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The growing discussion on "interdisciplinary integration" brings attention to the "interprofessional education" (IPE) in the field of plastic surgery. IPE not only improves the precision and effectiveness of plastic and reconstructive surgery but also plays an important role in personalized treatment. Whereas, the implementation of IPE in plastic and reconstructive surgery field faces huge difficulties such as technology combination, standard making, and lacking of qualified talents. This article individually summarizes the latest developments in the integration of plastic and reconstructive surgery with engineering, basic science, and human science. It looks forward to the future practice and innovation of IPE in the field of plastic and reconstructive surgery, analyzes the challenges in cultivating innovative professional talents, and proposes methods to overcome these difficulties in a way that invites further discussion. [ABSTRACT FROM AUTHOR]

Efferocytosis, by phagocytosing and processing apoptotic cells in injured skin, directly influences the immune microenvironment. However, the comprehensive widespread inflammation and disrupted efferocytosis in injured skin cannot be effectively halted. Herein, "Grid Efferocytosis" strategy within injury site is proposed, which segments the inflammation regulatory into grid microdomains, and further rectifies intra‐grid immune microenvironment to accelerate tissue repair. GelMA/PLA/Laponite gridded fiber membranes (GPL) are custom‐designed via near‐field electrostatic printing, and then coated with HAMA‐PBA/EGCG hydrogel by photo‐crosslinking and dynamic borate bonding to form a composite fiber membrane (GPL‐E). Gridded modulation via GPL‐E confines the entire chaotic inflammatory microenvironment into controllable microinflammatory niches. Leveraging the hydrogel coating and boronic ester bond dissociation induced by microenvironmental glucose and reactive oxygen species, GPL‐E achieves dynamic anti‐glucose and anti‐oxidation within microdomains, reconstructing macrophage efferocytosis. Notably, the "grid efferocytosis" recruits repair cells into the grid by magnesium ion release triggered by Laponite exposure on fibers, and enhances endothelial cell vascularization by ≈2.5‐fold. In a mouse diabetic ischemic flap model, implantation of grid GPL‐E maintains flap‐to‐base fusion, attenuates inflammatory infiltration & spread, and improves blood perfusion for flap survival. This study demonstrates that "Grid Efferocytosis" rectifies the immune microenvironment, fostering tissue repair and regeneration. [ABSTRACT FROM AUTHOR]

Doxorubicin (Dox), an anthracycline antibiotic, is widely used in cancer treatment. Although its antitumor efficacy appears significant, its clinical use is greatly restricted by its induction of cardiotoxicity. Cardiac senescence drives the Dox‐induced cardiotoxicity, but whether diminishing these senescent cardiomyocytes could alleviate the cardiotoxicity remains unclear. Here, we assessed whether senescent cardiomyocytes have a senescence‐associated secretory phenotype (SASP) that affects healthy non‐senescent cardiomyocytes, rendering them senescent via the delivery of exosomes. Additionally, we explored whether targeting SASP senescent cardiomyocytes using a Bcl‐2 inhibitor could alleviate cardiotoxicity. Cardiac damage was induced in a mouse model of continuous Dox treatment in vivo, and cardiomyocytes in vitro. Immunofluorescence of the senescence markers of Cdkn2a, Cdkn1a and γ‐H2A.X was used to assess the SASP in the Dox‐treated heart. To explore the molecular mechanisms involved, the Bcl‐2 inhibitor ABT‐199 was employed to eliminate SASP senescent cardiomyocytes. We show that the cardiomyocytes acquire a SASP during Dox treatment. The senescent cardiomyocytes upregulated Bcl‐2, although treatment of mice with ABT‐199 selectively eliminated SASP senescent cardiomyocytes involved in Dox‐induced cardiotoxicity, thus leading to partial alleviation of Dox‐induced cardiotoxicity. Moreover, we concluded that SASP factors secreted by senescent cardiomyocytes induced by Dox renders otherwise healthy cardiomyocytes senescent through exosome delivery. Our findings suggest that SASP senescent cardiomyocytes are a significant component of the pathogenesis of Dox‐dependent cardiotoxicity and indicate that targeting the clearance of SASP senescent cardiomyocytes could be a new therapeutic approach for Dox‐induced cardiac injury. [ABSTRACT FROM AUTHOR]

