Attenuated angiogenesis and macrophage infiltration during adipose tissue regeneration in a megavolume human fat grafting nude mouse model.

BACKGROUND: Survival and regeneration mechanisms of large (>250 mL) fat grafts remain incompletely understood. In fat grafts from volunteers with megavolume fat transfer breast augmentation, neovascularization and inflammatory cell infiltration decreased within 7 days according to histological analysis. We further investigated this phenomenon using a nude mouse model. METHODS: To simulate clinical contexts, chambers containing 1 mL human fat were implanted into nude mice. Chambers allowed selective transfer of tissue fluid from recipient nude mice into chambers, but not capillaries or macrophages. Seven days later, fat was removed from the chamber and reimplanted into a new nude mouse in the open-chambered fat group (OCFG, n=45). Adipose samples from volunteers and explanted grafts from OCFG were subjected to histological analyses. Graft weight, vascularization, and immune response were also compared between the OCFG and conventional direct fat grafting (control group (CG)). RESULTS: Percent tissue integrity, percent fibrosis, adipocyte viability, and neovascularization did not significantly differ between volunteer samples and OCFG grafts at day 7. On day 90, OCFG retention rate was decreased relative to CG and the fibrosis area was larger in the OCFG than in the CG. However, the macrophage and capillary counts were lower in the OCFG group relative to CG at days 7 and 14 after transplantation. CONCLUSIONS: The present study provides histological analyses of megavolume fat grafts sampled from clinical breast augmentation tissues and a xenograft nude mouse model. However, these preliminary results in a small clinical cohort should be further assessed in large allogeneic animal models.

The Association between Short-Term Exposure to PM1 and Daily Hospital Admission and Related Expenditures in Beijing.

Ambient particulate matter (PM) pollution is a leading environmental health threat worldwide. PM with an aerodynamic diameter ≤ 1.0 µm, also known as PM1, has been implicated in the morbidity and mortality of several cardiorespiratory and cerebrovascular diseases. However, previous studies have mostly focused on analyzing fine PM (PM2.5) associated with disease metrics, such as emergency department visits and mortality, rather than ultrafine PM, including PM1. This study aimed to evaluate the association between short-term PM1 exposure and hospital admissions (HAs) for all-cause diseases, chronic obstructive pulmonary disease (COPD), and respiratory infections (RIs), as well as the associated expenditures, using Beijing as a case study. Here, based on air pollution and hospital admission data in Beijing from 2015 to 2017, we performed a time-series analysis and meta-analysis. It was found that a 10 µg/m3 increase in the PM1 concentration significantly increased all-cause disease HAs by 0.07% (95% Confidence Interval (CI): [0, 0.14%]) in Beijing between 2015 and 2017, while the COPD and RI-related HAs were not significantly associated with short-term PM1 exposure. Meanwhile, we estimated the attributable number of HAs and hospital expenditures related to all-cause diseases. This study revealed that an average of 6644 (95% CI: [351, 12,917]) cases of HAs were attributable to ambient PM1, which was estimated to be associated with a 106 million CNY increase in hospital expenditure annually (95% CI: [5.6, 207]), accounting for 0.32% (95% CI: [0.02, 0.62%]) of the annual total expenses. The findings reported here highlight the underlying impact of ambient PM pollution on health risks and economic burden to society and indicate the need for further policy actions on public health.

Railway track settlement patterns and control measures for multi-tunnel construction underneath a station track group: a case study.

This paper is based on the proximity engineering project of the Baishiyi tunnel group passing under the Chongqing West Station track group. Considering the train load and the spatial relationship of the tunnel and track groups, the settlement patterns, horizontal displacement, and differential settlement of the tunnel-strata-tracks system during the excavation process are studied through theoretical calculations and numerical simulation methods. The results indicate that the tunnel vault, strata, and track settlement deformation patterns are similar. Throughout the tunnel construction process, the tracks underwent uplift, settlement, and eventually stabilized. The settlement trough formed by the excavation of the three tunnels below the track group has an impact range of 25-145 m. Between 35 and 75 m, the differential settlement of the double track gradually increases with excavation. As the tunnel face reaches 75 m, the track differential settlement gradually converges and tends to stabilize. To minimize the impact of underpass tunnel construction on track groups, it is recommended to use a combination of full-section hole grouting and surface reinforcement grouting for ground reinforcement. Additionally, optimizing the construction parameters, including the step length and primary support closure time, and strengthening the locking anchor can further reduce the impact.

