处死大鼠（ n=6）取创面组织，行HE染色和Masson三色染色观察组织病理学变化；免疫组织化学染色检测CD31阳性微血管数量。. 伤后7、10、14 d，C、D、E组创面愈合率均高于B组，E组高于D组（ P<0.05）；C组与E组各时间点差异均无统计学意义（ P>0.05）。组织学观察示，E组创面坏死组织最少、炎症浸润最轻、新生血管最丰富、上皮化范围最广、胶原沉积最致密且排列最规整，修复效果优于C、D组。CD31免疫组织化学染色示，伤后各时间点B～E组微血管数量均高于A组，C、D、E组均高于B组，C、E组高于D组（ P<0.05）；C组与E组差异无统计学意义（ P>0.05）。. 新型全营养组合物可减轻创面炎症、促胶原沉积与血管新生，加速皮肤创面愈合；修复效果优于等蛋白配方，与等能量营养制剂疗效相近，早期促愈合优势明显。.
MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression post-transcriptionally and play crucial roles in cancer biology and immune function. Among them, miR-150-5p has emerged as a key regulator with complex, context-dependent roles in both tumorigenesis and immune cell differentiation. This review provides a comprehensive synthesis of current knowledge on miR-150-5p, highlighting its dual function as a tumor suppressor or oncogene depending on cancer type and cellular context. We examine its involvement in hematologic malignancies and solid tumors, detailing the molecular mechanisms through which it influences proliferation, apoptosis, and metastasis. Particular emphasis is placed on the role of extracellular vesicle (EV)-associated miR-150-5p as a modulator of the tumor microenvironment (TME), including its impact on angiogenesis, immune evasion, and intercellular communication. We further explore miR-150-5p's regulation of key immune cell subsets-such as macrophages, dendritic cells, T cells, and natural killer cells-and its implications for anti-tumor immunity. Finally, we discuss the therapeutic potential and challenges of targeting miR-150-5p, including delivery barriers, off-target effects, and opportunities for personalized medicine. By integrating recent findings, this review underscores miR-150-5p's value as both a biomarker and a therapeutic target in cancer immunology.
Abdominal wall defects represent a common clinical challenge in surgical practice, and mesh repair remains the standard treatment. However, current synthetic materials often fail to replicate the mechanical properties of native tissue or actively promote functional regeneration. To address this, we developed a functional composite patch integrating a piezoelectric collagen matrix with an anisotropic polycaprolactone (PCL) scaffold for abdominal wall defect repair. The PCL scaffold, fabricated via electrostatic field-assisted direct writing, exhibits anisotropic mechanical properties with a transverse-to-longitudinal tensile modulus ratio of 1.62, closely matching that of native abdominal wall tissue (1.60). Collagen, as the key biological macromolecule, serves a dual function. Under mechanical loading, collagen generates high current and low voltage through its ionic piezoelectric effect, and in vitro cell assays confirmed that this signal promotes fibroblast proliferation and migration. Additionally, the dense surface structure of collagen acts as a physical barrier, reducing postoperative intra-abdominal adhesions in a rat model. In vivo evaluations further demonstrated that the patch promotes collagen deposition, attenuates inflammatory responses, and stimulates angiogenesis and myofibroblast activation. This collagen-based patch integrates mechanical anisotropy, piezoelectric bioactivity, and anti-adhesion functionality, offering a promising strategy for abdominal wall defect repair with potential for clinical translation.
Osteoporosis (OP) is a gradual metabolic bone disease characterized by decreased bone mass and degradation of bone microarchitecture. It affects hundreds of millions of people globally and places considerable pressure on healthcare systems. Current pharmacological treatments, such as bisphosphonates, selective estrogen receptor modulators, and anabolic agents, can reduce fracture risk; however, their prolonged use is limited by significant adverse effects, elevated treatment costs, and a lack of sustained disease remission. Their constraints have intensified interest in restorative approaches utilizing mesenchymal stem cells (MSCs). In the past 20 years, MSCs have emerged as attractive treatment options for OP due to their capacity to differentiate into osteoblasts, modulate immune responses, and exert paracrine effects. Bone marrow-MSCs are the best characterized; nevertheless, MSCs obtained from adipose tissue, umbilical cord, and dental pulp have distinct benefits. Preclinical data demonstrate that direct MSC transplantation enhances bone mineral density, promotes osteoblast production, and reestablishes the equilibrium of bone remodeling in many OP models, including Ovariectomy, glucocorticoid-induced OP, and diabetic OP. Nonetheless, significant obstacles persist: insufficient targeting of osteoporotic bone surfaces, suboptimal cell viability and integration, donor heterogeneity, and unresolved safety concerns. The discovery that the secretome and exosomes (EXOs) produced from MSCs recapitulate several therapeutic advantages of the original cells has initiated a transition toward cell-free methodologies. EXOs produced from MSCs include osteogenic microRNAs (including miR-150-3p and miR-21), inhibit NLRP3 inflammasome activation in osteoclasts, promote macrophage polarization toward an M2 phenotype via TRIM25/TREM1 signaling, and facilitate angiogenesis through the activation of the PI3K/Akt pathway. Furthermore, nanoparticle engineering and combinatorial medicines are advancing to enhance targeting and therapeutic efficacy.
This study aimed to evaluate the dose-dependent effects of extremely low-frequency sinusoidal electromagnetic fields (ELF-EMF) on survival and vascularization of random-pattern dorsal skin flaps in rats and to investigate associated histological and molecular changes. Twenty-one male Sprague-Dawley rats underwent McFarlane dorsal random-pattern flap surgery and were randomly assigned to three groups (n = 7/group): control, low-dose ELF-EMF (0.2 mT), and high-dose ELF-EMF (5 mT). Sinusoidal ELF-EMF exposure (50 Hz) was administered twice daily for 15 min for 14 postoperative days. Flap viability was assessed by digital planimetry. Histological evaluation included hematoxylin-eosin and Masson's trichrome staining. TNF-α immunohistochemistry and quantitative real-time PCR analysis of apoptosis-, inflammation-, and angiogenesis-related genes were performed. The low-dose ELF-EMF group demonstrated significantly higher flap viability than both the control and high-dose groups (76.3 ± 6.9% vs. 55.2 ± 9.1% and 55.7 ± 11.3%, respectively; p < 0.05). Histological analyses showed enhanced re-epithelialization, increased vascularization, improved collagen organization, and reduced inflammatory cell infiltration in the low-dose group. High-dose ELF-EMF did not improve flap survival and was associated with suppression of VEGF and MAPK pathway-related gene expression. The discordance between increased TNF-α mRNA expression and reduced immunohistochemical staining in the low-dose group suggests temporally dynamic and post-transcriptional regulation. Low-dose sinusoidal ELF-EMF improved survival and histological markers of repair in a rat random-pattern skin flap model, whereas high-dose exposure did not confer benefit. These findings support the existence of a dose-dependent biological window for ELF-EMF therapy. Given the exploratory preclinical nature of the study, further mechanistic and translational investigations are required before clinical application.