El reposicionamiento malar. Presentación de una técnica original: punto MM / Malar repositioning. Presentation of an original technique: point MM

El envejecimiento facial es una sinergia compleja de cambios texturales de la piel, hiper- o hipoactividad muscular, reabsorción del tejido graso y resorción ósea. El déficit de volumen resultante, la deflación y la posterior caída del tercio medio facial produce una cara menos atractiva y juvenil. Los procedimientos inyectables en región malar son cada vez más populares y solicitados por los pacientes. El conocimiento de la anatomía de la cara media es fundamental para el inyector. La comprensión de la irrigación facial puede ayudar a disminuir la exposición a la aparición de hematomas y complicaciones vasculares severas. Existen múltiples técnicas de inyección propuestas para el tercio medio, en este artículo presentamos una técnica original, simple, segura y eficaz con resultados satisfactorios y riesgo reducido

Facial aging is a complex synergy of textural skin changes, muscle hyperactivity, fat dysmorphism, bone resorption. The resulting volume deficit and deflation of the mid face produces a less attractive and youthful face. Injectable midface procedures are becoming increasingly popular and requested by patients. Knowledge of the anatomy of the midface is critical for the injector. Understanding the irrigation of the face can help decrease the risk of hematoma and severe vascular complications. There are multiple injection techniques proposed for the middle third, in this article we present a simple, safe and effective technique with satisfactory results and lower risk

Rejuvenecimiento periorbitario fisiológico / Physiological periorbital rejuvenation

Pivoting Brow Lift es una nueva opción terapéutica cuyas ventajas son tres mínimas incisiones, prácticamente imperceptibles, bien aceptadas por pacientes de todas las edades, sexo y incluso pacientes calvos. Una incisión se realiza en la región temporal y otra dentro del cuero cabelludo en la región medio frontal o en una arruga en pacientes calvos. La disección en región frontal es sub-perióstica, muchas veces llega a la punta nasal para reposicionarla. La disección en la región temporal se realiza entre las hojas superficiales y profundas extendiéndose hasta el tarso y canto externo del ojo; en la región palpebral la disección se realiza entre la piel y el musculo. La fijación son dos puntos externos en el cuero cabelludo y unos papeles adherentes. Los puntos del cuero cabelludo se retiran a los 14 días. Evita las complejas fijaciones que se realizan actualmente con tornillos, puntos internos o Endotime. La sencillez del procedimiento hace que este se pueda realizar entre 30 y 45 minutos, con anestesia local y sedación; esto permite lograr una mayor seguridad operatoria. Se han documentado pacientes tratados hace 9 años donde se demuestra la duración en el tiempo. El bajo índice de complicaciones y la alta satisfacción de los pacientes documentadas en encuestas hace que este procedimiento pueda ser considerado como una nueva opción terapéutica.

Importancia biológica de los telómeros / Biological importance of telomeres

Se exponen los hallazgos históricos y la importancia biológica de los telómeros en la vida celular y en los aspectos genéticos del ADN humano. (AU)

The discovery and the biological importance of the telomeres are exposed. (AU)

Modulación por Passiflora edulis de triglicéridos y colesterol intracelulares en líneas celulares de cáncer colorrectal SW480 y sus derivadas metastásicas (SW620) / Modulation by Passiflora edulis of intracellular triglycerides and cholesterol in SW480 col orectal cancer cell lines and their metastatic derivatives (SW620)

Cancer cells modify lipid metabolism to proliferate, Passiflora edulis ( P. edulis ) fruit juice (ZuFru) has antitumor activity, but whether a mechanism is through modulation of cell lipids is unknown. T o establish if ZuFru modifies cholesterol and triglycerides in SW480 and SW620. ZuFru composition was studied by phytochemical march; antiproliferative activity by sulforhodamine B, cholesterol , and triglycerides by Folch method. Z ufru contains anthocyanins, flavonoids, alkaloids , and tannins. Cell lines showed differences in their growth rate ( p =0.049). At 39.6 µg/m L of ZuFru, cell viability was decreased: SW480 (45.6%) and SW620 (45.1%). In SW480, cholesterol (44.6%) and triglycerides (46.5%) decreased; In SW620, cholesterol decreased 14.8% and triglycerides increased 7%, with significant differences for both lines. A ntiproliferative activity of ZuFru could be associated with the inhibition of intracellular biosynthesis of cholesterol and triglycerides in SW480. Action mechanisms need to be further investigated.