Aging and homeostasis of the hypodermis in the age-related deterioration of skin function.

Adipose tissues in the hypodermis, the crucial stem cell reservoir in the skin and the endocrine organ for the maintenance of skin homeostasis undergo significant changes during skin aging. Dermal white adipose tissue (dWAT) has recently been recognized as an important organ for both non-metabolic and metabolic health in skin regeneration and rejuvenation. Defective differentiation, adipogenesis, improper adipocytokine production, and immunological dissonance dysfunction in dWAT lead to age-associated clinical changes. Here, we review age-related alterations in dWAT across levels, emphasizing the mechanisms underlying the regulation of aging. We also discuss the pathogenic changes involved in age-related fat dysfunction and the unfavorable consequences of accelerated skin aging, such as chronic inflammaging, immunosenescence, delayed wound healing, and fibrosis. Research has shown that adipose aging is an early initiation event and a potential target for extending longevity. We believe that adipose tissues play an essential role in aging and form a potential therapeutic target for the treatment of age-related skin diseases. Further research is needed to improve our understanding of this phenomenon.

Erythrocyte Membrane Coating Alleviate Immune Response and Promoted Adipogenesis in Adipose Matrix.

Xenotransplantation of acellular adipose matrix (AAM) has come to prominence as an intriguing option for soft tissue reconstruction. However, the presence of immunogenic antigens within AAM can trigger unfavorable immune reactions, leading to inadequate in vivo regeneration outcomes. Therefore, the development of advanced technology capable of modulating immune responses is crucial for the therapeutic implementation of AAM xenografts. In this work, an innovative technique is created to bypass the immune system by covering the surface of both AAM and Arg-Gly-Asp (RGD) peptide-modified AAM xenografts with autologous red blood cell (RBC) membrane. The RBC membrane coating remained persistent and exhibited no significant decline even after 21 days. Moreover, it effectively reduced the expression of antigen major histocompatibility complex class 1 (MHC1) on the AAM surface. Following xenogeneic transplantation, the RBC-coated xenografts demonstrated increased expression of the adipogenic factor PPAR-γ, Adipoq, Fabp4, Fasn, and Plin1 and higher numbers of adipocytes. In addition, they exhibited decreased expression of immunological factors, including IL-6, IL-2, IFN-γ, and TNF-α, and fewer inflammatory cells. These findings indicate that RBC membrane coating successfully suppressed immune responses and promoted increased adipogenesis in AAM xenografts. Therefore, AAM camouflage coating with RBC has a lot of potential as a biomaterial for soft tissue reconstruction in clinical settings.

Lymphatic Vessel-Mediated Attenuation of Persistent Macrophage Infiltration Improves Fat Grafting Outcomes in Mice Models.

BACKGROUND: Persistent macrophage infiltration may lead to adverse consequences, such as calcifications and nodules in fat grafts. Lymphatic vessels, which transport inflammatory cells, are involved in regulating inflammatory responses. Less is known, however, about lymphatic vessels after fat grafting. OBJECTIVES: The aim of this study was to explore the regulation of fat graft survival by lymphatic vessels. METHODS: A common adipose graft model was constructed to assess the processes responsible for changes in the number of lymphatic vessels in grafts. Adipose tissue samples from C57/BL6 mice and green fluorescent protein-expressing mice were cross-grafted to determine the source of lymphatic vessels. The number of lymphatic vessels in the grafts was increased by treatment with vascular endothelial growth factor C, and the effects of this increase on fat grafting were evaluated. RESULTS: The number of lymphatic vessels was greater in postgrafted fat than in inguinal fat before transplantation, with lymphatic vessels in these grafts gradually transitioning from donor to recipient sources. Lymphatic vessels grew more slowly than blood vessels during early stages of grafting; during later stages, however, the number of blood vessels declined markedly, with more lymphatic vessels than blood vessels being observed 60 days after grafting. Vascular endothelial growth factor C treatment increased graft lymphatics and distant volume retention, while reducing fibrosis and oil sacs. Lymphatic vessels acted as drainage channels for macrophages, with the degree of sustained macrophage infiltration decreasing with increases in the number of lymphatic vessels. CONCLUSIONS: Increasing the number of lymphatic vessels is beneficial for fat graft survival, which may be related to a reduction in prolonged macrophage infiltration.

