FePt/MnO2@PEG Nanoparticles as Multifunctional Radiosensitizers for Enhancing Ferroptosis and Alleviating Hypoxia in Osteosarcoma Therapy.

Radiotherapy (RT) is a widely used cancer treatment, and the use of metal-based nanoradiotherapy sensitizers has demonstrated promise in enhancing its efficacy. However, achieving effective accumulation of these sensitizers within tumors and overcoming resistance induced by the hypoxic tumor microenvironment remain challenging issues. In this study, we developed FePt/MnO2@PEG nanoparticles with multiple radiosensitizing mechanisms, including high-atomic-number element-mediated radiation capture, catalase-mimicking oxygenation, and GSH depletion-induced ferroptosis. Both in vitro and in vivo experiments were conducted to validate the radiosensitizing mechanisms and therapeutic efficacy of FePt/MnO2@PEG. In conclusion, this study presents a novel and clinically relevant strategy and establishes a safe and effective combination radiotherapy approach for cancer treatment. These findings hold significant potential for improving radiotherapy outcomes and advancing the field of nanomedicine in cancer therapy.

Population structure and selective signature of Kirghiz sheep by Illumina Ovine SNP50 BeadChip.

Objective: By assessing the genetic diversity and associated selective traits of Kirghiz sheep (KIR), we aim to uncover the mechanisms that contribute to sheep's adaptability to the Pamir Plateau environment. Methods: This study utilized Illumina Ovine SNP50 BeadChip data from KIR residing in the Pamir Plateau, Qira Black sheep (QBS) inhabiting the Taklamakan Desert, and commonly introduced breeds including Dorper sheep (DOR), Suffolk sheep (SUF), and Hu sheep (HU). The data was analyzed using principal component analysis, phylogenetic analysis, population admixture analysis, kinship matrix analysis, linkage disequilibrium analysis, and selective signature analysis. We employed four methods for selective signature analysis: fixation index (Fst), cross-population extended homozygosity (XP-EHH), integrated haplotype score (iHS), and nucleotide diversity (Pi). These methods aim to uncover the genetic mechanisms underlying the germplasm resources of Kirghiz sheep, enhance their production traits, and explore their adaptation to challenging environmental conditions. Results: The test results unveiled potential selective signals associated with adaptive traits and growth characteristics in sheep under harsh environmental conditions, and annotated the corresponding genes accordingly. These genes encompass various functionalities such as adaptations associated with plateau, cold, and arid environment (ETAA1, UBE3D, TLE4, NXPH1, MAT2B, PPARGC1A, VEGFA, TBX15 and PLXNA4), wool traits (LMO3, TRPS1, EPHA5), body size traits (PLXNA2, EFNA5), reproductive traits (PPP3CA, PDHA2, NTRK2), and immunity (GATA3). Conclusion: Our study identified candidate genes associated with the production traits and adaptation to the harsh environment of the Pamir Plateau in Kirghiz sheep. These findings provide valuable resources for local sheep breeding programs. The objective of this study is to offer valuable insights for the sustainable development of the Kirghiz sheep industry.

Genetic structure and selective sweeps in Kirghiz sheep using SNP50K bead chip.

The objective of this study is to analyze environmental genetic selection signals in large-scale sheep populations with conflicting environmental adaptations, aiming to identify and isolate genes associated with environmental adaptations in sheep populations. Kirghiz sheep, which inhabit high-altitude environments year-round, demonstrate the ability to adapt to extreme conditions. In this study, 42 Kirghiz sheep, 24 Tien-Shan in Kyrgyzstan sheep, 189 Qira black sheep, and 160 Chinese Merino sheep were genotyped using Illumina Ovine SNP50K chip. Regions exhibiting a selection signal threshold of 5%, as well as PI analysis and haplotype statistical scanning gene data were annotated, and intersecting genes were identified as candidate genes. Through Fst and haplotype statistical analysis revealed the key gene PDGFD and its vicinity's impact on fat deposition in sheep tails. Additionally, Fst and PI analysis uncovered genes related to high-altitude adaptation as well as those linked to animal growth and reproduction.Further GO and KEGG enrichment pathway analyses unveiled pathways associated with high-altitude adaptation such as negative regulation of peptidyl-tyrosine phosphorylation and xenobiotic metabolism processes.This investigation into the adaptability of Kirghiz sheep provides theoretical support and practical guidance for the conservation and genetic enhancement of Kirghiz sheep germplasm resources.