Las células cancerosas modifican el metabolismo lipídico para proliferar; el zumo de fruta (ZuFru) de Passiflora edulis ( P. edulis ) tiene activida d antitumoral, sin embargo, se desconoce si se involucran los lípidos celulares. E stablecer si ZuFru modifica colesterol y triglicéridos en células SW480 y SW620. C omposición del ZuFru, actividad antiproliferativa, colesterol y triglicéridos. Se encontraro n antocianinas, flavonoides, alcaloides y taninos. Las líneas celulares mostraron diferencias en su tasa de crecimiento ( p =0 . 049); ZuFru 39,6 µg/ml se disminuyó la viabilidad celular; SW480 (45,6%) y SW620 (45,1%); en SW480 colesterol (44,6%) y triglicérid os (46,5%) en SW620, colesterol (14,8%) y los triglicéridos aumentaron 7%, con diferencias significativas para ambas líneas. La actividad antiproliferativa del ZuFru podría estar asociada a la inhibición de la biosíntesis intracelular de colesterol y de tr iglicéridos en SW480, pero no en SW620. Estos mecanismos de acción deben ser fuertemente investigados.

What triggers phenological events in plants under seasonal environments? A study with phylogenetically related plant species in sympatry / O que desencadeia eventos fenológicos em plantas em ambientes sazonais? Um estudo com espécies de plantas filogeneticamente relacionadas e em simpatria

In this study, we evaluated variation in vegetative and reproductive phenological events of four phylogenetically related plant species subjected to a seasonal environment. To this aim, we sampled 15 individuals of each plant species every fortnight for one year, between January and December of 2017. To assess when a given phenophase occurred more intensely in the population, the Fournier intensity index was used and the synchrony of individuals of the sample in a given phenological event was estimated using the activity index. The Rayleigh (Z) test was used to determine whether the phenological events have seasonal distribution. The relationship of abiotic factors (photoperiod, precipitation, relative humidity and temperature) with the intensity of phenophases was evaluated for each plant species using generalized linear models (GLMs). The phenophases of all plants showed a seasonal distribution pattern, as well as variation in synchrony of phenophases and specific sets of abiotic factors significantly influenced their phenophases. New leaves, for example, were produced throughout the seasons, with intense leaf fall in the dry season. Flowering periods, on the other hand, did not overlap. Indeed, species exhibited sequential flowering and asynchronous flowering among individuals. Our results suggest that the phenological patterns of four sympatric plant species are directly linked to climatic variables, but different abiotic factors affected different phenophases.

Neste estudo, avaliamos a variação nos eventos fenológicos vegetativos e reprodutivos de quatro espécies de plantas filogeneticamente relacionadas submetidas a um ambiente sazonal. Para isso, amostramos 15 indivíduos de cada espécie quinzenalmente, pelo período de um ano, entre janeiro e dezembro de 2017. Para avaliar quando uma determinada fenofase ocorreu de modo mais intenso na população foi utilizado o índice de intensidade de Fournier e a sincronia dos indivíduos da amostra em determinado evento fenológico foi estimada utilizando-se o índice de atividade. O teste de Rayleigh (Z) foi usado para determinar se os eventos fenológicos têm distribuição sazonal. A relação dos fatores abióticos (fotoperíodo, precipitação, temperatura e umidade relativa) com a intensidade das fenofases foi avaliada para cada espécie de planta usando modelos lineares generalizados (GLMs). As fenofases de todas as plantas apresentaram um padrão de distribuição sazonal, bem como variação na sincronia das fenofases e conjuntos específicos de fatores abióticos influenciaram significativamente suas fenofases. Folhas novas, por exemplo, foram produzidas ao longo das estações, com intensa queda de folhas na estação seca. Os períodos de floração, por outro lado, não se sobrepuseram. De fato, as espécies exibiram floração sequencial e floração assíncrona entre os indivíduos. Nossos resultados sugerem que os padrões fenológicos das quatro espécies de plantas simpátricas estão diretamente ligados às variáveis climáticas, mas diferentes fatores abióticos afetaram diferentes fenofases.