The browning and mobilization of subcutaneous white adipose tissue supports efficient skin repair.

Adipocytes in dermis are considered to be important participants in skin repair and regeneration, but the role of subcutaneous white adipose tissue (sWAT) in skin repair is poorly understood. Here, we revealed the dynamic changes of sWAT during wound healing process. Lineage-tracing mouse studies revealed that sWAT would enter into the large wound bed and participate in the formation of granulation tissue. Moreover, sWAT undergoes beiging after skin injury. Inhibition of sWAT beiging by genetically silencing PRDM16, a key regulator to beiging, hindered wound healing process. The transcriptomics results suggested that beige adipocytes in sWAT abundantly express neuregulin 4 (NRG4), which regulated macrophage polarization and the function of myofibroblasts. In diabetic wounds, the beiging of sWAT was significantly suppressed. Thus, adipocytes from sWAT regulate multiple aspects of repair and may be therapeutic for inflammatory diseases and defective wound healing associated with aging and diabetes.

Innate lymphoid cell-based immunomodulatory hydrogel microspheres containing Cutibacterium acnes extracellular vesicles for the treatment of psoriasis.

Psoriasis is a chronic skin inflammation influenced by dysregulated skin microbiota, with the role of microbiota in psoriasis gaining increasing prominence. Bacterial extracellular vesicles (bEVs) serve as crucial regulators in the interaction between hosts and microbiota. However, the mechanism underlying the therapeutic potential of bEVs from commensal bacteria in psoriasis remains unclear. Here, we investigated the therapeutic role of Cutibacterium acnes (C. acnes)-derived extracellular vesicles (CA-EVs) in psoriasis treatment. To prolong the active duration of CA-EVs, we encapsulated them in gelatin methacrylate (GelMA) to fabricate hydrogel microspheres (CA-EVs@GHM) with sustained release properties. As GelMA degraded, CA-EVs were gradually released, maintaining a high concentration in mouse skin even 96 h post-treatment. In human keratinocyte cells (HaCaT), CA-EVs@GHM enhanced resistance to Staphylococcus aureus (S. aureus), promoted proliferation and migration of HaCaT cells exposed to S. aureus, and significantly reduced the expression of inflammatory genes such as interleukin (IL)-6 and C-X-C motif chemokine ligand 8 (CXCL8). In vivo, CA-EVs@GHM, more potent than CA-EVs alone, markedly attenuated proinflammatory gene expression, including tumor necrosis factor (TNF), Il6, Il17a, Il22 and Il23a in imiquimod (IMQ)-induced psoriasis-like mice, and restored skin barrier function. 16S rRNA sequencing revealed that CA-EVs@GHM might provide therapeutic effects against psoriasis by restoring microbiota diversity on the back skin of mice, reducing Staphylococcus colonization, and augmenting lipid metabolism. Furthermore, flow cytometry analysis showed that CA-EVs@GHM prevented the conversion of type 2 innate lymphoid cells (ILC2) to type 3 innate lymphoid cells (ILC3) in psoriasis-like mouse skin, reducing the pathogenic ILC3 population and suppressing the secretion of IL-17 and IL-22. In summary, our findings demonstrate that the long-term sustained release of CA-EVs alleviated psoriasis symptoms by controlling the transformation of innate lymphoid cells (ILCs) subgroups and restoring skin microbiota homeostasis, thus offering a promising therapy for psoriasis treatment. STATEMENT OF SIGNIFICANCE: Cutibacterium acnes, which is reduced in psoriasis skin, has been reported to promote skin homeostasis by regulating immune balance. Compared to live bacteria, bacterial extracellular vesicles (bEVs) are less prone to toxicity and safety concerns. bEVs play a pivotal role in maintaining bacterial homeostasis and modulating the immune system. However,bEVs without sustained release materials are unable to function continuously in chronic diseases. Therefore, we utilized hydrogel microspheres to encapsulate Cutibacterium acnes (C. acnes)-derived extracellular vesicles (CA-EVs), enabling long term sustained release. Our findings indicate that, CA-EVs loaded gelatin methacrylate hydrogel microspheres (CA-EVs@GHM) showed superior therapeutic effects in treating psoriasis compared to CA-EVs. CA-EVs@GHM exhibited a more significant regulation of pathological type 3 innate lymphoid cells (ILC3) and skin microbiota, providing a promising approach for microbiota-derived extracellular vesicle therapy in the treatment of skin inflammation.

