Maternal androgen exposure induces intergenerational effects via paternal inheritance.

Polycystic ovary syndrome (PCOS) is a condition that results from the interaction between environmental factors and hereditary components, profoundly affecting offspring development. Although the etiology of this disease remains unclear, aberrant in-utero androgen exposure is considered one of the pivotal pathogenic factors. Herein, we demonstrate the intergenerational inheritance of PCOS-like phenotypes in F2 female offspring through F1 males caused by maternal testosterone exposure in F0 mice. We found impaired serum hormone expression and reproductive system development in prenatal testosterone treated F1 male and F2 female mice (PTF1 and PTF2). In addition, down-regulated N6-methyladenosine (m6A) methyltransferase and binding proteins induced mRNA hypomethylation in the PTF1 testis, including Frizzled-6 (Fzd6). In the PTF2 ovary, decreased FZD6 protein expression inhibited the mammalian target of rapamycin (mTOR) signaling pathway and activated Forkhead box O3 (FoxO3) phosphorylation, which led to impaired follicular development. These data indicate that epigenetic modification of the mTOR signaling pathway could be involved in the intergenerational inheritance of maternal testosterone exposure induced impairments in the PTF2 ovary through male PTF1 mice.

Oxysterol 25-hydroxycholesterol activation of ferritinophagy inhibits the development of squamous intraepithelial lesion of cervix in HPV-positive patients.

Squamous intraepithelial lesion of cervix (SIL) in human papillomavirus (HPV)-positive patient often undergoes a silent and long-course development, and most of them with high-grade transit to cervical squamous cell carcinoma (CSCC). The oxysterol 25-hydroxycholesterol (25-HC) is associated with HPV inhibition, autophagy and cholesterol synthesis, however, its function in this long process of SIL development remain unclear. In this study, we demonstrate that 25-HC generation is inhibited through HSIL-to-CSCC transition. The 25-HC activates ferritinophagy in the early stage of SIL, promoting the vulnerability of HSILs to ferroptosis. Therefore, maintaining 25-HC level is crucial for suppressing HSIL progression and holds promise for developing novel clinical therapies for CSCC.

Ceftazidime-assisted synthesis of ultrasmall chitosan nanoparticles for biofilm penetration and eradication of Pseudomonas aeruginosa.

Pseudomonas aeruginosa (P. aeruginosa) infections present a grave threat to immunocompromised individuals, particularly those with cystic fibrosis due to the development of bacterial biofilms. In this study, we engineered self-assembling chitosan-ceftazidime nanoparticles (CSCE) capable of effectively penetrating biofilms and eradicating P. aeruginosa. The CSCE nanoparticles were synthesized through ionic cross-linking, combining negatively charged ceftazidime with positively charged chitosan, resulting in uniform nanoparticles measuring approximately 40 nm in diameter, exhibiting high dispersity and excellent biocompatibility. Remarkably, these nanoparticles exhibited significant inhibition of P. aeruginosa growth, reduced pyocyanin production, and diminished biofilm formation, achieving a maximum inhibition rate of 22.44%. Furthermore, in vivo investigations demonstrated enhanced survival in mice with abdominal P. aeruginosa infection following treatment with CSCE nanoparticles, accompanied by reduced levels of inflammatory cytokines Interleukin-6 (125.79 ± 18.63 pg/mL), Interleukin-17 (125.67 ± 5.94 pg/mL), and Tumor Necrosis Factor-α (135.4 ± 11.77 pg/mL). Critically, mice treated with CSCE nanoparticles showed no presence of bacteria in the bloodstream following intraperitoneal P. aeruginosa infection. Collectively, our findings highlight the potential of these synthesized nanoparticles as effective agents against P. aeruginosa infections.

Functional characterization of rice (Oryza sativa) thioredoxins for detoxification and degradation of atrazine.