Chronic non-healing wounds, a prevalent complication of diabetes, are associated with increased mortality in diabetic patients. Excessive accumulation of M1 macrophages in diabetic wounds promotes inflammation and results in dysregulated tissue repair. Adipose tissue macrophages (ATMs) derived from healthy lean donors have the ability to improve glucose tolerance and insulin sensitivity, as well as modulate inflammation. MicroRNAs (miRs), which can be packaged into exosomes (Exos) and secreted from cells, serve as essential regulators of macrophage polarization. Here, we revealed that ATMs isolated from lean mice secrete miRs-containing Exos, which modulate macrophage polarization and promote rapid diabetic wound healing when administered to diabetes-prone db/db mice. The miRs sequence of tissue samples from wounds treated with Exos secreted by lean ATMs (ExosLean) revealed that miR-222-3p was up-regulated. Further analyses showed that inhibiting miR-222-3p using a miR inhibitor impaired the macrophage-reprogramming effect of ExosLean. In the excisional skin wound mouse model, locally inhibiting miR-222-3p disrupted healing dynamics and failed to modulate macrophage polarization. Mechanistic studies revealed a connection between miR-222-3p, Bcl2l11/Bim, an inflammatory response effector, macrophage polarization, and diabetic wound healing. In summary, ExosLean act as positive regulators of macrophage polarization by regulating miR levels in wounds and accelerating wound healing, and thus have important implications for wound management in diabetes. [ABSTRACT FROM AUTHOR]

Aged skin wounds heal poorly, resulting in medical, economic, and social burdens posed by nonhealing wounds. Age-related defects in repair are associated with reduced myofibroblasts and dysfunctional extracellular matrix (ECM) deposition. Bidirectional cell-cell communication involving exosome-borne cargo such as micro RNAs (miRs) has emerged as a critical mechanism for wound healing and aged tissue regeneration. Here we report that at the wound edge, aged fibroblasts display reduced migration and differentiation into myofibroblasts, with impaired ECM deposition, when compared with young tissue. Proper activation of fibroblasts to myofibroblasts may alleviate age-related defects in wound healing. Herein, an exosome-guided cell technique was performed to induce effective wound healing. Supplementing wounds with exosomes isolated from young mouse wound-edge fibroblasts (exosomesYoung) significantly improved the abundance of myofibroblasts and wound healing in aged mice and caused fibroblasts to migrate and transition to myofibroblasts in vitro. To determine the underlying mechanism, we found that exosomal transfer of miR-125b to fibroblasts inhibited sirtuin 7 (Sirt7), thus accelerating myofibroblast differentiation and wound healing in aged mice. Notably, after epidermal inhibition of miR-125b or overexpression of Sirt7 in fibroblasts, migration and myofibroblast transition were perturbed. Our findings thus reveal that miR-125b is transferred through exosomes from young fibroblasts to old fibroblasts contributes to promoting fibroblast migration and transition to counteract aging, suggesting a potential avenue for anti-aging interventions in wound healing. [ABSTRACT FROM AUTHOR]