Probiotics intervention in colorectal cancer: From traditional approaches to novel strategies / 中华医学杂志(英文版)

The intestine harbors a large population of microorganisms that interact with epithelial cells to maintain host healthy physiological status. These intestinal microbiota engage in the fermentation of non-digestible nutrients and produce beneficial metabolites to regulate host homeostasis, metabolism, and immune response. The disruption of microbiota, known as dysbiosis, has been implicated in many intestinal diseases, including colorectal cancer (CRC). As the third most common cancer and the second leading cause of cancer-related death worldwide, CRC poses a significant health burden. There is an urgent need for novel interventions to reduce CRC incidence and improve clinical outcomes. Modulating the intestinal microbiota has emerged as a promising approach for CRC prevention and treatment. Current research efforts in CRC probiotics primarily focus on reducing the incidence of CRC, alleviating treatment-related side effects, and potentiating the efficacy of anticancer therapy, which is the key to successful translation to clinical practice. This paper aims to review the traditional probiotics and new interventions, such as next-generation probiotics and postbiotics, in the context of CRC. The underlying mechanisms of probiotic anti-cancer effects are also discussed, including the restoration of microbial composition, reinforcement of gut barrier integrity, induction of cancer cell apoptosis, inactivation of carcinogens, and modulation of host immune response. This paper further evaluates the novel strategy of probiotics as an adjuvant therapy in boosting the efficacy of chemotherapy and immunotherapy. Despite all the promising findings presented in studies, the evaluation of potential risks, optimization of delivery methods, and consideration of intra-patient variability of gut microbial baseline must be thoroughly interpreted before bench-to-bedside translation.

Association of stage 1 hypertension defined by the 2017 ACC/AHA guideline with cardiovascular events and mortality in Chinese adults / 中华医学杂志(英文版)

BACKGROUND@#The 2017 American College of Cardiology/American Heart Association (ACC/AHA) blood pressure (BP) guideline lowered the threshold defining hypertension to 130/80 mmHg. However, how stage 1 hypertension defined using this guideline is associated with cardiovascular events in Chinese adults remains unclear. This study assessed the association between stage 1 hypertension defined by the 2017 ACC/AHA guideline and clinical outcomes in the Chinese population.@*METHODS@#Participants with stage 1 hypertension ( n = 69,509) or normal BP ( n = 34,142) were followed in this study from 2006/2007 to 2020. Stage 1 hypertension was defined as a systolic blood pressure of 130-139 mmHg or a diastolic blood pressure of 80-89 mmHg. None were taking antihypertensive medication or had a history of myocardial infarction (MI), stroke, or cancer at baseline. The primary outcome was a composite of MI, stroke, and all-cause mortality. The secondary outcomes were individual components of the primary outcome. Cox proportional hazards models were used for the analysis.@*RESULTS@#During a median follow-up of 11.09 years, we observed 10,479 events (MI, n = 995; stroke, n = 3408; all-cause mortality, n = 7094). After multivariable adjustment, the hazard ratios for stage 1 hypertension vs. normal BP were 1.20 (95% confidence interval [CI], 1.13-1.25) for primary outcome, 1.24 (95% CI, 1.05-1.46) for MI, 1.45 (95% CI, 1.33-1.59) for stroke, and 1.11 (95% CI, 1.04-1.17) for all-cause mortality. The hazard ratios for participants with stage 1 hypertension who were prescribed antihypertensive medications compared with those without antihypertensive treatment during the follow-up was 0.90 (95% CI, 0.85-0.96).@*CONCLUSIONS@#Using the new definition, Chinese adults with untreated stage 1 hypertension are at higher risk for MI, stroke, and all-cause mortality. This finding may help to validate the new BP classification system in China.

