The spatio-temporal heterogeneity of breast cell subsets forms the fundamental biological basis for physiological development and pathological progression, including tumorigenesis; however, its complex regulatory mechanisms are not yet fully elucidated. With its high-resolution capabilities, single-cell RNA sequencing (scRNA-seq) technology offers a powerful tool for dissecting this cellular heterogeneity. This technology enables the construction of high-precision breast cell atlases, the accurate identification of distinct cell subsets, and the reconstruction of differentiation trajectories from stem/progenitor cells to functional epithelial cells. By resolving the transcriptional regulatory networks that govern cell fate determination, intercellular communication patterns, and dynamic microenvironmental interactions, scRNA-seq has unveiled the molecular foundations of breast development and provided new perspectives on the pathogenesis of related diseases such as breast cancer and macromastia. Furthermore, scRNA-seq demonstrates significant potential for discovering early molecular markers of disease, deciphering tumor heterogeneity, and elucidating mechanisms of therapeutic resistance. The continued application of scRNA-seq for dissecting breast cell heterogeneity, combined with its integration with multi-modal data such as spatial omics, promises to provide critical evidence and new insights for revealing the molecular mechanisms of breast development-related diseases and for formulating precision therapeutic strategies.
Humans ; Single-Cell Analysis/methods* ; Female ; Breast Neoplasms/pathology* ; Sequence Analysis, RNA/methods* ; Breast/cytology*

OBJECTIVES: Keloids are fibrotic skin disorders characterized by excessive collagen deposition and a high recurrence rate, closely associated with inflammatory mediators. However, existing epidemiological studies are limited by confounding factors and reverse causality, making it difficult to establish causation. This study aims to investigate the causal relationship between circulating cytokines and keloids using Mendelian randomization analysis. METHODS: Significant single nucleotide polymorphisms (SNPs) associated with circulating cytokines (exposures) and keloids (outcomes) were extracted from genome-wide association study (GWAS) summary datasets. Eligible SNPs were selected as instrumental variables (IVs). Exposure data were derived from a cytokine GWAS including 8 293 Finnish participants, and outcome data from a keloid GWAS based on the UK Biobank. The inverse-variance weighted (IVW) method served as the primary analytical approach to estimate causal effects, supplemented by weighted median (WME), MR-Egger regression, and other sensitivity analyses. Horizontal pleiotropy was assessed using MR-Egger regression and the MR pleiotropy residual sum and outlier (MR-PRESSO) test, while Cochran's Q test evaluated heterogeneity. Leave-one-out analysis was used to verify robustness and consistency. A reverse MR analysis was also conducted, with keloid as the exposure and cytokines as outcomes, to rule out reverse causation. RESULTS: IVW analysis identified significant positive causal associations between two cytokines and keloids-macrophage migration inhibitory factor (MIF) [odds ratio (OR)=2.081, 95% confidence interval (CI) 1.219 to 3.552, P=0.007] and monocyte chemoattractant protein-1 (MCP-1) (OR=1.673, 95% CI 1.036 to 2.701, P=0.035). Conversely, stem cell factor (SCF) showed a negative causal relationship with keloids (OR=0.518, 95% CI 0.269 to 0.998, P=0.049). Results from the MR-Egger and weighted median analyses were consistent with IVW findings. No evidence of horizontal pleiotropy was observed (P>0.05). Except for interleukin-6 (P=0.014), no heterogeneity was detected in other cytokines. Leave-one-out analysis further confirmed the robustness of the causal associations. In reverse MR analysis, keloids were causally related only to β-nerve growth factor (beta-NGF) (OR=1.048, 95% CI 1.002 to 1.095, P=0.039), with no heterogeneity or pleiotropy detected in most cytokines (P>0.05). CONCLUSIONS MIF and MCP-1 exhibit positive causal associations with keloid formation, while SCF shows a negative causal relationship. These findings provide new evidence for the causal involvement of inflammatory cytokines in keloid pathogenesis and offer potential molecular targets for developing novel keloid therapies.
Humans ; Keloid/blood* ; Mendelian Randomization Analysis ; Cytokines/genetics* ; Polymorphism, Single Nucleotide ; Genome-Wide Association Study ; Chemokine CCL2/genetics* ; Interleukin-6/genetics* ; Macrophage Migration-Inhibitory Factors/genetics* ; Male ; Stem Cell Factor/blood* ; Female ; Intramolecular Oxidoreductases

