Both cell migration and proliferation are indispensable parts of reepithelialization during skin wound healing, which is a complex process for which the underlying molecular mechanisms are largely unknown.Here, we identify a novel role for microtubule-associated protein 4 (MAP4), a cytosolic microtubule-binding protein that regulates microtubule dynamics through phosphorylation modification, as a critical regulator of epidermal wound repair.We showed that MAP4 phosphorylation was induced in skin wounds.In an aberrant phosphorylated MAP4 mouse model, hyperphosphorylation of MAP4 (S737 and S760) accelerated keratinocyte migration and proliferation and skin wound healing.Data from both primary cultured keratinocytes and HaCaT cells in vitro revealed the same results.The promigration and proproliferation effects of MAP4 phosphorylation depended on microtubule rearrangement and could be abolished by MAP4 dephosphorylation.We also identified p38/MAPK as an upstream regulator of MAP4 phosphorylation in keratinocytes.Our findings provide new insights into the molecular mechanisms underlying wound-associated keratinocyte migration and proliferation and identify potential targets for the remediation of defective wound healing.
Abstract Although near‐infrared (NIR) light‐based photothermal therapies have shown therapeutic potential for infected wounds, the attenuation of NIR light intensity in tissue has severely limited the usage in deep bacterial infections. Herein, magneto‐thermal responsive bilayer microneedles (Fe‐Se‐HA MNs) consisting of functionalized hyaluronic acid (HA), ferro‐ferric oxide (Fe 3 O 4 ), and micelle‐protected selenium nanoparticles (SeNPs@LAS) are constructed to overcome this challenge based on a self‐designed disk‐shaped electromagnetic field device (Disk‐ZVS). The electromagnetic field generated by the Disk‐ZVS shows virtually no intensity attenuation in living tissue. Finite element simulations showed that the field intensity and electromagnetic loss are concentrated on the tips of Fe‐Se‐HA MNs. The MNs are able to puncture hard scabs, penetrate into bacterial biofilms, and perform effective magnetic‐thermal conversion for deep hyperthermia sterilization. Following, the Fe‐Se‐HA MNs can be gradually degraded by excessive hyaluronidase in diabetic wound to release SeNPs, which reduce reactive oxygen species (ROS) to regulate wound redox homeostasis. Meanwhile, the SeNPs are beneficial to angiogenesis, which facilitates blood vessel formation and promotes wound repair. Therefore, various functions can be achieved for the Fe‐Se‐HA MNs, such as magneto‐thermal disinfection, deep and non‐invasive tissue penetration, anti‐inflammation, and pro‐angiogenesis, which shows great potential as an adjunctive therapy for infected diabetic wounds.
Wound healing is delayed frequently in patients with diabetes. Proper keratinocyte migration is an essential step during re-epithelialization. Impaired keratinocyte migration is a critical underlying factor responsible for the deficiency of diabetic wound healing, which is mainly attributed to the hyperglycemic state. However, the underlying mechanisms remain largely unknown. Previously, we demonstrated a marked activation of p38/mitogen-activated protein kinase (MAPK) pathway in the regenerated migrating epidermis, which in turn promoted keratinocyte migration. In the present study, we find that p38/MAPK pathway is downregulated and accompanied by inactivation of autophagy under high glucose (HG) environment. In addition, we demonstrate that inactivation of p38/MAPK and autophagy result in the inhibition of keratinocyte migration under HG environment, and the activating p38/MAPK by MKK6(Glu) overexpression rescues cell migration through an autophagy-dependent way. Moreover, diabetic wound epidermis shows a significant inhibition of p38/MAPK and autophagy. Targeting these dysfunctions may provide novel therapeutic approaches.