[Prognostic Significance of Progression of Disease within 24 Months in Mantle Cell Lymphoma].

OBJECTIVE: To investigate the effect of progression of disease within 24 months (POD24) on overall survival (OS) in patients with mantle cell lymphoma (MCL), and compare the clinical characteristics between POD24 and non-POD24 patients. METHODS: A retrospective analysis was performed on 50 MCL patients with treatment indications and regular treatment who were admitted to the Affiliated Hospital of Xuzhou Medical University from January 2010 to August 2020. According to the occurrence of POD24, the patients were grouped for prognostic evaluation and clinical characteristics comparison. RESULTS: Univariate Cox regression analysis showed that POD24, PLT, albumin, MIPI score, ECOG PS score, LDH were the factors influencing OS in newly diagnosed MCL patients (all P < 0.05). The results of multivariate Cox regression analysis showed that POD24ï¼»HR=16.797(95%CI : 3.671-76.861),P < 0.001ï¼½, albumin<40 g/Lï¼»HR=3.238(95%CI :1.095-9.572),P =0.034ï¼½ and ECOG PS score≥2ï¼»HR=4.005(95%CI :1.033-15.521),P =0.045ï¼½ were independent risk factors influencing OS in MCL patients. The incidence of PLT<100×109/L (33.3% vs 5.9%, P =0.033) and ECOG PS score ≥2 (45.5% vs 5.9%, P =0.040) were significantly higher in POD24 patients than those in non-POD24 patients. CONCLUSION: POD24 is an independent poor prognostic factor affecting the OS of MCL patients, and the patients with PLT<100×109/L and ECOG PS score≥2 at diagnosis have a higher probability of POD24.

Rapid solar-driven atmospheric water-harvesting with MAF-4-derived nitrogen-doped nanoporous carbon.

Sorption-based atmospheric water-harvesting (AWH) could help to solve global freshwater scarcity. The search for adsorbents with high water-uptake capacity at low relative humidity, rapid adsorption-desorption kinetics and high thermal conductivity is a critical challenge in AWH. Herein, we report a MAF-4 (aka ZIF-8)-derived nanoporous carbon (NPCMAF-4-800) with multiple N-doped sites, considerable micropore characteristics and inherent photothermal properties, for efficient water production in a relatively arid climate. NPCMAF-4-800 exhibited optimal water-sorption performance of 306 mg g-1 at 40% relative humidity (RH). An excellent sunlight-absorption rate was realized (97%) attributed to its high degree of graphitization. A proof-of-concept device was designed and investigated for the practical harvesting of water from the atmosphere using natural sunlight. NPCMAF-4-800 achieved an unprecedentedly high water production rate of 380 mg g-1 h-1 at 40% RH, and could produce 1.77 L kg-1 freshwater during daylight hours in an outdoor low-humidity climate of ∼25 °C and 40% RH. These findings may shed light on the potential of MOF-derived porous carbons in the AWH field, and inspire the future development of solar-driven water-generation systems.

Plasmodium vivax serological exposure markers: PvMSP1-42-induced humoral and memory B-cell response generates long-lived antibodies.

Plasmodium vivax serological exposure markers (SEMs) have emerged as promising tools for the actionable surveillance and implementation of targeted interventions to accelerate malaria elimination. To determine the dynamic profiles of SEMs in current and past P. vivax infections, we screened and selected 11 P. vivax proteins from 210 putative proteins using protein arrays, with a set of serum samples obtained from patients with acute P. vivax and documented past P. vivax infections. Then we used a murine protein immune model to initially investigate the humoral and memory B cell response involved in the generation of long-lived antibodies. We show that of the 11 proteins, especially C-terminal 42-kDa region of P. vivax merozoite surface protein 1 (PvMSP1-42) induced longer-lasting long-lived antibodies, as these antibodies were detected in individuals infected with P. vivax in the 1960-1970s who were not re-infected until 2012. In addition, we provide a potential mechanism for the maintenance of long-lived antibodies after the induction of PvMSP1-42. The results indicate that PvMSP1-42 induces more CD73+CD80+ memory B cells (MBCs) compared to P. vivax GPI-anchored micronemal antigen (PvGAMA), allowing IgG anti-PvMSP1-42 antibodies to be maintained for a long time.