Genetic analysis of key agronomic traits of local sheep breeds in Xinjiang, China.

The formation of sheep (Ovis aries) breeds is influenced by different ecological environments and populations with different living habits, resulting in the development of germplasm resources with stable genetic key agronomic traits. Thus, investigating the genetic mechanisms behind various agronomic traits can enhance the conservation and utilization of diverse sheep breeds. Here, we explored the sheep variome and selection signatures using the Ovine Infinium HD SNP BeadChip (600 K SNPs) from 23 sheep breeds, comprising a total of 1215 sheep. The genetic mechanisms of wool quality and tail morphology were analyzed by selective sweep and genome-wide association study. Based on the results of within-population selective sweep analysis, we performed gene network analysis and divided them into 6 gene communities. We identified genetic regions containing genes linked to sheep wool and tail, which have been and may continue to be important targets for breeding and selection. Furthermore, our results revealed the expression profiles of genes in these regions across different biological systems. Our study provides insights into categorizing sheep breeds into distinct gene communities, as well as references for constructing genetic network pathways related to key agronomic traits in sheep and other domestic animals.

Population structure and selection signal analysis of indigenous sheep from the southern edge of the Taklamakan Desert.

Analyzing the genetic diversity and selection characteristics of sheep (Ovis aries) holds significant value in understanding their environmental adaptability, enhancing breeding efficiency, and achieving effective conservation and rational utilization of genetic resources. In this study, we utilized Illumina Ovine SNP 50 K BeadChip data from four indigenous sheep breeds from the southern margin of the Taklamakan Desert (Duolang sheep: n = 36, Hetian sheep: n = 74, Kunlun sheep: n = 27, Qira black sheep: n = 178) and three foreign meat sheep breeds (Poll Dorset sheep: n = 105, Suffolk sheep: n = 153, Texel sheep: n = 150) to investigate the population structure, genetic diversity, and genomic signals of positive selection within the indigenous sheep. According to the Principal component analysis (PCA), the Neighbor-Joining tree (NJ tree), and Admixture, we revealed distinct clustering patterns of these seven sheep breeds based on their geographical distribution. Then used Cross Population Extended Haplotype Homozygosity (XP-EHH), Fixation Index (FST), and Integrated Haplotype Score (iHS), we identified a collective set of 32 overlapping genes under positive selection across four indigenous sheep breeds. These genes are associated with wool follicle development and wool traits, desert environmental adaptability, disease resistance, reproduction, and high-altitude adaptability. This study reveals the population structure and genomic selection characteristics in the extreme desert environments of native sheep breeds from the southern edge of the Taklimakan Desert, providing new insights into the conservation and sustainable use of indigenous sheep genetic resources in extreme environments. Additionally, these findings offer valuable genetic resources for sheep and other mammals to adapt to global climate change.

Genome-wide selection reveals candidate genes associated with multiple teats in Hu sheep.

Increasing the number of teats in sheep helps to improve the survival rate of sheep lambs after birth. In order to analyze the candidate genes related to the formation of multiple teats in Hu sheep, the present study was conducted to investigate the genetic pattern of multiple teats in Hu sheep. In this study, based on genome-wide data from 157 Hu sheep, Fst, xp-EHH, Pi and iHS signaling were performed, and the top 5% signal regions of each analyzed result were annotated based on the Oar_v4.0 for sheep. The results show that a total of 142 SNP loci were selected. We found that PTPRG, TMEM117 and LRP1B genes were closely associated with polypodium formation in Hu sheep, in addition, among the candidate genes related to polypodium we found genes such as TMEM117, SLC25A21 and NCKAP5 related to milk traits. The present study screened out candidate genes for the formation of multiple teats at the genomic level in Hu sheep.

Effects of Transport Duration and Pre-Transport Fasting on Blood Biochemistry in Dorper × Mongolian Sheep.