Facial paralysis can result in severe implications for patients. A good prognosis depends on the degree of nerve regeneration. Schwann cells (SCs) play an important role in facial nerve development and regeneration through migration. Forkhead box C1 (Foxc1), a member of the forkhead transcription factor family, is implicated in cell migration. However, the role of Foxc1 in the progression after facial nerve crush remains unknown. Our aim was to evaluate the effect of Foxc1 overexpression on SC migration and recovery of facial nerves after crush injury. The rat facial nerve crush injury model was established through the use of unilateral surgery. The results showed that the expression of Foxc1 was increased in the surgery group compared to that of the control group. SCs were isolated from the sciatic nerves and cultured. Foxc1, delivered by an adeno‐associated virus in vivo, or adenovirus in vitro, both induced overexpression of Foxc1, and increased the expression of CXCL12 and β‐catenin. After the transfection of Foxc1, the migration of SC was increased both in vitro and in vivo, was reduced by the inhibition of CXCL12 or β‐catenin. The facial nerve function and the nerve axon remyelination of the rats transfected with Foxc1 were significantly improved after nerve crush injury. Overall, the results demonstrated that overexpression of Foxc1 promoted SC migration by regulating CXCL12 via the Wnt/β‐catenin pathway, thus contributing to improved facial nerve function after crush injury. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Ionizing radiation (IR) is a standard treatment for GBM patients and results in DNA damage. However, the clinical efficacy of IR is limited due to therapeutic resistance. The programmed death ligand 1 (PD-L1) blockade has a shown the potential to increase the efficacy of radiotherapy by inhibiting DNA damage and repair responses. The miR-33a-5p is an essential microRNA that promotes GBM growth and self-renewal. In this study, we investigated whether a PD-L1 inhibitor (a small molecule inhibitor) exerted radio-sensitive effects to impart an anti-tumor function in GBM cells by modulating miR-33a-5p. U87 MG cells and U251 cells were pretreated with PD-L1 inhibitor. The PD-L1 inhibitor-induced radio-sensitivity in these cells was assessed by assaying cellular apoptosis, clonogenic survival assays, and migration. TargetScan and luciferase assay showed that miR-33a-5p targeted the phosphatase and tensin homolog (PTEN) 3′ untranslated region. The expression level of PTEN was measured by western blotting, and was also silenced using small interfering RNAs. The levels of DNA damage following radiation was measured by the presence of γ-H2AX foci, cell cycle, and the mRNA of the DNA damage-related genes, BRCA1, NBS1, RAD50, and MRE11. Our results demonstrated that the PD-L1 inhibitor significantly decreased the expression of the target gene, miR-33a-5p. In addition, pretreatment of U87 MG and U251 cells with the PD-L1 inhibitor increased radio-sensitivity, as indicated by increased apoptosis, while decreased survival and migration of GBM cells. Mir-33a-5p overexpression or silencing PTEN in U87 MG and U251 cells significantly attenuated PD-L1 radiosensitive effect. Additionally, PD-L1 inhibitor treatment suppressed the expression of the DNA damage response-related genes, BRCA1, NBS1, RAD50, and MRE11. Our results demonstrated a novel role for the PD-L1 inhibitor in inducing radio- sensitivity in GBM cells, where inhibiting miR-33a-5p, leading to PTEN activated, and inducing DNA damage was crucial for antitumor immunotherapies to treat GBM. [ABSTRACT FROM AUTHOR]