Cell-Penetrating Drug Carrier by Molecular Recognition of Sphingomyelin on Plasma Membranes.

Plasma membranes not only maintain the intracellular microenvironment through their phospholipid bilayer but also eliminate exogenous compounds outside the cell membranes. Most drugs especially with high polarity are prevented from entering into cells to exert their effects. Therefore, it is of great significance to design effective drug carriers with a penetrating ability toward plasma membranes. In this study, a dual-templated MIP (dt-MIPs) carrier with controllable microstructure and high drug loading capacity was prepared using highly expressed sphingomyelin on the plasma membrane and tenofovir (TFV), a first-line drug for HIV and chronic hepatitis B, as template molecules. The drug release experiments performed in vitro under simulated physiological conditions demonstrated that sustained and stable adsorption of TFV on dt-MIPs was more than 80% over 50 h. By a combination of flow cytometry and confocal microscopy, dt-MIPs were found to have efficient cell permeability. Furthermore, mass-spectrometry-based intracellular pharmacokinetic studies demonstrated that TFV was delivered completely into cells within 30 min with the delivery of dt-MIPs. The study presented above suggested that dt-MIPs are expected to be alternative nanoscale drug carriers for enhanced drug permeability and controlled release.

Global climate change: Effects of future temperatures on emergency department visits for mental disorders in Beijing, China.

Rising temperatures can increase the risk of mental disorders. As climate change intensifies, the future disease burden due to mental disorders may be underestimated. Using data on the number of daily emergency department visits for mental disorders at 30 hospitals in Beijing, China during 2016-2018, the relationship between daily mean temperature and such visits was assessed using a quasi-Poisson model integrated with a distributed lag nonlinear model. Emergency department visits for mental disorders attributed to temperature changes were projected using 26 general circulation models under four climate change scenarios. Stratification analyses were then conducted by disease subtype, sex, and age. The results indicate that the temperature-related health burden from mental disorders was projected to increase consistently throughout the 21st century, mainly driven by high temperatures. The future temperature-related health burden was higher for patients with mental disorders due to the use of psychoactive substances and schizophrenia as well as for women and those aged <65 years. These findings enhance our knowledge of how climate change could affect mental well-being and can be used to advance and refine targeted approaches to mitigating and adapting to climate change with a view on addressing mental disorders.

Ant-eating spiders from Xizang, China (Araneae, Zodariidae).

Six species of the ant-eating spider of the family Zodariidae are described from Xizang, China, including five new species: Asceuachayusp. nov. (♀), A.dawaisp. nov. (♂♀), Mallinellamigusp. nov. (♂), M.mеdogsp. nov. (♂♀), and M.yadongsp. nov. (♂♀). The female of Cydrelalinzhiensis (Hu, 2001) is described here for the first time. Descriptions and photographs of all the species are provided.

Meibomian glands segmentation in infrared images with limited annotation.

AIM: To investigate a pioneering framework for the segmentation of meibomian glands (MGs), using limited annotations to reduce the workload on ophthalmologists and enhance the efficiency of clinical diagnosis. METHODS: Totally 203 infrared meibomian images from 138 patients with dry eye disease, accompanied by corresponding annotations, were gathered for the study. A rectified scribble-supervised gland segmentation (RSSGS) model, incorporating temporal ensemble prediction, uncertainty estimation, and a transformation equivariance constraint, was introduced to address constraints imposed by limited supervision information inherent in scribble annotations. The viability and efficacy of the proposed model were assessed based on accuracy, intersection over union (IoU), and dice coefficient. RESULTS: Using manual labels as the gold standard, RSSGS demonstrated outcomes with an accuracy of 93.54%, a dice coefficient of 78.02%, and an IoU of 64.18%. Notably, these performance metrics exceed the current weakly supervised state-of-the-art methods by 0.76%, 2.06%, and 2.69%, respectively. Furthermore, despite achieving a substantial 80% reduction in annotation costs, it only lags behind fully annotated methods by 0.72%, 1.51%, and 2.04%. CONCLUSION: An innovative automatic segmentation model is developed for MGs in infrared eyelid images, using scribble annotation for training. This model maintains an exceptionally high level of segmentation accuracy while substantially reducing training costs. It holds substantial utility for calculating clinical parameters, thereby greatly enhancing the diagnostic efficiency of ophthalmologists in evaluating meibomian gland dysfunction.