Transport is a high-risk time for sheep, especially if the distances are long and sheep are fasted for a long time beforehand. Two experiments were conducted to compare transport durations of 1 hour (1 h) and 3 hours (3 h) and the effects of feeding before transport using Dorper × Mongolian sheep, which are typical of the region and may be tolerant of the high temperatures in the Inner Mongolian summer. Thirty 4-month-old male sheep were randomly divided into two treatment groups, with 15 sheep/treatment in each experiment, to evaluate the effects on blood biochemical indicators, stress hormone levels, rectal temperatures, and antioxidant status of lambs in summer. In Experiment 1, the levels of triglycerides and free fatty acids after 3 h transport were significantly lower than after 1 h transport (p < 0.05). The levels of thyroxine and malondialdehyde in blood were greater after 3 h transport than 1 h transport (p < 0.05). Creatine kinase levels after 3 h transport tended to be lower than after 1 h transport (p = 0.051). In Experiment 2, the levels of urea and superoxide dismutase in the group fasted pre-transport was significantly lower than those of the group fed pre-transport (p < 0.05). The serum cortisol level in the pre-transport fed group was higher compared to the group fed pre-transport (p = 0.04). Total antioxidant capacity in the pre-transport fasted group tended to be lower compared to that in the pre-transport fed group (p < 0.0001). We conclude that the reduction in nutritional status of sheep transported for longer and without feed pre-transport suggests that transporting sheep in hot conditions in northern China after fasting for a long period should be restricted. However, a decrease in the stress induced by transport following fasting is worthy of further study.

[Correlation study of NCF2 in chronic rhinosinusitis with nasal polyps].

Objective:After selecting NCF2 based on bioinformatics, clinical experiments were conducted to verify the expression of NCF2 in chronic rhinosinusitis with nasal polyps to study its correlation. Methods:The differentially expressed genes（DEGs） between CRSwNP and non-CRS patients were explored using the CRS-related dataset from the gene expression omnibus GEO database. The weighted gene co-expression network（WGCNA） was used for cluster analysis. The expression and cell distribution of NCF2 in the tissues were determined by single gene enrichment analysis（GSEA）, immune inflammatory infiltration analysis, and principal component（PCA） analysis. The expression degree of NCF2 in the tissues of the subjects was determined by immunohistochemistry, and the percentage of EOS in the peripheral blood of the subjects was detected and the correlation was analyzed. EOS in the tissues of the subjects were counted under a microscope and compared. Results:①The Venn diagram was obtained by crossing the module with the highest correlation between DEGs and WGCNA to determine the core gene NCF2. ②GSEA analysis showed that NCF2 was significantly related to the immunological processes such as allogeneic rejection and asthma. ③The area under the ROC curve was 1, indicating that NCF2 had diagnostic value for CRSwNP. ④NCF2 was highly expressed in nasal polyps, mainly distributed in monocytes and eosinophils. ⑤HE staining showed that the number of EOS in ECRSwNP tissues and the percentage of eosinophils in peripheral blood were higher than those in nonECRSwNP and control groups. ⑥The immunohistochemistry results showed that NCF2 was significantly expressed in the nasal polyps of ECRSwNP patients, which was higher than that in the nasal mucosa of nonECRSwNP group and control group. ⑦The expression of NCF2 in tissues was positively correlated with EOS count in ECRSwNP group and EOS expression in peripheral blood. Conclusion:The expression of NCF2 is increased in eosinophilic chronic rhinosinusitis with nasal polyps, and it is significantly correlated with the expression of eosinophils in peripheral blood and tissues, suggesting that NCF2 may be used as a basis for the intrinsic classification of ECRSwNP and a reference index for clinical diagnosis and treatment.

The Effects of Housing on Growth, Immune Function and Antioxidant Status of Young Female Lambs in Cold Conditions.

Cold conditions in northern China during winter may reduce sheep growth and affect their health, especially if they are young, unless housing is provided. We allocated 45 two-month-old female lambs to be housed in an enclosed building, a polytunnel, or kept outdoors, for 28 days. The daily weight gain and scalp and ear skin temperature of outdoor lambs were less than those of lambs that were housed in either a house or polytunnel; however, rectal temperature was unaffected by treatment. There was a progressive change in blood composition over time, and by the end of the experiment, outdoor lambs had reduced total antioxidant capacity (T-AOC), catalase (CAT), glutathione peroxidase (GSH-Px) and total superoxide dismutase (T-SOD) and increased malondialdehyde compared to those in the house or polytunnel. In relation to immune responses in the lambs' serum, in the polytunnel, immunoglobulin A (IgA), tumor necrosis factor-α (TNF-α) and interleukin-4 (IL-4) were higher and immunoglobulin G (IgG) lower compared with the concentrations in lambs that were outdoors. Over the course of the experiment, genes expressing heat shock proteins and antioxidant enzymes increased in lambs in the outdoor treatment, whereas they decreased in lambs in the indoor treatments. It is concluded that although there were no treatment effects on core body temperature, the trends for progressive changes in blood composition and gene expression indicate that the outdoor lambs were not physiologically stable; hence, they should not be kept outdoors in these environmental conditions for long periods.