Aims: Extracellular vesicles, especially exosomes, have emerged as key mediators of intercellular communication with the potential to improve cardiac function as part of cell-based therapies. We previously demonstrated that the cardioprotective factor, macrophage migration inhibitory factor (MIF), had an optimizing effect on mesenchymal stem cells (MSCs). The aim of this study was to determine the protective function of exosomes derived from MIF-pretreated MSCs in cardiomyocytes and to explore the underlying mechanisms. Methods and results: Exosomes were isolated from control MSCs (exosome) and MIF-pretreated MSCs (exosomeMIF), and delivered to cardiomyocytes subjected to H2O2 in vitro. Regulatory long non-coding RNAs (lncRNAs) activated by MIF pretreatment were explored using genomics approaches. ExosomeMIF protected cardiomyocytes from H2O2-induced apoptosis. Mechanistically, we identified lncRNA-NEAT1 as a mediator of exosomeMIF by regulating the expression of miR-142-3p and activating Forkhead class O1 (FOXO1). The cardioprotective effects of exosomeMIF were consistently abrogated by depletion of lncRNA-NEAT1, by overexpression of miR-142-3p, or by FOXO1 silencing. Furthermore, exosomeMIF inhibited H2O2-induced apoptosis through modulating oxidative stress. Conclusions: Exosomes obtained from MIF-pretreated MSCs have a protective effect on cardiomyocytes. The lncRNA-NEAT1 functions as an anti-apoptotic molecule via competitive endogenous RNA activity towards miR-142-3p. LncRNA-NEAT1/miR-142-3p/FOXO1 at least partially mediates the cardioprotective roles of exosomeMIF in protecting cardiomyocytes from apoptosis. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOXO) is a chemotherapeutic agent widely used in the treatment of various types of cancer. However, cardiotoxicity is a major side effect of DOXO therapy due to the ability of this compound to induce cardiac cellular senescence. It is well known that microRNA (miR)‑34a serves a role in cardiac dysfunction and ageing, and that it is involved in several cellular processes associated with DOXO‑induced cardiotoxicity. Furthermore, mesenchymal stem cell (MSC)‑based therapies have been reported to modulate cellular senescence. In the present study, the Transwell system was used to co‑culture H9c2 cells and MSCs, and cell proliferation and viability were assessed. The expression of senescence‑related genes, p53 and p16, and telomere length were analyzed using reverse transcription‑quantitative polymerase chain reaction (PCR), and the protein expression levels of situin 1 (SIRT1) were detected by western blotting. Additionally, telomerase activity of H9c2 was examined using the Telo TAGGG Telomerase PCR ELISA PLUS kit. The present study revealed that, in the presence of DOXO, H9c2 cells were in senescence, as characterized by a low proliferation rate, poor viability and a marked increase in the expression of p53 and p16. By contrast, when co‑cultured with MSCs in the presence of DOXO, the proliferation and viability of H9c2 cells increased. Additionally, the expression of p53 and p16 decreased, and increased length of telomere and telomerase activity was also observed. Additionally, the mechanism underlying the anti‑senescence function of MSCs was revealed to involve the miR‑34a‑SIRT1 axis, confirmed by overexpressing miR‑34a using a miR‑34a mimic or silencing SIRT1 using small interfering RNA, which abolished the anti‑senescence effect of MSCs on DOXO‑treated H9c2 cells. Taken together, the results of the present study suggest that MSCs may rejuvenate H9c2 cells from a state of DOXO‑induced senescence by increasing SIRT1 expression, there by inhibiting miR‑34a. Therefore, treatment with MSCs may have important therapeutic implications in the restoration of cardiotoxicity in patients with cancer undergoing treatment with DOXO. [ABSTRACT FROM AUTHOR]

Doxorubicin (Dox)-induced cardiotoxicity has been a well-known phenomenon to clinicians and scientists for decades. It has been confirmed that Dox-dependent cardiotoxicity is accompanied by cardiac cellular senescence. However, the molecular mechanisms underlying Dox cardiotoxicity remains to be fully elucidated. Long non-coding (lnc) RNAs regulate gene transcription and the fate of post-transcriptional mRNA, which affects a broad range of age-associated physiological and pathological conditions, including cardiovascular disease and cellular senescence. However, the functional role of lncRNAs in Dox-induced cardiac cellular senescence remains largely unknown. Using the reverse transcription-quantitative polymerase chain reaction method, the present study indicated that long intergenic non-coding (linc) RNA-p21 was highly expressed in Dox-treated HL-1 murine cardiomyocytes. Dox-induced cardiac senescence was accompanied by decreased cellular proliferation and viability, increased expression of p53 and p16, and decreased telomere length and telomerase activity, while these effects were relieved by silencing endogenous lincRNA-p21. We found that lincRNA-p21 interacted with β-catenin and that silencing β-catenin abolished the anti-senescent effect of lincRNA-p21 silencing. It was observed that modulating lincRNA-p21 to exert an anti-senescent effect was dependent on decreasing oxidant stress. To conclude, the present findings suggest that lincRNA-p21 may be involved in Dox-associated cardiac cellular senescence and that silencing lincRNA-p21 effectively protects against Dox cardiotoxicity by regulating the Wnt/β-catenin signaling pathway and decreasing oxidant stress. Furthermore, modulating lincRNA-p21 may have cardioprotective potential in patients with cancer receiving Dox treatment. [ABSTRACT FROM AUTHOR]