Thioredoxins (TRXs) are a group of antioxidant enzymes that play a critical role in plant growth and resistance to stress. However, the functional role and mechanism of rice TRXs in response to pesticides (e.g. atrazine, ATZ) stress remain largely unexplored. Here, 24 differentially expressed TRX genes (14 up and 10 down) of ATZ-exposed rice were identified through high-throughput RNA-sequencing analysis. Twenty-four TRX genes were unevenly mapped to 11 chromosomes and some of the genes were validated by quantitative RT-PCR. Bioinformatics analysis revealed that ATZ-responsive TRX genes contain multiple functional cis-elements and conserved domains. To demonstrate the functional role of the genes in ATZ degradation, one representative TRX gene LOC_Os07g08840 was transformed into yeast cells and observed significantly lower ATZ content compared to the control. Using LC-Q-TOF-MS/MS, five metabolites were characterized. One hydroxylation (HA) and two N-dealkylation products (DIA and DEA) were significantly increased in the medium with positive transformants. Our work indicated that TRX-coding genes here were responsible for ATZ degradation, suggesting that thioredoxins could be one of the vital strategies for pesticide degradation and detoxification in crops.

A Human-Specific De Novo Gene Promotes Cortical Expansion and Folding.

Newly originated de novo genes have been linked to the formation and function of the human brain. However, how a specific gene originates from ancestral noncoding DNAs and becomes involved in the preexisting network for functional outcomes remains elusive. Here, a human-specific de novo gene, SP0535, is identified that is preferentially expressed in the ventricular zone of the human fetal brain and plays an important role in cortical development and function. In human embryonic stem cell-derived cortical organoids, knockout of SP0535 compromises their growth and neurogenesis. In SP0535 transgenic (TG) mice, expression of SP0535 induces fetal cortex expansion and sulci and gyri-like structure formation. The progenitors and neurons in the SP0535 TG mouse cortex tend to proliferate and differentiate in ways that are unique to humans. SP0535 TG adult mice also exhibit improved cognitive ability and working memory. Mechanistically, SP0535 interacts with the membrane protein Na+ /K+ ATPase subunit alpha-1 (ATP1A1) and releases Src from the ATP1A1-Src complex, allowing increased level of Src phosphorylation that promotes cell proliferation. Thus, SP0535 is the first proven human-specific de novo gene that promotes cortical expansion and folding, and can function through incorporating into an existing conserved molecular network.

A Network Comparison of Motives behind Online Sexual Activities and Problematic Pornography Use during the COVID-19 Outbreak and the Post-Pandemic Period.

Many researchers have considered whether online sexual activities (OSAs) increased over the course of the COVID-19 pandemic and whether these have led to an increase in problematic pornography use (PPU). This study investigated the impact of COVID-19 on PPU through pornography use motivations (PUMs) and OSAs to develop a better understanding of the mechanism and changes affecting PPU. Two groups of Chinese adults were recruited during the initial months of the pandemic (April 2020, n1 = 496) and the post-pandemic period (October 2021, n2 = 504). A network analysis was conducted to compare the structures of PPU symptoms among the two groups. The results showed that PUMs and OSAs were stronger predictors of PPU during the pandemic than post-pandemic (R2pandemic = 57.6% vs. R2post-pandemic = 28.7%). The motives of fantasy, sexual pleasure, stress reduction, and self-exploration were the prominent motivations during these two periods, but we found distinct PPU-related communities. PPU, sexual pleasure, and viewing sexually explicit materials (a type of OSAs) constituted a community during the pandemic but not in the post-pandemic's network. The present study indicated that the pandemic may not have been the only factor impacting the higher rate of PPU. Instead, the higher frequency of OSAs during the pandemic may have been a strategy to cope with stress and to safely satisfy sexual desire.

Persistent ferroptosis promotes cervical squamous intraepithelial lesion development and oncogenesis by regulating KRAS expression in patients with high risk-HPV infection.

