Balancing macrophage polarization via stem cell-derived apoptotic bodies for diabetic wound healing.
Med (New York, N.Y.)
BACKGROUND:Adipose tissue-derived stem cell-derived apoptotic bodies (ADSC-ABs) have shown great potential for immunomodulation and regeneration, particularly in diabetic wound therapy. However, their local application has been limited by unclear regulatory mechanisms, rapid clearance, and short tissue retention times. METHODS:We analyzed the key role molecules and regulatory pathways of ADSC-ABs in regulating inflammatory macrophages by mRNA sequencing and microRNA (miRNA) sequencing and then verified them by gene knockdown. To prevent rapid clearance, we employed microfluidics technology to prepare methacrylate-anhydride gelatin (GelMA) microspheres (GMS) for controlled release of ABs. Finally, we evaluated the effectiveness of ADSC-AB-laden GMSs (ABs@GMSs) in a diabetic rat wound model. FINDINGS:Our results demonstrated that ADSC-ABs effectively balanced macrophage inflammatory polarization through the janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, mediated by miR-20a-5p. Furthermore, we showed that AB@GMSs had good biocompatibility, significantly delayed local clearance of ABs, and ameliorated diabetic wound inflammation and promoted vascularization, thus facilitating its healing. CONCLUSIONS:Our study reveals the regulatory mechanism of ADSC-ABs in balancing macrophage inflammatory polarization and highlightsthe importance of delaying their local clearance by GMSs. These findings have important implications for the development of novel therapies for diabetic wound healing. FUNDING:This research was supported by the National Key Research and Development Program of China (2020YFA0908200), National Natural Science Foundation of China (82272263, 82002053, 32000937, and 82202467), Shanghai "Rising Stars of Medical Talents" Youth Development Program (22MC1940300), Shanghai Municipal Health Commission (20204Y0354), and Shanghai Science and Technology Development Funds (22YF1421400).
10.1016/j.medj.2024.01.006
Restoring Prohealing/Remodeling-Associated M2a/c Macrophages Using ON101 Accelerates Diabetic Wound Healing.
JID innovations : skin science from molecules to population health
Diabetic wounds exhibit chronic inflammation and delayed tissue proliferation or remodeling, mainly owing to prolonged proinflammatory (M1) macrophage activity and defects in transition to prohealing/proremodeling (M2a/M2c; CD206 and/or CD163) macrophages. We found that topical treatment with ON101, a plant-based potential therapeutic for diabetic foot ulcers, increased M2c-like (CD163 and CD206) cells and suppressed M1-like cells, altering the inflammatory gene profile in a diabetic mouse model compared with that in the controls. An in vitro macrophage-polarizing model revealed that ON101 directly suppressed CD80 and CD86 M1-macrophage polarization and M1-associated proinflammatory cytokines at both protein and transcriptional levels. Notably, conditioned medium collected from ON101-treated M1 macrophages reversed the M1-conditioned medium‒mediated suppression of CD206 macrophages. Furthermore, conditioned medium from ON101-treated adipocyte progenitor cells significantly promoted CD206 and CD163 macrophages but strongly inhibited M1-like cells. ON101 treatment also stimulated the expression of and genes in human adipocyte progenitor cells. Interestingly, treatment with recombinant GCSF protein enhanced both CD206 and CD163 M2 markers, whereas CXCL3 treatment only stimulated CD163 M2 macrophages. Depletion of cutaneous M2 macrophages inhibited ON101-induced diabetic wound healing. Thus, ON101 directly suppressed M1 macrophages and facilitated the GCSF- and CXCL3-mediated transition from M1 to M2 macrophages, lowering inflammation and leading to faster diabetic wound healing.
10.1016/j.xjidi.2022.100138
Promoting Diabetic Wound Healing through a Hydrogel-Based Cascade Regulation Strategy of Fibroblast-Macrophage.
Advanced healthcare materials
The management of diabetic wounds (DWs) continues to pose a significant challenge in the field of medicine. DWs are primarily prevented from healing due to damage to macrophage efferocytosis and fibroblast dysfunction. Consequently, a treatment strategy that involves both immunoregulation and the promotion of extracellular matrix (ECM) formation holds promise for healing DWs. Nevertheless, existing treatment methods necessitate complex interventions and are associated with increased costs, for example, the use of cytokines and cell therapy, both of which have limited effectiveness. In this study, a new type of ruthenium (IV) oxide nanoparticles (RNPs)-laden hybrid hydrogel dressing with a double network of Pluronic F127 and F68 has been developed. Notably, the hybrid hydrogel demonstrates remarkable thermosensitivity, injectability, immunoregulatory characteristics, and healing capability. RNPs in hydrogel effectively regulate both fibroblasts and macrophages in a cascade manner, stimulating fibroblast differentiation while synergistically enhancing the efferocytosis of macrophage. The immunoregulatory character of the hydrogel aids in restoring the intrinsic stability of the immune microenvironment in the wound and facilitates essential remodeling of the ECM. This hydrogel therefore offers a novel approach for treating DWs through intercellular communication.
10.1002/adhm.202400526
Quercetin Promotes Diabetic Wound Healing via Switching Macrophages From M1 to M2 Polarization.