Study on gene therapy for DPOAE and ABR threshold changes in adult Otof-/- mice / 临床耳鼻咽喉头颈外科杂志

Objective:This study aims to analyze the threshold changes in distortion product otoacoustic emissions（DPOAE） and auditory brainstem response（ABR） in adult Otof-/- mice before and after gene therapy, evaluating its effectiveness and exploring methods for assessing hearing recovery post-treatment. Methods:At the age of 4 weeks, adult Otof-/- mice received an inner ear injection of a therapeutic agent containing intein-mediated recombination of the OTOF gene, delivered via dual AAV vectors through the round window membrane（RWM）. Immunofluorescence staining assessed the proportion of inner ear hair cells with restored otoferlin expression and the number of synapses.Statistical analysis was performed to compare the DPOAE and ABR thresholds before and after the treatment. Results:AAV-PHP. eB demonstrates high transduction efficiency in inner ear hair cells. The therapeutic regimen corrected hearing loss in adult Otof-/- mice without impacting auditory function in wild-type mice. The changes in DPOAE and ABR thresholds after gene therapy are significantly correlated at 16 kHz. Post-treatment,a slight increase in DPOAE was observeds,followed by a recovery trend at 2 months post-treatment. Conclusion:Gene therapy significantly restored hearing in adult Otof-/- mice, though the surgical delivery may cause transient hearing damage. Precise and gentle surgical techniques are essential to maximize gene therapy's efficacy.

Human ESC-derived vascular cells promote vascular regeneration in a HIF-1α dependent manner

Hypoxia-inducible factor (HIF-1α), a core transcription factor responding to changes in cellular oxygen levels, is closely associated with a wide range of physiological and pathological conditions. However, its differential impacts on vascular cell types and molecular programs modulating human vascular homeostasis and regeneration remain largely elusive. Here, we applied CRISPR/Cas9-mediated gene editing of human embryonic stem cells and directed differentiation to generate HIF-1α-deficient human vascular cells including vascular endothelial cells, vascular smooth muscle cells, and mesenchymal stem cells (MSCs), as a platform for discovering cell type-specific hypoxia-induced response mechanisms. Through comparative molecular profiling across cell types under normoxic and hypoxic conditions, we provide insight into the indispensable role of HIF-1α in the promotion of ischemic vascular regeneration. We found human MSCs to be the vascular cell type most susceptible to HIF-1α deficiency, and that transcriptional inactivation of ANKZF1, an effector of HIF-1α, impaired pro-angiogenic processes. Altogether, our findings deepen the understanding of HIF-1α in human angiogenesis and support further explorations of novel therapeutic strategies of vascular regeneration against ischemic damage.

Force-induced Caspase-1-dependent pyroptosis regulates orthodontic tooth movement / 国际口腔科学杂志·英文版

Pyroptosis, an inflammatory caspase-dependent programmed cell death, plays a vital role in maintaining tissue homeostasis and activating inflammatory responses. Orthodontic tooth movement (OTM) is an aseptic force-induced inflammatory bone remodeling process mediated by the activation of periodontal ligament (PDL) progenitor cells. However, whether and how force induces PDL progenitor cell pyroptosis, thereby influencing OTM and alveolar bone remodeling remains unknown. In this study, we found that mechanical force induced the expression of pyroptosis-related markers in rat OTM and alveolar bone remodeling process. Blocking or enhancing pyroptosis level could suppress or promote OTM and alveolar bone remodeling respectively. Using Caspase-1-/- mice, we further demonstrated that the functional role of the force-induced pyroptosis in PDL progenitor cells depended on Caspase-1. Moreover, mechanical force could also induce pyroptosis in human ex-vivo force-treated PDL progenitor cells and in compressive force-loaded PDL progenitor cells in vitro, which influenced osteoclastogenesis. Mechanistically, transient receptor potential subfamily V member 4 signaling was involved in force-induced Caspase-1-dependent pyroptosis in PDL progenitor cells. Overall, this study suggested a novel mechanism contributing to the modulation of osteoclastogenesis and alveolar bone remodeling under mechanical stimuli, indicating a promising approach to accelerate OTM by targeting Caspase-1.