Corrigendum: Genetic diversity, population structure, and selective signature of sheep in the northeastern Tarim Basin.

[This corrects the article DOI: 10.3389/fgene.2023.1281601.].

Genetic diversity, population structure, and selective signature of sheep in the northeastern Tarim Basin.

Local sheep in the northeastern Tarim Basin can adapt to dry and low-rainfall regional environments. In this study, three local sheep breeds in the northeastern Tarim Basin, LOP (LOP) sheep, Bayinbuluke (BYK) sheep, and Kunlun (KUN, also known as the Qiemo sheep) sheep, and three introduced sheep breeds, Suffolk (SUF) sheep, Dorset (APD) sheep, and Texel (TEX) sheep, were analyzed for genetic diversity, population structure, and selective signature using the Illumina OvineSNP50K BeadChip. We found that LOP, BYK, and KUN had lower observed heterozygosity and expected heterozygosity than TEX, SUF, and ADP, which were differentiated based on geographic distribution. We performed fixation index (FST) analysis on three local sheep breeds in the northeastern Tarim Basin (LOP, BYK, and KUN) and introduced sheep breeds (TEX, SUF, and ADP) to measure genetic differentiation. Nucleotide diversity (PI) analysis was performed on single-nucleotide polymorphism (SNP) data of LOP, BYK, and KUN. A total of 493 candidate genes were obtained by taking the intersection at a threshold of 5%. Among them, SMAD2, ESR2, and HAS2 were related to reproductive traits. PCDH15, TLE4, and TFAP2B were related to growth traits. SOD1, TSHR, and DNAJB5 were related to desert environmental adaptation. Analyzing the genetic patterns of local sheep in the northeastern Tarim Basin can protect the germplasm resources of local sheep and promote the development and utilization of sheep genetic resources.

Landscape genomics reveals adaptive divergence of indigenous sheep in different ecological environments of Xinjiang, China.

Sheep are important livestock animals that have evolved under various ecological pressures. Xinjiang is a region with diverse and harsh environments that have shaped many local sheep breeds with unique characteristics and environmental adaptability. However, these breeds are losing ecological flexibility due to the promotion of intensive farming practices. Here we sequenced 14 local sheep breeds from Xinjiang and analyzed their genetic structure and gene flow with other sheep breeds from neighboring regions. The Tibetan Plateau was the geographic origin of Xinjiang native sheep evolution. We performed genome-environment association analysis and identified Bio9: Mean Temperature of Driest Quarter and Bio15: Precipitation Seasonality as the key environmental factors affecting Xinjiang local sheep and the key genes involved in their survival and adaptation. We classified Xinjiang native sheep breeds into six groups based on their differential genes by pairwise selective sweep analysis and Community Network Analysis. We analyzed transcriptome expression data of 832 sheep tissues and detected tissue-specific enrichment of six group-specific genes in different biological systems. Our results revealed the genetic basis of year-round estrus, drought tolerance, hypoxia resistance, and cold tolerance traits of Xinjiang sheep breeds. Moreover, we proposed conservation strategies for Xinjiang local sheep breeds and provided theoretical guidance for breeding new sheep breeds under global extreme environments.

Preparation and Characterization of Body-Temperature-Responsive Thermoset Shape Memory Polyurethane for Medical Applications.

Shape memory polymers (SMPs) are currently one of the most attractive smart materials expected to replace traditional shape memory alloys and ceramics (SMAs and SMCs, respectively) in some fields because of their unique properties of high deformability, low density, easy processing, and low cost. As one of the most popular SMPs, shape memory polyurethane (SMPU) has received extensive attention in the fields of biomedicine and smart textiles due to its biocompatibility and adjustable thermal transition temperature. However, its laborious synthesis, limitation to thermal response, poor conductivity, and low modulus limit its wider application. In this work, biocompatible poly(ε-caprolactone) diol (PCL-2OH) is used as the soft segment, isophorone diisocyanate (IPDI) is used as the hard segment, and glycerol (GL) is used as the crosslinking agent to prepare thermoset SMPU with a thermal transition temperature close to body temperature for convenient medical applications. The effects of different soft-chain molecular weights and crosslinking densities on the SMPU's properties are studied. It is determined that the SMPU has the best comprehensive performance when the molar ratio of IPDI:PCL-2OH:GL is 2:1.5:0.33, which can trigger shape memory recovery at body temperature and maintain 450% recoverable strain. Such materials are excellent candidates for medical devices and can make great contributions to human health.