Fu Jia,Huang Jingjuan,Lin Man,Xie Tingting,You Tianhui
The Journal of surgical research
BACKGROUND:For patients with diabetes mellitus, excessive and long-lasting inflammatory reactions at the wound site commonly lead to the delayed refractory wound healing. The polarization of macrophages in terms of M1 and M2 phenotypes is closely related to the production of inflammatory cytokines. Quercetin is traditionally recognized to have anti-inflammatory effect; however, whether quercetin modulates macrophage polarization from M1 to M2 and thus promotes diabetic wound healing remain unknown. MATERIALS AND METHODS:Wounded male diabetic rats were equally divided into five groups: model group, solvent control group (10% DMSO), and three drug groups treated with quercetin (Q) at concentrations of 10 mg/mL (Q-LD [low dose]), 20 mg/mL (Q-MD [medium dose]), and 40 mg/mL (Q-HD [high dose]), respectively. The anti-inflammatory effect of quercetin on diabetic wounds was observed. Immunohistochemistry and quantificational real-time polymerase chain reaction were applied to test the changes in macrophage polarization and inflammatory responses. RESULTS:The wound contraction was fastest in Q-HD group. Hematoxylin and eosin (H&E) and Masson's trichrome staining revealed that fibroblast distribution and collagen deposition in quercetin-treated groups were significantly higher than those in the model group. Immunohistochemistry tests showed more CD206-positive cells and less iNOS-positive cells in quercetin-treated groups. Furthermore, the levels of proinflammatory factors in quercetin-treated groups were lower than those in the model group, whereas the levels of the anti-inflammatory factors and angiogenesis-related factors were relatively higher. CONCLUSIONS:In short, quercetin inhibits inflammatory reactions via modulating macrophage polarization switching from M1 to M2 phenotype, thereby accelerating the diabetic wound repair.
10.1016/j.jss.2019.09.011
Macrophages as a therapeutic target to promote diabetic wound healing.
Molecular therapy : the journal of the American Society of Gene Therapy
It is well established that macrophages are key regulators of wound healing, displaying impressive plasticity and an evolving phenotype, from an aggressive pro-inflammatory or "M1" phenotype to a pro-healing or "M2" phenotype, depending on the wound healing stage, to ensure proper healing. Because dysregulated macrophage responses have been linked to impaired healing of diabetic wounds, macrophages are being considered as a therapeutic target for improved wound healing. In this review, we first discuss the role of macrophages in a normal skin wound healing process and discuss the aberrations that occur in macrophages under diabetic conditions. Next we provide an overview of recent macrophage-based therapeutic approaches, including delivery of ex-vivo-activated macrophages and delivery of pharmacological strategies aimed at eliminating or re-educating local skin macrophages. In particular, we focus on strategies to silence key regulator genes to repolarize wound macrophages to the M2 phenotype, and we provide a discussion of their potential future clinical translation.
10.1016/j.ymthe.2022.07.016
IL-10 Dysregulation Underlies Chemokine Insufficiency, Delayed Macrophage Response, and Impaired Healing in Diabetic Wounds.
The Journal of investigative dermatology
Persistent inflammation is a major contributor to healing impairment in diabetic chronic wounds. Paradoxically, diabetic wound environment during the acute phase of healing is completely different because it exhibits a reduced macrophage response owing to inadequate expression of CCL2 proinflammatory cytokine. What causes a reduction in CCL2 expression in diabetic wounds early after injury remains unknown. In this study, we report that in contrast to prolonged exposure to high glucose, which makes monocytes proinflammatory, short-term exposure to high glucose causes a rapid monocyte reprogramming, manifested by increased expression and secretion of IL-10, which in an autocrine/paracrine fashion reduces glucose uptake and transforms monocytes into an anti-inflammatory phenotype by dampening signaling through toll-like receptors. We show that IL-10 expression is significantly increased in diabetic wounds during the acute phase of healing, causing significant reductions in toll-like receptor signaling and proinflammatory cytokine production, delaying macrophage and leukocyte responses, and underlying healing impairment in diabetic wounds. Importantly, blocking IL-10 signaling during the acute phase of healing improves toll-like receptor signaling, increases proinflammatory cytokine production, enhances macrophage and leukocyte responses, and stimulates healing in diabetic wounds. We posit that anti-IL-10 strategies have therapeutic potential if added topically after surgical debridement, which resets chronic wounds into acute fresh wounds.
10.1016/j.jid.2021.08.428
Reduced apoptosis of monocytes and macrophages is associated with their persistence in wounds of diabetic mice.
Cytokine
Monocytes and macrophages (Mo/MΦ) rapidly accumulate in skin wounds after injury, then disappear as healing progresses. However, the mechanisms underlying their ultimate fate in wounds remain to be elucidated. Here, we show that apoptosis of Mo/MΦ parallels their reduction as wound healing progresses in non-diabetic mice. scRNAseq analysis confirmed enriched apoptosis GO pathways on day 6 post-injury in wound Mo/MΦ from non-diabetic mice. In contrast, there was significantly less Mo/MΦ apoptosis in wounds from diabetic mice, particularly in the pro-inflammatory Ly6C+ population, which may contribute to persistent Mo/MΦ accumulation and chronic inflammation. scRNAseq analysis implicated TNF, MAPK, Jak-STAT, and FoxO signaling pathways in promoting wound Mo/MΦ apoptosis in non-diabetic mice while cell proliferation related pathways appeared to be activated in diabetic mice. These novel findings indicate that reduced apoptosis is a contributor to persistent Mo/MΦ accumulation in diabetic wounds. These findings also highlight pathways that may regulate Mo/MΦ apoptosis during wound healing, which could be targeted to help resolve inflammation and improve healing.
10.1016/j.cyto.2021.155516