Temporal-spatial Generation of Astrocytes in the Developing Diencephalon / 神经科学通报·英文版

Astrocytes are the largest glial population in the mammalian brain. However, we have a minimal understanding of astrocyte development, especially fate specification in different regions of the brain. Through lineage tracing of the progenitors of the third ventricle (3V) wall via in-utero electroporation in the embryonic mouse brain, we show the fate specification and migration pattern of astrocytes derived from radial glia along the 3V wall. Unexpectedly, radial glia located in different regions along the 3V wall of the diencephalon produce distinct cell types: radial glia in the upper region produce astrocytes and those in the lower region produce neurons in the diencephalon. With genetic fate mapping analysis, we reveal that the first population of astrocytes appears along the zona incerta in the diencephalon. Astrogenesis occurs at an early time point in the dorsal region relative to that in the ventral region of the developing diencephalon. With transcriptomic analysis of the region-specific 3V wall and lateral ventricle (LV) wall, we identified cohorts of differentially-expressed genes in the dorsal 3V wall compared to the ventral 3V wall and LV wall that may regulate astrogenesis in the dorsal diencephalon. Together, these results demonstrate that the generation of astrocytes shows a spatiotemporal pattern in the developing mouse diencephalon.

Stem Cell-Based Hair Cell Regeneration and Therapy in the Inner Ear / 神经科学通报·英文版

Hearing loss has become increasingly prevalent and causes considerable disability, thus gravely burdening the global economy. Irreversible loss of hair cells is a main cause of sensorineural hearing loss, and currently, the only relatively effective clinical treatments are limited to digital hearing equipment like cochlear implants and hearing aids, but these are of limited benefit in patients. It is therefore urgent to understand the mechanisms of damage repair in order to develop new neuroprotective strategies. At present, how to promote the regeneration of functional hair cells is a key scientific question in the field of hearing research. Multiple signaling pathways and transcriptional factors trigger the activation of hair cell progenitors and ensure the maturation of newborn hair cells, and in this article, we first review the principal mechanisms underlying hair cell reproduction. We then further discuss therapeutic strategies involving the co-regulation of multiple signaling pathways in order to induce effective functional hair cell regeneration after degeneration, and we summarize current achievements in hair cell regeneration. Lastly, we discuss potential future approaches, such as small molecule drugs and gene therapy, which might be applied for regenerating functional hair cells in the clinic.

Single-Cell Mapping of Brain Myeloid Cell Subsets Reveals Key Transcriptomic Changes Favoring Neuroplasticity after Ischemic Stroke / 神经科学通报·英文版

Interactions between brain-resident and peripheral infiltrated immune cells are thought to contribute to neuroplasticity after cerebral ischemia. However, conventional bulk sequencing makes it challenging to depict this complex immune network. Using single-cell RNA sequencing, we mapped compositional and transcriptional features of peri-infarct immune cells. Microglia were the predominant cell type in the peri-infarct region, displaying a more diverse activation pattern than the typical pro- and anti-inflammatory state, with axon tract-associated microglia (ATMs) being associated with neuronal regeneration. Trajectory inference suggested that infiltrated monocyte-derived macrophages (MDMs) exhibited a gradual fate trajectory transition to activated MDMs. Inter-cellular crosstalk between MDMs and microglia orchestrated anti-inflammatory and repair-promoting microglia phenotypes and promoted post-stroke neurogenesis, with SOX2 and related Akt/CREB signaling as the underlying mechanisms. This description of the brain's immune landscape and its relationship with neurogenesis provides new insight into promoting neural repair by regulating neuroinflammatory responses.