OBJECTIVES: To investigate the mechanism by which chitosan (CS) hydrogel loaded with human umbilical cord mesenchymal stem cell (HUVECs)-derived exosomes (hUCMSC-exos) (Exos@CS-Gel) improves diabetic wound healing. METHODS: hUCMSC-exos were extracted and Exos@CS-Gel was prepared. The effect of Exos@CS-Gel on proliferation and migration of HUVECs were evaluated using scratch wound assay and CCK-8 assay. Diabetic rat models with full-thickness skin wounds established by streptozotocin induction were randomized divided into 4 groups for treatment with Exos@CS-Gel (100 µg hUCMSC-exos dissolved in 100 µL 24% CS hydrogel), hUCMSC-exos (100 µg hUCMSC-exos dissolved in 100 µL PBS), CS hydrogel (100 µL 24% CS hydrogel), or PBS (control group). Wound healing and the therapeutic mechanisms were assessed using immunohistochemistry, HE staining, immunofluorescence, and qRT-PCR. RESULTS: In cultured HUVECs, Exos@CS-Gel treatment significantly promoted cell proliferation and migration. In the rat models of chronic diabetic wounds, the wound healing rate in Exos@CS-Gel group reached 92.7% on day 14, significantly higher than those in hUCMSC-exos group (9.12%), CS hydrogel group (16.28%), and control group (25.98%). Microvessel density and the expression levels of vascular endothelial growth factor and transforming growth factor β-1 were significantly increased in the Exos@CS-Gel group. CONCLUSIONS Exos@CS-Gel promotes survival capacity of hUCMSC-exos in vitro and accelerates diabetic wound healing in rats by promoting angiogenesis and cell proliferation.
Animals ; Wound Healing ; Humans ; Chitosan ; Exosomes ; Mesenchymal Stem Cells/cytology* ; Diabetes Mellitus, Experimental ; Rats ; Umbilical Cord/cytology* ; Hydrogels ; Human Umbilical Vein Endothelial Cells ; Cell Proliferation ; Rats, Sprague-Dawley ; Male

BACKGROUND:Satellite cells are a specific population of adult stem cells contained in skeletal muscle that promote the regenerative reconstruction of injured skeletal muscle,but their specific mechanisms are not well established. OBJECTIVE:To review the regulatory role of satellite cells during skeletal muscle regeneration and the mechanism of interaction between satellite cells and their ecological niche signals,aiming to provide new research ideas and perspectives based on the summary of existing knowledge. METHODS:Web of Science,PubMed,CNKI,WanFang,and VIP databases were searched for literature published between January 2002 and June 2022.English search terms were"muscle,skeletal muscle,muscle injury,stem cells,satellite cells,muscle repair".Chinese search terms were"skeletal muscle,skeletal muscle regeneration,skeletal muscle reconstruction,satellite cells,ecological niche".The 66 included papers were organized and analyzed. RESULTS AND CONCLUSION:(1)Satellite cells exist in skeletal muscle and contribute to both the formation of new muscle fibers after injury and the effective growth of existing adult muscle fibers.(2)After the activation of quiescent satellite cells in satellite cells,the steps of satellite cell proliferation,differentiation and fusion to form muscle fibers during skeletal muscle regeneration are influenced by their intrinsic regulatory effects of different mechanisms.(3)Satellite cells can interact with myofibers,extracellular matrix,skeletal muscle junctions,fibroblast progenitor cells,immune cells and endothelial cells in the ecological niche signal to promote satellite cell activation,proliferation and differentiation to achieve effective skeletal muscle regeneration.(4)Possible breakthroughs in future research include:the division pattern of satellite cells in the body;the mechanisms regulating satellite cell transfer;the specific timing of satellite cell differentiation or self-renewal in vivo;and the interaction mechanisms between satellite cells and skeletal muscle junctions.(5)This review may provide some theoretical reference values for the field of injury reconstruction of skeletal muscle and its innovation.