Cervical squamous cell carcinoma (CSCC) is a type of female cancer that affects millions of families worldwide. Human papillomavirus (HPV) infection is the main reason for CSCC formation, and squamous intraepithelial lesions (SILs) induced by high-risk HPV (HR-HPV) infection are considered precancerous lesions. A previous study reported that HPV-infected cancer cells were able to counteract lipid peroxidation for survival. Recent research has reported that ferroptosis acts in an iron-dependent lipid peroxidation manner to kill cancer cells, and it is proposed as a new approach for female cancer therapy. Here, we investigated the role of ferroptosis throughout SIL development into CSCC. We found that ferroptosis occurred in SIL, but anti-ferroptosis emerged in CSCC. Our data further indicated that an antiferroptotic effect was formed in response to persistent ferroptosis and then promoted oncogenesis. Altogether, we provide novel insight into ferroptosis in cervical SIL development and suggest a potential therapeutic target for the treatment of CSCC.

lnc-MRGPRF-6:1 Promotes M1 Polarization of Macrophage and Inflammatory Response through the TLR4-MyD88-MAPK Pathway.

BACKGROUND: Macrophage-mediated inflammation plays an essential role in the development of atherosclerosis (AS). Long noncoding RNAs (lncRNAs), as crucial regulators, participate in this process. We identified that lnc-MRGPRF-6:1 was significantly upregulated in the plasma exosomes of coronary atherosclerotic disease (CAD) patients in a preliminary work. In the present study, we aim to assess the role of lnc-MRGPRF-6:1 in macrophage-mediated inflammatory process of AS. METHODS: The correlation between lnc-MRGPRF-6:1 and inflammatory factors was estimated firstly in plasma exosomes of CAD patients. Subsequently, we established lnc-MRGPRF-6:1 knockout macrophage model via the CRISPR/Cas9 system. We then investigated the regulatory effects of lnc-MRGPRF-6:1 on macrophage polarization and foam cell formation. Eventually, transcriptome analysis by RNA sequencing was carried out to explore the contribution of differential genes and signaling pathways in this process. RESULTS: lnc-MRGPRF-6:1 was highly expressed in the plasma exosomes of CAD patients and was positively correlated with the expression of inflammatory cytokines in plasma. lnc-MRGPRF-6:1 inhibition significantly reduced the formation of foam cells. The expression of lnc-MRGPRF-6:1 was upregulated in M1 macrophage, and lnc-MRGPRF-6:1 knockout decreased the polarization of M1 macrophage. lnc-MRGPRF-6:1 regulates macrophage polarization via the TLR4-MyD88-MAPK signaling pathway. CONCLUSIONS: lnc-MRGPRF-6:1 knockdown can inhibit M1 polarization of macrophage and inflammatory response through the TLR4-MyD88-MAPK signaling pathway. lnc-MRGPRF-6:1 is a vital regulator in macrophage-mediated inflammatory process of AS.

Prenatal androgen excess impairs beta-cell function by decreased sirtuin 3 expression.

Prenatal androgen exposure induces metabolic disorders in female offspring. However, the long-term effect of maternal testosterone excess on glucose metabolism, especially on pancreatic beta-cell function, is rarely investigated. Our current study mainly focused on the effects of prenatal testosterone exposure on glucose metabolism and pancreatic beta- cell function in aged female offspring. By using maternal mice and their female offspring as animal models, we found that prenatal androgen treatment induced obesity and glucose intolerance in aged offspring. These influences were accompanied by decreased fasting serum insulin concentration, elevated serum triglyceride, and testosterone concentrations. Glucose stimulated insulin secretion in pancreatic beta cells of aged female offspring was also affected by prenatal testosterone exposure. We further confirmed that increased serum testosterone contributed to downregulation of sirtuin 3 expression, activated oxidative stress, and impaired pancreatic beta-cell function in aged female offspring. Moreover, over-expression of sirtuin 3 in islets isolated from female offspring treated with prenatal testosterone normalized the oxidative stress level, restored cyclic AMP, and ATP generation, which finally improved glucose-stimulated insulin secretion in beta cells. Taken together, these results demonstrated that prenatal testosterone exposure caused a metabolic disturbance in aged female offspring via suppression of sirtuin 3 expression and activation of oxidative stress in pancreatic beta cells.