Base-Modulated 1,3-Regio- and Stereoselective Carboboration of Cyclohexenes.

While chain-walking stimulates wide interest in both polymerization and organic synthesis, site- and stereoselective control of chain-walking on rings is still a challenging task in the realm of organometallic catalysis. Inspired by a controllable chain-walking on cyclohexane rings in olefin polymerization, we have developed a set of chain-walking carboborations of cyclohexenes based on nickel catalysis. Different from the 1,4-trans-selectivity disclosed in polymer science, a high level of 1,3-regio- and cis-stereoselectivity is obtained in our reactions. Mechanistically, we discovery that the base affects the reduction ability of B2 pin2 and different bases lead to different catalytic cycles and different regioselective products (1,2- Vs 1,3-addition). This study provides a concise and modular method for the synthesis of 1,3-disubstituted cyclohexylboron compounds. The incorporation of a readily modifiable boronate group greatly enhances the value of this method, the synthetic potential of which was highlighted by the synthesis of a series of high-valued commercial chemicals and pharmaceutically interesting molecules.

Babao Dan decreases hepatocarcinogenesis by inhibiting hepatic progenitor cells malignant transformation via down-regulating toll-like receptor 4.

Background: Babao Dan (BBD) is a traditional Chinese medicine that has been widely used as a complementary and alternative medicine to treat chronic liver diseases. In this study, we aimed to observe the effect of BBD on the incidence of diethylnitrosamine (DEN)-initiated hepatocellular carcinoma formation in rats and explored its possible mechanism. Methods: To verify this hypothesis, BBD was administrated to rats at a dose of 0.5g/kg body weight per two days from the 9th to 12th week in HCC-induced by DEN. Liver injury biomarkers and hepatic inflammatory parameters were evaluated by histopathology as well as serum and hepatic content analysis. We applied immunohistochemical analysis to investigate the expression of CK-19 and SOX-9 in liver tissues. The expression of TLR4 was determined by immunohistochemical, RT-PCR, and western blot analysis. Furthermore, we also detected the efficacy of BBD against primary HPCs neoplastic transformation induced by LPS. Results: We observed that DEN could induce hepatocarcinogenesis, and BBD could obviously decrease the incidence. The biochemical and histopathological examination results confirmed that BBD could protect against liver injury and decrease inflammatory infiltration. Immunohistochemistry staining results showed that BBD could effectively inhibit the ductal reaction and the expression of TLR4. The results showed that BBD-serumcould obviously inhibit primary HPCs neoplastic transformation induced by regulating the TLR4/Ras/ERK signaling pathway. Conclusion: In summary, our results indicate that BBD has potential applications in the prevention and treatment of HCC, which may be related to its effect on hepatic progenitor cells malignant transformation via inhibiting the TLR4/Ras/ERK signaling pathway.

Synthesis of Azoxy Compounds: from Copper Compounds to Mesoporous Silica-Encaged Ultrasmall Copper Catalysts.

Azoxy compounds have aroused extensive attention due to their unique biological activities, but the chemical synthesis of these compounds often suffers from limitations due to their requirement for stoichiometric oxidants, high costs, and restricted substrate range. Herein, a series of azoxy compounds were constructed via facile coupling reactions by using cost-effective N-methoxyformamide and nitroso compounds over Cu-based catalysts, affording high product yields with excellent tolerance of functional groups. Significantly, the mesoporous silica nanosphere-encapsulated ultrasmall Cu (Cu@MSN) catalyst was developed via a one-pot synthetic method and first used for the synthesis of azoxy compounds. As compared with copper salt catalysts, the Cu@MSN catalyst exhibited remarkably enhanced catalytic activity and superior recycling stability. Such a Cu@MSN catalyst overcame the inherent drawbacks of low activity, fast deactivation, and difficult recycling of traditional metal salt catalysts in organic reactions. This work provides a green and efficient method for the construction of azoxy compounds and also creates new prospects for the application of nanoporous materials confined metal catalysts in organic synthesis.