BACKGROUND:Sarcopenia is a chronic condition that leads to strength loss and functional decline,increasing the risk of frailty,disability,falls,and death in older adults.Blood flow restriction training can be effective in the treatment of sarcopenia,but a comprehensive review of its advantages,disadvantages,biological mechanisms,and application options is lacking. OBJECTIVE:To review the advantages,limitations,and biological mechanisms of blood flow restriction training interventions for sarcopenia and to give recommendations for application protocols based on current published evidence. METHODS:A search of major databases was conducted for literature published in the time frame up to February 2023.The search terms were"blood flow restriction training,KAATSU,elderly,sarcopenia,muscle"in English and Chinese.Finally,82 included papers were compiled and analyzed. RESULTS AND CONCLUSION:Blood flow restriction training as an intervention for sarcopenia has been effective in peripheral muscle groups,but there are limitations in its application.Blood flow restriction training is highly operational and safe.This training can improve muscle strength and physical performance,but there are potential risks,including adverse events on skeletal muscle,cardiovascular and endothelial cells.Therefore,blood flow restriction training needs to be performed under scientific guidance and further studies are needed to verify its efficacy in patients with sarcopenia.The biological mechanisms of blood flow restriction training intervention in sarcopenia may include:increasing muscle hypertrophy due to reactive muscle congestion,improving muscle protein synthesis capacity,inducing metabolic stress adaptation,promoting skeletal muscle growth and repair,activating vascular endothelial growth factor signaling pathway to promote angiogenesis,and promoting satellite cell proliferation.However,these specific roles and combined effects of these mechanisms need to be determined by more in-depth studies.Blood flow restriction training interventions for sarcopenia are mainly influenced by training and cuffs.To avoid adverse events,it is recommended that 20%to 50%1RM,20 to 75 repetitions,2 to 3 times per week,30-60 seconds interval between sessions,smaller size cuffs with a pressurization value≤140 mmHg for upper limb training,and larger size cuffs with a pressurization value≤180 mmHg for lower limb training,usually 50%to 80%of the pressure value in the completely occluded artery.However,more research is needed on the training frequency and interval between sessions in older adults,and further research is needed on the optimal choice of cuff pressurization values.

BACKGROUND:Satellite cells are myogenic stem cells located between the muscle fiber membrane and the basement membrane.However,a comprehensive review of the aging mechanisms of satellite cells and their potential mitigation strategies is still lacking.This gap in knowledge hinders the effective guidance for current strategies aimed at attenuating skeletal muscle aging. OBJECTIVE:To review the mechanisms of satellite cell aging in skeletal muscle and the relevant strategies for mitigating this aging process. METHODS:Major databases were searched up to May 2023,including Web of Science,PubMed,China National Knowledge Infrastructure(CNKI),WanFang Data,and VIP.Chinese and English search terms included"skeletal muscle,satellite cells,aging,mechanism,and solution strategy".After strict inclusion and exclusion criteria were applied,78 articles were finally included. RESULTS AND CONCLUSION:(1)Satellite cells,situated between the muscle fiber membrane and basement membrane,possess proliferative and differentiative potential.They usually remain in a quiescent state but become activated in response to muscle tissue stimuli,participating in processes of repair and restoration of normal tissue structure.Aging leads to a reduction in satellite cell numbers,resulting in symptoms such as muscle weakness and decreased endurance.(2)Mechanisms of satellite cell aging primarily involve diminished regenerative capacity,perturbed niche interactions with changing ecology,age-dependent loss,and heterogeneity changes.Reduced satellite cell numbers and activity due to aging lead to slower muscle regeneration and increased injury recovery time.Errors during differentiation may occur,resulting in decreased muscle quality and function deterioration.(3)Strategies for mitigating satellite cell aging encompass modulation of the receptor environment of intra-body satellite cells,peripheral interventions to promote satellite cell regeneration,construction of human muscle models,and exercise and nutritional interventions to induce satellite cell proliferation.These strategies hold promise in offering novel insights and methods for satellite cell regeneration and treatment of skeletal muscle diseases.(4)Future research should delve into the mechanisms of satellite cell aging,explore the interaction between satellite cells and their niches,investigate the relationship of satellite cells with the immune system and mitochondrial function,and develop human muscle models to enhance research depth and accuracy.