MicroRNA-378 Suppressed Osteogenesis of MSCs and Impaired Bone Formation via Inactivating Wnt/ß-Catenin Signaling.

MicroRNAs (miRNAs) have been reported to serve as silencers to repress gene expression at post-transcriptional levels. Multiple miRNAs have been demonstrated to play important roles in osteogenesis. MicroRNA (miR)-378, a conserved miRNA, was reported to mediate bone metabolism and influence bone development, but the detailed function and underlying mechanism remain obscure. In this study, the miR-378 transgenic (TG) mouse was developed to study the role of miR-378 in osteogenic differentiation as well as bone formation. The abnormal bone tissues and impaired bone quality were displayed in the miR-378 TG mice, and a delayed healing effect was observed during bone fracture of the miR-378 TG mice. The osteogenic differentiation of mesenchymal stem cells (MSCs) derived from this TG mouse was also inhibited. We also found that miR-378 mimics suppressed, whereas anti-miR-378 promoted osteogenesis of human MSCs. Two Wnt family members, Wnt6 and Wnt10a, were identified as bona fide targets of miR-378, and their expression was decreased by this miRNA, which eventually induced the inactivation of Wnt/ß-catenin signaling. Finally, the short hairpin (sh)-miR-378-modified MSCs were locally injected into the fracture sites in an established mouse fracture model. The results indicated that miR-378 inhibitor therapy could promote bone formation and stimulate the healing process in vivo. In conclusion, miR-378 suppressed osteogenesis and bone formation via inactivating Wnt/ß-catenin signaling, suggesting that miR-378 may be a potential therapeutic target for bone diseases.

Circular RNA expression profiling in the fetal side of placenta from maternal polycystic ovary syndrome and circ_0023942 inhibits the proliferation of human ovarian granulosa cell.

PURPOSE: Circular RNAs (circRNAs) are widely expressed noncoding RNAs which play important roles in various processes. The present study aimed to explore the effect of maternal PCOS on the expression of circRNAs in fetus and assessed the potential role of circRNA in human ovarian granulosa cell proliferation. METHODS: Total RNA was extracted from the fetal side of placental tissues from maternal PCOS (n = 3) and healthy puerpera (n = 3) for circRNA microarray. Real-time reverse transcriptase quantitative PCR (RT-qPCR) was used to validate the microarray data in fetal side of placental tissues from puerpera with (n = 18) and without (n = 30) PCOS. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were applied to predict the functions and pathways of circ_0023942 host genes. The circRNA-miRNA-mRNA network was constructed through bioinformatics prediction. Circ_0023942 overexpression vector was transiently transfected into human ovarian granulosa cell lines KGN and COV434. Cell proliferation was detected by cell counting kit-8. The protein expression level was determined by western blot. RESULTS: Compared with healthy puerpera, 14 circRNAs were significantly upregulated and 101 circRNAs were significantly downregulated in the fetal side of placenta from maternal PCOS according to the microarray data. Six differentially expressed circRNAs were selected for validation by RT-qPCR, and the expression patterns of circ_0023942, circ_0002151, circ_0001274, and circ_0008514 were consistent with the microarray data. Circ_0023942 was chosen for further investigation. GO and KEGG analysis predicted that circ_0023942 participated in the regulation of developmental process and the MAPK signaling pathway. Seven miRNAs were predicted to be the targets of circ_0023942. Overexpression of circ_0023942 inhibited human ovarian granulosa cell proliferation and suppressed the expression of CDK-4. CONCLUSION: Maternal PCOS impairs circ_0023942 expression in fetus. Overexpression of circ_0023942 inhibits human ovarian granulosa cell proliferation possibly via regulating CDK-4.