Temporal Unfolding of Racial Ingroup Bias in Neural Responses to Perceived Dynamic Pain in Others / 神经科学通报·英文版

In this study, we investigated how empathic neural responses unfold over time in different empathy networks when viewing same-race and other-race individuals in dynamic painful conditions. We recorded magnetoencephalography signals from Chinese adults when viewing video clips showing a dynamic painful (or non-painful) stimulation to Asian and White models' faces to trigger painful (or neutral) expressions. We found that perceived dynamic pain in Asian models modulated neural activities in the visual cortex at 100 ms-200 ms, in the orbitofrontal and subgenual anterior cingulate cortices at 150 ms-200 ms, in the anterior cingulate cortex around 250 ms-350 ms, and in the temporoparietal junction and middle temporal gyrus around 600 ms after video onset. Perceived dynamic pain in White models modulated activities in the visual, anterior cingulate, and primary sensory cortices after 500 ms. Our findings unraveled earlier dynamic activities in multiple neural circuits in response to same-race (vs other-race) individuals in dynamic painful situations.

Neuronomodulation of Excitable Neurons / 神经科学通报·英文版

Neuronomodulation refers to the modulation of neural conduction and synaptic transmission (i.e., the conduction process involved in synaptic transmission) of excitable neurons via changes in the membrane potential in response to chemical substances, from spillover neurotransmitters to paracrine or endocrine hormones circulating in the blood. Neuronomodulation can be direct or indirect, depending on the transduction pathways from the ligand binding site to the ion pore, either on the same molecule, i.e. the ion channel, or through an intermediate step on different molecules. The major players in direct neuronomodulation are ligand-gated or voltage-gated ion channels. The key process of direct neuronomodulation is the binding and chemoactivation of ligand-gated or voltage-gated ion channels, either orthosterically or allosterically, by various ligands. Indirect neuronomodulation involves metabotropic receptor-mediated slow potentials, where steroid hormones, cytokines, and chemokines can implement these actions. Elucidating neuronomodulation is of great significance for understanding the physiological mechanisms of brain function, and the occurrence and treatment of diseases.

Distributions of Visual Receptive Fields from Retinotopic to Craniotopic Coordinates in the Lateral Intraparietal Area and Frontal Eye Fields of the Macaque / 神经科学通报·英文版

Even though retinal images of objects change their locations following each eye movement, we perceive a stable and continuous world. One possible mechanism by which the brain achieves such visual stability is to construct a craniotopic coordinate by integrating retinal and extraretinal information. There have been several proposals on how this may be done, including eye-position modulation (gain fields) of retinotopic receptive fields (RFs) and craniotopic RFs. In the present study, we investigated coordinate systems used by RFs in the lateral intraparietal (LIP) cortex and frontal eye fields (FEF) and compared the two areas. We mapped the two-dimensional RFs of neurons in detail under two eye fixations and analyzed how the RF of a given neuron changes with eye position to determine its coordinate representation. The same recording and analysis procedures were applied to the two brain areas. We found that, in both areas, RFs were distributed from retinotopic to craniotopic representations. There was no significant difference between the distributions in the LIP and FEF. Only a small fraction of neurons was fully craniotopic, whereas most neurons were between the retinotopic and craniotopic representations. The distributions were strongly biased toward the retinotopic side but with significant craniotopic shifts. These results suggest that there is only weak evidence for craniotopic RFs in the LIP and FEF, and that transformation from retinotopic to craniotopic coordinates in these areas must rely on other factors such as gain fields.

Bilateral tonic pupil during a migraine attack: a case report / Pupila tônica bilateral durante crise de enxaqueca: relato de caso

INTRODUCTION:Tonic pupil or Adie's pupil occurs due to parasympathetic denervation, and it is characterized by mydriasis with little or no response to light, with pupillary contraction to accommodation. It is caused by eye pathologies, such as infections, trauma, neoplasms, inflammatory diseases, and systemic diseases with autonomic dysfunction. Few cases have been reported of bilateral tonic pupils associated with migraine attacks. CASE REPORT: Our aimed to describe the case of a young female patient with a history of chronic migraine without aura, who presented acutely with bilateral pupillary mydriasis during a migraine attack, characterized as tonic pupil, and to discuss the possible causes of mydriasis during a migraine attack.