Abstract Phosphorylation of MAP4 (p-MAP4) causes cardiac remodeling, with the cardiac microvascular endothelium being considered a vital mediator of this process. In the current study, we investigated the mechanism underlying p-MAP4 influences on cardiac microvascular density. We firstly confirmed elevated MAP4 phosphorylation in the myocardium of MAP4 knock-in (KI) mice. When compared with the corresponding control group, we detected the decreased expression of CD31, CD34, VEGFA, VEGFR2, ANG2, and TIE2 in the myocardium of MAP4 KI mice, accompanied by a reduced plasma concentration of VEGF. Moreover, we observed apoptosis and mitochondrial disruption in the cardiac microvascular endothelium of MAP4 KI animals. Consistently, we noted a decreased cardiac microvascular density, measured by CD31 and lectin staining, in MAP4 KI mice. To explore the underlying mechanism, we targeted the NLRP3-related pyroptosis and found increased expression of the corresponding proteins, including NLRP3, ASC, mature IL-1β, IL-18, and GSDMD-N in the myocardium of MAP4 KI mice. Furthermore, we utilized a MAP4 (Glu) adenovirus to mimic cellular p-MAP4. After incubating HUVECs with MAP4 (Glu) adenovirus, the angiogenic ability was inhibited, and NLRP3-related pyroptosis were significantly activated. Moreover, both cytotoxicity and PI signal were upregulated by the MAP4 (Glu) adenovirus. Finally, NLRP3 inflammasome blockage alleviated the inhibited angiogenic ability induced by MAP4 (Glu) adenovirus. These results demonstrated that p-MAP4 reduced cardiac microvascular density by activating NLRP3-related pyroptosis in both young and aged mice. We thus managed to provide clues explaining MAP4 phosphorylation-induced cardiac remodeling and enriched current knowledge regarding the role of MAP4.
Abstract Medical implants, important consumables, significantly promote patients’ healthcare, but still face challenges of foreign body responses and bacterial infection. Hydrogels can be ideal alternative materials, however, a few of them can meet the requirements. Herein, a TAFe@PVA photothermal hydrogel integrating with negative swelling, long‐term stability, antibacterial, anti‐adhesion, and tissue mechanical matching is developed to solve these issues. The TAFe@PVA hydrogel is crosslinked by H‐bonds and microcrystal domains which both can be enhanced by cations or anions based on Hofmeister effect, showing unique negative swelling and long‐term mechanical self‐enhancement performances in the physiological fluid. Attributing to self‐polymerization of tannic acid (TA) and negative swelling of polyvinyl alcohol (PVA) molecular networks, TAFe complexes can be strongly locked in PVA molecular networks, reaching long‐term photothermal stability. The TAFe@PVA hydrogel also exhibits great biocompatibility, anti‐oxidation, anti‐adhesion, and anti‐bacterial performances, comparing to the traditional implant material. Since the TAFe@PVA hydrogel can better match with skin tissues, fewer macrophages and myofibroblasts are activated, which depresses unexpected foreign body responses. Finally, the TAFe@PVA hydrogel as the implant can effectively solve abdominal adhesions after abdominal operation and promote defects healing. This study introduces a promising hydrogel implant, which potentially extends hydrogels to wider medical applications.
Maladaptive cardiac metabolism is a common trigger of cardiac lipid accumulation and cardiac injury under serious burn challenge. Adipose triglyceride lipase (ATGL) is the key enzyme that catalyzes triglyceride hydrolysis; however, its alteration and impact on cardiac function following serious burn injury are still unknown. Here, we found that the cardiac fatty acid (FA) metabolism increased, accompanied by augmented FA accumulation and ATGL expression, after serious burn injury. We generated heterozygous ATGL knockout and heterozygous cardiac-specific ATGL overexpression thermal burn mice. The results demonstrated that partial loss of ATGL could not relieve burn-induced cardiac lipid accumulation and cardiac injury, possibly due to the suppression of cardiac FA metabolism plus insufficient compensatory glucose utilization. In contrast, cardiac-specific overexpression of ATGL alleviated cardiac lipid accumulation and cardiac injury following burn challenge by switching the substrate preference from FA towards increased glucose utilization. The underlying mechanism was possibly related to increased glucose transporter-1 expression and reduced cardiac lipid accumulation induced by ATGL overexpression. Our data first demonstrated that elevated cardiac ATGL expression after serious burn injury is an adaptive, albeit insufficient, response to compensate for the increase in energy consumption and that further overexpression of ATGL is beneficial for ameliorating cardiac injury, indicating its therapeutic potential.
Abstract The migration of keratinocytes from wound margins plays a critical role in the re‐epithelialization of skin wounds. Hypoxia occurs immediately after injury and acts as an early stimulus to initiate the healing processes. Although our previous studies have revealed that hypoxia promotes keratinocyte migration, the precise mechanisms involved remain unclear. Here, we found that BNIP 3 expression was upregulated in hypoxic keratinocytes, and BNIP 3 silencing suppressed hypoxia‐induced cell migration. Additionally, hypoxia activated the focal adhesion kinase ( FAK ) pathway through upregulation of BNIP 3, while FAK inhibition attenuated hypoxic keratinocyte migration. Here, we conclusively demonstrate a novel role for BNIP 3 in hypoxia‐induced keratinocyte migration. Furthermore, we provide a new perspective on the molecular mechanisms of wound healing and identify BNIP 3 as a potential new molecular target for clinical treatments to enhance wound healing.
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