Objective:To study and screen the differential expression of inflammatory proteins in diabetes skin ulcers and common skin ulcers, so as to provide experimental basis for further research on anti-inflammatory and healing drug targets of diabetes skin ulcers.Methods:The tissues of 11 patients with diabetes skin ulcer, 12 patients with common skin ulcer and 11 patients with normal skin were collected from the First Hospital of Hunan University of Chinese Medicine. The levels of inflammatory protein Toll like receptor 4 (TLR4), nuclear factor κB (NF-κB), pro-inflammatory factor interferon -γ (IFN -γ), tumor necrosis factor - α (TNF -α), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-1β (IL-1β), macrophage chemotactic protein-1 (MCP-1), anti-inflammatory factors epidermal growth factor (EGF), interleukin-4 (IL-4), and interleukin-10 (IL-10) were detected in three groups of tissues using enzyme-linked immunosorbent assay (ELISA).Results:Compared with normal tissues, the concentrations of TLR4, NF-κB, IFN -γ, TNF -α, IL-1β, IL-6, IL-8, MCP-1 and EGF in common ulcer skin tissues and diabetes ulcer tissues were higher, and the concentrations of IL-10 were lower, with statistically significant differences (all P<0.05); Compared with the normal tissue, the concentration of IL-4 in diabetes ulcer tissue was lower, the difference was statistically significant ( P<0.05); Compared with ordinary ulcer skin tissue, the concentrations of TLR4, NF-κB and MCP-1 in diabetes ulcer tissue were higher, and the concentrations of IL-4 were lower, with statistically significant differences (all P<0.05). Conclusions:The skin ulcer in diabetes patients will have inflammatory reaction, and high glucose promotes the inflammatory reaction of skin ulcer, which may be related to the abnormal expression of TLR4, NF-κB, MCP-1 and IL-4. TLR4/NF-κB signal pathway and inflammatory factors MCP-1 and IL-4 may be the target of the inflammation regulation of diabetes skin ulcer.

Objective:To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China.Methods:Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed.Results:6 893 patients in CP ( n=6 453, 93.6%) or AP ( n=440, 6.4%) receiving initial imatinib ( n=4 906, 71.2%), nilotinib ( n=1 157, 16.8%), dasatinib ( n=298, 4.3%) or flumatinib ( n=532, 7.2%) -therapy. With the median follow-up of 43 ( IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance ( n=1 055, 15.3%), intolerance ( n=248, 3.6%), pursuit of better efficacy ( n=168, 2.4%), economic or other reasons ( n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph + ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph + ACA, poorer TFS; Ph + ACA, poorer OS. Conclusion:At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.

Objective:To study the predictive role of tumor burden score (TBS) for tumor recurrence after radical resection in patients with hepatocellular carcinoma (HCC).Methods:Clinical data of 202 patients with HCC undergoing radical surgery at the 900th Hospital of Joint Logistics Support Force of the Chinese People's Liberation Army, between January 2015 and December 2017 were retrospectively analyzed, including 128 males and 74 females, aged (53.66±11.93) years old. The receiver operating characteristic (ROC) curve was used to assess the accuracy of TBS in predicting postoperative tumor recurrence. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors influencing postoperative tumor recurrence. A nomogram was established and validated using calibration curves and the C-index. Kaplan-Meier survival analysis was utilized to compare survival differences between the two patient groups.Results:The area under the ROC curve for TBS in predicting postoperative tumor recurrence in HCC patients was 0.779 (95% CI: 0.717-0.842), with an optimal cutoff value of 6.2. Univariate analysis revealed that factors such as hepatitis B virus DNA level >500 IU/ml, larger maximum tumor dia-meter, and TBS>6.2 were significant risk factors for postoperative tumor recurrence (all P<0.05). Multivariate analysis further indicated that TBS>6.2 ( OR=3.60, 95% CI: 1.081-12.012, P=0.037) and maximum tumor diameter ( OR=1.240, 95% CI: 1.034-1.487, P=0.020) were independent risk factors for postoperative recurrence. Based on these risk factors, a nomogram model was established, achieving a C-index of 0.788. Kaplan-Meier survival analysis showed a better postoperative overall survival and recurrence-free survival of the low TBS group compared to those of the high TBS group (all P<0.05). Conclusion:TBS can serve as a predictive indicator for the recurrence after radical resection in patients with HCC. Both TBS and tumor size are independent risk factors for postoperative recurrence. The nomogram model can be used for predicting recurrence following radical resection in HCC patients.

Adipose stem cells (ADSCs) are adult stem cells that originate from the mesoderm and exist in the adipose tissue matrix. They have strong proliferative ability and multi-directional differentiation potential. Exosomes are membranous vesicles released into the extracellular matrix after the fusion of intracellular vesicles and cell membranes. They have the characteristics of small size and can pass through biological cell barriers, and can mediate information exchange between cells. At present, the technology of isolating exosomes from ADSCs is quite mature and has been widely applied in various medical fields. This article will review the research progress of adipose stem cell exosomes (ADSCsexo) in skin wounds and tissue repair.