INTRODUÇÃO: A pupila tônica ou pupila de Adie ocorre devido à denervação parassimpática e é caracterizada por midríase com pouca ou nenhuma resposta à luz, com contração pupilar à acomodação. É causada por patologias oculares, como infecções, traumas, neoplasias, doenças inflamatórias e doenças sistêmicas com disfunção autonômica. Poucos casos foram relatados de pupilas tônicas bilaterais associadas a crises de enxaqueca. RELATO DE CASO: Nosso objetivo foi descrever o caso de uma paciente jovem, com história de enxaqueca crônica sem aura, que apresentou agudamente midríase pupilar bilateral durante uma crise de enxaqueca, caracterizada como pupila tônica, e discutir as possíveis causas da midríase durante uma crise de enxaqueca. ataque de enxaqueca.

Fibroblasts inhibit osteogenesis by regulating nuclear-cytoplasmic shuttling of YAP in mesenchymal stem cells and secreting DKK1

BACKGROUND: Fibrous scars frequently form at the sites of bone nonunion when attempts to repair bone fractures have failed. However, the detailed mechanism by which fibroblasts, which are the main components of fibrous scars, impede osteogenesis remains largely unknown. RESULTS: In this study, we found that fibroblasts compete with osteogenesis in both human bone nonunion tissues and BMP2-induced ectopic osteogenesis in a mouse model. Fibroblasts could inhibit the osteoblastic differentiation of mesenchymal stem cells (MSCs) via direct and indirect cell competition. During this process, fibroblasts modulated the nuclear-cytoplasmic shuttling of YAP in MSCs. Knocking down YAP could inhibit osteoblast differentiation of MSCs, while overexpression of nuclear-localized YAP-5SA could reverse the inhibition of osteoblast differentiation of MSCs caused by fibroblasts. Furthermore, fibroblasts secreted DKK1, which further inhibited the formation of calcium nodules during the late stage of osteogenesis but did not affect the early stage of osteogenesis. Thus, fibroblasts could inhibit osteogenesis by regulating YAP localization in MSCs and secreting DKK1. CONCLUSIONS: Our research revealed that fibroblasts could modulate the nuclear-cytoplasmic shuttling of YAP in MSCs, thereby inhibiting their osteoblast differentiation. Fibroblasts could also secrete DKK1, which inhibited calcium nodule formation at the late stage of osteogenesis.

MSC-derived exosomes protect auditory hair cells from neomycin-induced damage via autophagy regulation

BACKGROUND: Sensorineural hearing loss (SNHL) poses a major threat to both physical and mental health; however, there is still a lack of effective drugs to treat the disease. Recently, novel biological therapies, such as mesenchymal stem cells (MSCs) and their products, namely, exosomes, are showing promising therapeutic potential due to their low immunogenicity, few ethical concerns, and easy accessibility. Nevertheless, the precise mechanisms underlying the therapeutic effects of MSC-derived exosomes remain unclear. RESULTS: Exosomes derived from MSCs reduced hearing and hair cell loss caused by neomycin-induced damage in models in vivo and in vitro. In addition, MSC-derived exosomes modulated autophagy in hair cells to exert a protective effect. Mechanistically, exogenously administered exosomes were internalized by hair cells and subsequently upregulated endocytic gene expression and endosome formation, ultimately leading to autophagy activation. This increased autophagic activity promoted cell survival, decreased the mitochondrial oxidative stress level and the apoptosis rate in hair cells, and ameliorated neomycin-induced ototoxicity. CONCLUSIONS: In summary, our findings reveal the otoprotective capacity of exogenous exosome-mediated autophagy activation in hair cells in an endocytosis-dependent manner, suggesting possibilities for deafness treatment.