TWEAK Signaling-Induced ID1 Expression Drives Malignant Transformation of Hepatic Progenitor Cells During Hepatocarcinogenesis.

The malignant transformation of hepatic progenitor cells (HPCs) in the inflammatory microenvironment is the root cause of hepatocarcinogenesis. However, the potential molecular mechanisms are still elusive. The HPCs subgroup is identified by single-cell RNA (scRNA) sequencing and the phenotype of HPCs is investigated in the primary HCC model. Bulk RNA sequencing (RNA-seq) and proteomic analyses are also performed on HPC-derived organoids. It is found that tumors are formed from HPCs in peritumor tissue at the 16th week in a HCC model. Furthermore, it is confirmed that the macrophage-derived TWEAK/Fn14 promoted the expression of inhibitor of differentiation-1 (ID1) in HPCs via NF-κB signaling and a high level of ID1 induced aberrant differentiation of HPCs. Mechanistically, ID1 suppressed differentiation and promoted proliferation in HPCs through the inhibition of HNF4α and Rap1GAP transcriptions. Finally, scRNA sequencing of HCC patients and investigation of clinical specimens also verified that the expression of ID1 is correlated with aberrant differentiation of HPCs into cancer stem cells, patients with high levels of ID1 in HPCs showed a poorer prognosis. This study provides important intervention targets and a theoretical basis for the clinical diagnosis and treatment of HCC.

Mesenchymal stromal cells in hepatic fibrosis/cirrhosis: from pathogenesis to treatment.

Hepatic fibrosis/cirrhosis is a significant health burden worldwide, resulting in liver failure or hepatocellular carcinoma (HCC) and accounting for many deaths each year. The pathogenesis of hepatic fibrosis/cirrhosis is very complex, which makes treatment challenging. Endogenous mesenchymal stromal cells (MSCs) have been shown to play pivotal roles in the pathogenesis of hepatic fibrosis. Paradoxically, exogenous MSCs have also been used in clinical trials for liver cirrhosis, and their effectiveness has been observed in most completed clinical trials. There are still many issues to be resolved to promote the use of MSCs in the clinic in the future. In this review, we will examine the controversial role of MSCs in the pathogenesis and treatment of hepatic fibrosis/cirrhosis. We also investigated the clinical trials involving MSCs in liver cirrhosis, summarized the parameters that need to be standardized, and discussed how to promote the use of MSCs from a clinical perspective.

AIF1 + CSF1R + MSCs, induced by TNF-α, act to generate an inflammatory microenvironment and promote hepatocarcinogenesis.

BACKGROUND AND AIMS: Increasing evidence suggests that mesenchymal stem cells (MSCs) home to injured local tissues and the tumor microenvironment in the liver. Chronic inflammation is regarded as the major trait of primary liver cancer. However, the characteristics of endogenous MSCs in the inflammatory environment and their role in the occurrence of liver cancer remain obscure. APPROACH AND RESULTS: Using single-cell RNA sequencing, we identified a distinct inflammation-associated subset of MSCs, namely AIF1 + CSF1R + MSCs, which existed in the microenvironment before the occurrence of liver cancer. Furthermore, we found that this MSC subgroup is likely to be induced by TNF-α stimulation through the TNFR1/SIRT1 (sirtuin 1) pathway. In a rat primary liver cancer model, we showed that MSCs with high SIRT1 expression (Ad-Sirt1-MSCs) promoted macrophage recruitment and synergistically facilitated liver cancer occurrence by secreting C-C motif chemokine ligand (CCL) 5. Interestingly, depletion of macrophages or knockdown of CCL5 expression in Ad-Sirt1-MSCs attenuated the promotive effect of Ad-Sirt1-MSCs on liver inflammation and hepatocarcinogenesis (HCG). Finally, we demonstrated that SIRT1 up-regulated CCL5 expression through activation of the AKT/HIF1α signaling axis in MSCs. CONCLUSIONS: Together, our results show that MSCs, which are mobilized to the injured site, can be educated by macrophages. In turn, the educated MSCs are involved in generating a chronic inflammatory microenvironment and promoting HCG.