Macrophage migration inhibitory factor (MIF) is a critical inflammatory cytokine that was recently associated with progenitor cell survival and potently inhibits apoptosis. We examined the protective effect of MIF on hypoxia/serum deprivation (SD)-induced apoptosis of mesenchymal stem cells (MSCs), as well as the possible mechanisms. MSCs were obtained from rat bone marrow and cultured in vitro. Apoptosis was induced by culturing MSCs under hypoxia/SD conditions for up to 24 h and assessed by flow cytometry. Expression levels of c-Met, Akt, and FOXO3a were detected by Western blotting. CD74 expression was detected by qRT-PCR, Western blot, and immunofluorescence. Oxidative stress under hypoxia/SD was examined by detection of reactive oxygen species (ROS) and activity of superoxide dismutase (SOD) and malondialdehyde (MDA). Hypoxia/SD-induced apoptosis was significantly attenuated by recombinant rat MIF in a concentration-dependent manner. MIF induced CD74-asssociated c-Met activation, which was blocked by knocking down CD74 expression using siRNA. MIF also induced Akt and associated FOXO3a phosphorylation, and this effect was abolished by knocking down either CD74 or Akt. In addition, MIF decreased oxidative stress in MSCs, as shown by decreased ROS and MDA, and increased the activity of SOD. Knockdown of CD74, Akt, or FOXO3a largely attenuated the anti-apoptotic effect of MIF and its ability to protect against oxidative stress. MIF protected MSCs from hypoxia/SD-induced apoptosis by interacting with CD74 to stimulate c-Met, leading to downstream PI3K/Akt-FOXO3a signaling and decreased oxidative stress. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via the original article. [ABSTRACT FROM AUTHOR]

Background: The chemotherapy drug doxorubicin (Dox) is widely used for treating a variety of cancers. However, its high cardiotoxicity hampered its clinical use. Exosomes derived from stem cells showed a therapeutic effect against Dox-induced cardiomyopathy (DIC). Previous studies reported that exosomes derived from mesenchymal stem cells (MSCs) pretreated with macrophage migration inhibitory factor (MIF) (exosomeMIF) showed a cardioprotective effect through modulating long noncoding RNAs/microRNAs (lncRNAs/miRs). This study aimed to investigate the role of exosomeMIF in the treatment of DIC. Results: Exosomes were isolated from control MSCs (exosome) and MIF-pretreated MSCs (exosomeMIF). Regulatory lncRNAs activated by MIF pretreatment were explored using genomics approaches. Fluorescence-labeled exosomes were tracked in vitro by fluorescence imaging. In vivo and in vitro, miR-221-3p mimic transfection enforced miR-221-3p overexpression, and senescence-associated β-galactosidase assay was applied to test cellular senescence. Exosomal delivering LncRNA-NEAT1 induced therapeutic effect in vivo was confirmed by echocardiography. It demonstrated that exosomesMIF recovered the cardiac function and exerted the anti-senescent effect through LncRNA–NEAT1 transfer against Dox. TargetScan and luciferase assay showed that miR-221-3p targeted the Sirt2 3′-untranslated region. Silencing LncRNA–NEAT1 in MSCs, miR-221-3p overexpression or Sirt2 silencing in cardiomyocytes decreased the exosomeMIF-induced anti-senescent effect against Dox. Conclusions: The results indicated exosomeMIF serving as a promising anti-senescent effector against Dox-induced cardiotoxicity through LncRNA–NEAT1 transfer, thus inhibiting miR-221-3p and leading to Sirt2 activation. The study proposed that exosomeMIF might have the potential to serve as a cardioprotective therapeutic agent during cancer chemotherapy. [ABSTRACT FROM AUTHOR]