Rising Incidence of Acute Epiglottitis in Eastern China: An Eight-Year Retrospective Study and Its Association with the 24 Solar Terms.

Purpose: This study aimed to investigate the clinical characteristics of acute epiglottitis (AE) patients in East China and examine the correlation between the incidence of AE and the 24 solar terms (24 STs). Methods: A retrospective, observational study was conducted on patients diagnosed with AE between January 2014 and December 2021 at a single-center medical institution in East China. The clinical characteristics of patients with AE and their correlation with the 24 STs were investigated. Results: A total of 287 patients with AE were included in this study, among which there were 179 males (62.37%) and 108 females (37.63%), with a mean age of 47.79 ± 13.83 years (range 16-87 years). Of these patients, 100 (34.84%) had at least one comorbidity and the most common comorbidities were hypertension, smoking and type 2 diabetes. The duration of hospitalization was 3 days (IQR, 1-16 days). All patients, except for one who required tracheal intubation, were cured with intravenous antibiotic administration and the combined use of corticosteroids. The incidence of AE showed significant fluctuations between the 24 STs and the highest number of cases occurred during the Summer solstice (24 cases, 8.36%). Conclusion: The incidence of AE was seen to increase annually in this study. The main features of AE are sore throat, dysphagia, odynophagia and fever, which may be accompanied by inflammation in surrounding areas. A clear correlation exists between the incidence of AE and the fluctuations within the 24 STs, notably with the peak incidence observed during the Summer solstice, which approximately corresponds to June 21 to July 7 in the Gregorian calendar.

Vascular smooth muscle-specific LRRC8A knockout ameliorates angiotensin II-induced cerebrovascular remodeling by inhibiting the WNK1/FOXO3a/MMP signaling pathway.

Hypertensive cerebrovascular remodeling involves the enlargement of vascular smooth muscle cells (VSMCs), which activates volume-regulated Cl- channels (VRCCs). The leucine-rich repeat-containing family 8 A (LRRC8A) has been shown to be the molecular identity of VRCCs. However, its role in vascular remodeling during hypertension is unclear. In this study, we used vascular smooth muscle-specific LRRC8A knockout (CKO) mice and an angiotensin II (Ang II)-induced hypertension model. The results showed that cerebrovascular remodeling during hypertension was ameliorated in CKO mice, and extracellular matrix (ECM) deposition was reduced. Based on the RNA-sequencing analysis of aortic tissues, the level of matrix metalloproteinases (MMPs), such as MMP-9 and MMP-14, were reduced in CKO mice with hypertension, which was further verified in vivo by qPCR and immunofluorescence analysis. Knockdown of LRRC8A in VSMCs inhibited the Ang II-induced upregulation of collagen I, fibronectin, and matrix metalloproteinases (MMPs), and overexpression of LRRC8A had the opposite effect. Further experiments revealed an interaction between with-no-lysine (K)-1 (WNK1), which is a "Cl--sensitive kinase", and Forkhead transcription factor O3a (FOXO3a), which is a transcription factor that regulates MMP expression. Ang II induced the phosphorylation of WNK1 and downstream FOXO3a, which then increased the expression of MMP-2 and MMP-9. This process was inhibited or potentiated when LRRC8A was knocked down or overexpressed, respectively. Overall, these results demonstrate that LRRC8A knockout in vascular smooth muscle protects against cerebrovascular remodeling during hypertension by reducing ECM deposition and inhibiting the WNK1/FOXO3a/MMP signaling pathway, demonstrating that LRRC8A is a potential therapeutic target for vascular remodeling-associated diseases such as stroke.

Migrasomes from adipose derived stem cells enrich CXCL12 to recruit stem cells via CXCR4/RhoA for a positive feedback loop mediating soft tissue regeneration.