Lipotoxicity Impairs Granulosa Cell Function Through Activated Endoplasmic Reticulum Stress Pathway.

Obesity is closely related to reproductive disorders, which may eventually lead to infertility in both males and females. Ovarian granulosa cells play a critical role during the maintenance of oocyte development through the generation of sex steroids (mainly estradiol and progesterone) and different kinds of growth factors. However, the molecular mechanism of obesity-induced granulosa cell dysfunction remains poorly investigated. In our current study, we observed that high-fat diet feeding significantly increased the level of glucose-regulated protein 78 kDa (GRP78) protein expression in mouse granulosa cells; testosterone-induced estradiol generation was impaired accordingly. To further evaluate the precise mechanism of lipotoxicity-induced granulosa cell dysfunction, mouse primary granulosa cells were treated with palmitate, and the expression levels of ER stress markers were evaluated by real-time PCR and western blot. Lipotoxicity significantly increased ER stress but impaired the mRNA expression of granulosa cell function-related makers, including androgen receptor (Ar), cytochrome P450 family 19 subfamily A member 1 (Cyp19a1), hydroxysteroid 17-beta dehydrogenase 1 (Hsd17b1), and insulin receptor substrate 1 (Irs1). Impaired testosterone-induced estradiol generation was also observed in cultured mouse granulosa cells after palmitate treatment. Insulin augmented testosterone induced estradiol generation through activation of the AKT pathway. However, palmitate treatment abolished insulin-promoted aromatase expression and estradiol generation by the stimulation of ER stress. Overexpression of IRS1 significantly ameliorated palmitate- or tunicamycin-induced impairment of aromatase expression and estradiol generation. Taken together, our current study demonstrated that lipotoxicity impaired insulin-stimulated estradiol generation through activated ER stress and inhibited IRS1 pathway.

Maternal Testosterone Excess Contributes to Reproductive System Dysfunction of Female Offspring Mice.

Hyperandrogenism is considered 1 of the most important characteristics of polycystic ovary syndrome, which affects more than 10% of females of reproductive age and is a common cause of infertility. In addition to the effects on patients themselves, maternal androgen excess has also been reported to impair the growth and development of offspring. In our current study, we found that maternal testosterone (T) treatment during different gestational stages increased the percentage of atretic follicle and decreased corpus luteum formation in female offspring. In addition, decreased serum estradiol and increased T levels were also observed in female offspring of T-treated mice during late gestational stage. Further studies revealed that Forkhead box protein L2 (FOXL2) and Cytochrome P450 family 19 subfamily a member 1 (CYP19A1) expression in granulosa cells of these female offspring mice were decreased. By using mouse primary granulosa cells and the KGN cell line, we demonstrated that decreasing FOXL2 and CYP19A1 levels in ovarian granulosa cells partially may contribute to disturbed sex hormone synthesis in female offspring of T-treated mice during the late gestational stage. Findings from our current study highlight a critical role of excess maternal T exposure, especially during the late gestational stage, which could further lead to aberrant ovary development and sex hormone synthesis in female offspring.

Selenium Deficiency Induces Inflammation via the iNOS/NF-κB Pathway in the Brain of Pigs.

