Diabetic foot ulceration is a severe complication of diabetes that lacks effective treatment. Mast cells (MCs) contribute to wound healing, but their role in diabetes skin complications is poorly understood. Here we show that the number of degranulated MCs is increased in unwounded forearm and foot skin of patients with diabetes and in unwounded dorsal skin of diabetic mice (P < 0.05). Conversely, postwounding MC degranulation increases in nondiabetic mice, but not in diabetic mice. Pretreatment with the MC degranulation inhibitor disodium cromoglycate rescues diabetes-associated wound-healing impairment in mice and shifts macrophages to the regenerative M2 phenotype (P < 0.05). Nevertheless, nondiabetic and diabetic mice deficient in MCs have delayed wound healing compared with their wild-type (WT) controls, implying that some MC mediator is needed for proper healing. MCs are a major source of vascular endothelial growth factor (VEGF) in mouse skin, but the level of VEGF is reduced in diabetic mouse skin, and its release from human MCs is reduced in hyperglycemic conditions. Topical treatment with the MC trigger substance P does not affect wound healing in MC-deficient mice, but improves it in WT mice. In conclusion, the presence of nondegranulated MCs in unwounded skin is required for proper wound healing, and therapies inhibiting MC degranulation could improve wound healing in diabetes.

Background: Diabetic wounds are one of the most common and serious complications of diabetes mellitus, characterized by the dysfunction of wound-healing-related cells in quantity and quality. Our previous studies revealed that human amniotic epithelial cells (hAECs) could promote diabetic wound healing by paracrine action. Interestingly, numerous studies demonstrated that exosomes derived from stem cells are the critical paracrine vehicles for stem cell therapy. However, whether exosomes derived from hAECs (hAECs-Exos) mediate the effects of hAECs on diabetic wound healing remains unclear. This study aimed to investigate the biological effects of hAECs-Exos on diabetic wound healing and preliminarily elucidate the underlying mechanism. Methods: hAECs-Exos were isolated by ultracentrifugation and identified by transmission electron microscopy, dynamic light scattering and flow cytometry. A series of in vitro functional analyses were performed to assess the regulatory effects of hAECs-Exos on human fibroblasts (HFBs) and human umbilical vein endothelial cells (HUVECs) in a high-glycemic microenvironment. High-throughput sequencing and bioinformatics analyses were conducted to speculate the related mechanisms of actions of hAECs-Exos on HFBs and HUVECs. Subsequently, the role of the candidate signaling pathway of hAECs-Exos in regulating the function of HUVECs and HFBs, as well as in diabetic wound healing, was assessed. Results: hAECs-Exos presented a cup- or sphere-shaped morphology with a mean diameter of 105.89 ± 10.36 nm, were positive for CD63 and TSG101 and could be internalized by HFBs and HUVECs. After that, hAECs-Exos not only significantly promoted the proliferation and migration of HFBs, but also facilitated the angiogenic activity of HUVECs in vitro. High-throughput sequencing revealed enriched miRNAs of hAECs-Exos involved in wound healing. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses have shown that the target genes of the top 15 miRNAs were highly enriched in the PI3K-AKT pathway. Further functional studies demonstrated that the PI3K-AKT-mTOR pathway was necessary for the induced biological effects of hAECs-Exos on HFBs and HUVECs, as well as on wound healing, in diabetic mice. Conclusions: Our findings demonstrated that hAECs-Exos represent a promising, novel strategy for diabetic wound healing by promoting angiogenesis and fibroblast function via activation of the PI3K-AKT-mTOR pathway.

Sepsis is a systemic inflammatory disease caused by an infection that can lead to multiple organ failure. Sepsis alters energy metabolism, leading to metabolic reprogramming of immune cells, which consequently disrupts innate and adaptive immune responses, triggering hyperinflammation and immunosuppression. This review summarizes metabolic reprogramming and its regulatory mechanism in sepsis-induced hyperinflammation and immunosuppression, highlights the significance and intricacies of immune cell metabolic reprogramming, and emphasizes the pivotal role of mitochondria in metabolic regulation and treatment of sepsis. This review provides an up-to-date overview of the relevant literature to inform future research directions in understanding the regulation of sepsis immunometabolism. Metabolic reprogramming has great promise as a new target for sepsis treatment in the future.

Hydrogels have long been used for encapsulating stem cell-derived conditioned mediums to achieve skin regeneration after wounding. However, inappropriate mechanical strength, low adhesion and low elasticity limit their clinical application. To address these challenges, we engineered a hyaluronic acid-based hydrogel grafted with methacrylic anhydride and N-(2-aminoethyl)-4-[4-(hydroxymethyl)-2-methoxy-5-nitrophenoxy]-butanamide (NB) groups to encapsulate a lyophilized amnion-derived conditioned medium (AM-CM). This hydrogel can photopolymerize in situ within 3 s by photo-initiated free-radical crosslinking between methacrylate moieties. Meanwhile, the formed o-nitrosobenzaldehyde groups by photo-irradiation could covalently bond with the amino groups of tissue surface, which allowed strong tissue adhesion. Furthermore, the hydrogel possessed excellent mechanical properties, high elasticity, favorable biocompatibility and prolonged AM-CM release. Our further vitro and in vivo studies showed that the hydrogel significantly accelerated diabetic wound healing by regulating macrophage polarization and promoting angiogenesis. The engineered hydrogel with AM-CM release has high potential to treat chronic wounds in clinics.