BACKGROUND: Adipose-derived stem cells (ASCs) represent the most advantageous choice for soft tissue regeneration. Studies proved the recruitment of ASCs post tissue injury was mediated by chemokine CXCL12, but the mechanism by which CXCL12 is generated after tissue injury remains unclear. Migrasomes are newly discovered membrane-bound organelles that could deliver CXCL12 spatially and temporally in vivo. In this study, we sought to investigate whether migrasomes participate ASC-mediated tissue regeneration. METHODS: Discrepant and asymmetrical soft tissue regeneration mice model were established, in which HE staining, immunofluorescent staining, western blot and qPCR were conducted to confirm the role of CXCL12 and migrasomes in ASC-mediated tissue regeneration. Characterization of ASC-derived migrasomes were carried out by confocal microscopy, scanning electron microscopy, transmission electron microscopy as well as western blot analysis. The function and mechanism of migrasomes were further testified by assisting tissue regeneration with isolated migrasomes in vivo and by in vitro transwell combined with co-culture system. RESULTS: Here, we show for the first time that migrasomes participate in soft tissue regeneration. ASCs generate migrasomes enriched with CXCL12 to mediate tissue regeneration. Migrasomes from ASCs could promote stem cells migration by activating CXCR4/RhoA signaling in vivo and in vitro. Chemoattracted ASCs facilitate regeneration, as demonstrated by the upregulation of an adipogenesis-associated protein. This positive feed-back-loop creates a favorable microenvironment for soft tissue regeneration. Thus, migrasomes represent a new therapeutic target for ASC-mediated tissue regeneration. CONCLUSIONS: Our findings reveal a previously unknown function of ASCs in mediating tissue regeneration by generating migrasomes. The ASC-derived migrasomes can restore tissue regeneration by recruiting stem cells, which highlighting the potential application of ASC-derived migrasomes in regenerative medicine.

Inhibition of Adipocyte Necroptosis Alleviates Fat Necrosis and Fibrosis after Grafting: In a Mice Model.

BACKGROUND: Owing to the delicate structure of the adipose tissue, fat necrosis accounts for 43.7% of all complications after autologous fat grafting; however, its regulation remains unclear. OBJECTIVES: The purpose of this study was to examine the role of necroptosis in fat graft remodeling after grafting. METHODS: Clinical fat graft necrosis samples were collected, and the expression levels of the necroptosis marker phosphorylated(p)-MLKL were analyzed. Transcriptome analysis was performed on fat grafts before and one week after transplantation in C57BL/6 mouse fat grafting models. Additionally, the in vivo effects of RIPK1 inhibitor Nec-1s or RIPK3 inhibitor GSK'872 on the fat grafting complications including fat necrosis and fibrosis were investigated. RESULTS: Necroptosis markers were observed and associated with higher occurrence of fibrosis in clinical fat graft necrosis samples compared to normal fat tissue. Amplification and RNA-Seq were conducted on RNA isolated from fat grafts before and after grafting. MLKL, RIPK1 and RIPK3 expression levels were significantly upregulated in comparison to controls. Higher expression levels of necroptotic RNAs were associated with higher levels of DAMPs, including Cxcl2, HMGB1, S100a8, S100a9, Nlrp3 and IL33, and activated pro-inflammatory signaling pathways, including the TNF, NF-kappa B and chemokine signaling pathways. Necroptotic inhibitor Nec-1s and GSK'872 robustly suppressed the p-MLKL expression level and significantly inhibited necroptotic cell death, especially in adipocytes. Moreover, administration of Nec-1s and GSK'872 significantly alleviated fat necrosis and subsequent fibrosis in fat grafts. CONCLUSIONS: Collectively, our study findings highlight the potential therapeutic applications of necroptosis inhibitors in preventing fat necrosis and fibrosis after grafting.

Challenges and opportunities in obesity: the role of adipocytes during tissue fibrosis.

Obesity is a chronic disease that affects the energy balance of the whole body. In addition to increasing fat mass, tissue fibrosis occurred in white adipose tissue in obese condition. Fibrosis is the over-activation of fibroblasts leading to excessive accumulation of extracellular matrix, which could be caused by various factors, including the status of adipocytes. The morphology of adipocytes responds rapidly and dynamically to nutrient fluctuations. Adaptive hypertrophy of normal adipocytes protects peripheral organs from damage from lipotoxicity. However, the biological behavior of hypertrophic adipocytes in chronic obesity is abnormally altered. Adipocytes lead to fibrotic remodeling of the extracellular matrix by inducing unresolved chronic inflammation, persistent hypoxia, and increasing myofibroblast numbers. Moreover, adipocyte-induced fibrosis not only restricts the flexible expansion and contraction of adipose tissue but also initiates the development of various diseases through cellular autonomic and paracrine effects. Regarding anti-fibrotic therapy, dysregulated intracellular signaling and epigenetic changes represent potential candidate targets. Thus, modulation of adipocytes may provide potential therapeutic avenues for reversing pathological fibrosis in adipose tissue and achieving the anti-obesity purpose.