Selenium (Se) is an essential trace element to maintain homeostasis in humans and animals. The aim of the present study was to clarify the mechanism of Se deficiency-induced inflammation in the pig's brain. Twenty-four healthy pigs were randomly divided into two groups (n = 12/group): control group (group C) was fed diet with 0.3 mg/kg inorganic Se, and Se-deficient group (group L) was fed diet with 0.007 mg/kg inorganic Se. At the 90th day of the experiment, the histology in the pig's brain was observed by the microscope, the NO levels and iNOS activity were assayed, and the mRNA and protein expression levels of inflammatory cytokines (iNOS, COX-2, NF-κB, and PTGEs) and HSPs (HSP27, HSP40, HSP60, HSP70, and HSP90) were detected by real-time quantitative PCR and Western blot. Compared with group C, both of NO levels and iNOS activity were increased in group L, and the mRNA and protein expression levels of inflammatory cytokines (iNOS, COX-2, NF-κB, and PTGEs) and HSPs (HSP27, HSP40, HSP60, HSP70, and HSP90) were also upregulated; histological observation displayed inflammatory response in the brain of pig. In summary, diet with Se deficiency can activate the iNOS/NF-κB pathway to upregulate the expression of inflammatory cytokines, thereby leading to inflammatory lesions in the pig's brain, and HSPs are involved in the compensatory regulation of inflammation. This study provides a reference for the prevention of pig brain inflammation from the perspective of nutrition.

Human-animal chimeras for autologous organ transplantation: technological advances and future perspectives.

Organ transplantation is the most promising curation for end-stage organ disease. However, the donor organ shortage has become a global problem that has limited the development of organ transplantation. Human-animal chimeras provide the ability to produce human organs in other species using autologous stem cells [e.g., induced pluripotent stem cells (iPSCs) or adult stem cells], which would be patient-specific and immune-matched for transplantation. Due to the potential application prospect of interspecies chimeras in basic and translational research, this technology has attracted much interest. This review focuses primarily on technological advances, including options of donor stem cell types and gene editing in donor cells and host animals, in addition to perspectives on human-animal chimeras in clinical and basic research.

Linc-ROR Promotes Osteogenic Differentiation of Mesenchymal Stem Cells by Functioning as a Competing Endogenous RNA for miR-138 and miR-145.

Long noncoding RNAs (lncRNAs), which serve as important and powerful regulators of various biological activities, have gained widespread attention in recent years. Emerging evidence has shown that some lncRNAs play important regulatory roles in osteoblast differentiation of mesenchymal stem cells (MSCs), suggesting a potential therapeutic strategy for bone fracture. As a recently identified lncRNA, linc-ROR was reported to mediate the reprogramming ability of differentiated cells into induced pluripotent stem cells (iPSCs) and human embryonic stem cells (ESCs) self-renewal. However, other functions of linc-ROR remain elusive. In this study, linc-ROR was found to be upregulated during osteogenesis of human bone-marrow-derived MSCs. Ectopic expression of linc-ROR significantly accelerated, whereas knockdown of linc-ROR suppressed, osteoblast differentiation. Using bioinformatic prediction and luciferase reporter assays, we demonstrated that linc-ROR functioned as a microRNA (miRNA) sponge for miR-138 and miR-145, both of which were negative regulators of osteogenesis. Further investigations revealed that linc-ROR antagonized the functions of these two miRNAs and led to the de-repression of their shared target ZEB2, which eventually activated Wnt/ß-catenin pathway and hence potentiated osteogenesis. Taken together, linc-ROR modulated osteoblast differentiation by acting as a competing endogenous RNA (ceRNA), which may shed light on the functional characterization of lncRNAs in coordinating osteogenesis.

Usp5 functions as an oncogene for stimulating tumorigenesis in hepatocellular carcinoma.

As deubiquitinases, several ubiquitin specific protease members have been reported to mediate tumorigenesis. Although ubiquitin specific protease 5 (Usp5) was previously demonstrated to suppress p53 transcriptional activity and DNA repair, its role in carcinogenesis remains elusive. In this study, we sought to define a novel role of Usp5 in tumorigenesis. It was found that Usp5 was significantly upregulated in hepatocellular carcinoma (HCC) cells and most clinical specimens. Further functional investigation also showed that Usp5 knockdown suppressed cell proliferation, migration, drug resistance and induced apoptosis; on the other hand, Usp5 overexpression promoted colony formation, migration, drug resistance and tumorigenesis. Additionally, the inactivated p14ARF-p53 signaling was observed in Usp5 overexpressed HCC cells, while this signaling was activated by Usp5 knockdown. Therefore, our data demonstrated that Usp5 contributed to hepatocarcinogenesis by acting as an oncogene, which provides new insights into the pathogenesis of HCC and explores a promising molecular target for HCC diagnosis and therapy.

miR-133a Promotes TRAIL Resistance in Glioblastoma via Suppressing Death Receptor 5 and Activating NF-κB Signaling.

Recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), as a novel cancer therapeutic, is being tested in phase II and III clinical trials; however, TRAIL resistance remains a big obstacle preventing its clinical application. Considering that TRAIL-induced apoptosis through death receptors DR4 and DR5, their activation may be an alternative pathway to suppress TRAIL resistance. In this study, a negative correlation between DR5 expression and TRAIL resistance was observed, and miR-133a was predicted to be the most promising candidate to suppress DR5 expression. Further investigation demonstrated that miR-133a knockdown dramatically suppressed TRAIL resistance in glioblastoma in vitro and in vivo. An NF-κB family member, phosphorylated IκBα (P-IκBα), was shown to be stimulated by miR-133a, leading to the activation of this signaling. Finally, miR-133a was found to be inversely correlated with DR5 expression in human clinical specimens. In conclusion, our data demonstrate that miR-133a promotes TRAIL resistance in glioblastoma by suppressing DR5 expression and activating NF-κB signaling.

Long noncoding RNA H19 accelerates tenogenic differentiation and promotes tendon healing through targeting miR-29b-3p and activating TGF-ß1 signaling.

Tendon injures are common orthopedic conditions, but tendon development and the pathogenesis of tendon injures, such as tendinopathy, remain largely unknown and have limited the development of clinical therapy. Studies on tenogenic differentiation at the molecular level may help in developing novel therapeutic strategies. As novel regulators, long noncoding RNAs (lncRNAs) have been found to have widespread biological functions, and emerging evidence demonstrates that lncRNAs may play important regulatory roles in cell differentiation and tissue regeneration. In this study, we found that lncRNA H19 stimulated tenogenesis of human tendon-derived stem cells. Stable overexpression of H19 significantly accelerated TGF-ß1-induced tenogenic differentiation in vitro and accelerated tendon healing in a mouse tendon defect model. H19 directly targeted miR-29b-3p, which is considered to be a negative regulator of tenogenesis. Furthermore, miR-29b-3p directly suppressed the expression of TGF-ß1 and type I collagen, thereby forming a novel regulatory feedback loop between H19 and TGF-ß1 to mediate tenogenic differentiation. Our study demonstrated that H19 promotes tenogenic differentiation both in vitro and in vivo by targeting miR-29b-3p and activating TGF-ß1 signaling. Regulation of the TGF-ß1/H19/miR-29b-3p regulatory loop may be a new strategy for treating tendon injury.-Lu, Y.-F., Liu, Y., Fu, W.-M., Xu, J., Wang, B., Sun, Y.-X., Wu, T.-Y., Xu, L.-L, Chan, K.-M., Zhang, J.-F., Li, G. Long noncoding RNA H19 accelerates tenogenic differentiation and promotes tendon healing through targeting miR-29b-3p and activating TGF-ß1 signaling.

Tenogenic differentiation of mesenchymal stem cells and noncoding RNA: From bench to bedside.

Tendon is a critical unit of musculoskeletal system that connects muscle to bone to control bone movement. More population participate in physical activities, tendon injuries, such as acute tendon rupture and tendinopathy due to overuse, are common causing unbearable pain and disability. However, the process of tendon development and the pathogenesis of tendinopathy are not well defined, limiting the development of clinical therapy for tendon injuries. Studying the tendon differentiation control pathways may help to develop novel therapeutic strategies. This review summarized the novel molecular and cellular events in tendon development and highlighted the clinical application potential of non-coding RNAs and tendon-derived stem cells in gene and cell therapy for tendon injuries, which may bring insights into research and new therapy for tendon disorders.