The genomic profile of animal models is not completely matched with the genomic profile of humans, and 2D cultures do not represent the cellular heterogeneity and tissue architecture found in tissues ...of their origin. Derived from 3D culture systems, organoids establish a crucial bridge between 2D cell cultures and
in vivo
animal models. Organoids have wide and promising applications in developmental research, disease modeling, drug screening, precision therapy, and regenerative medicine. However, current organoids represent only single or partial components of a tissue, which lack blood vessels, native microenvironment, communication with near tissues, and a continuous dorsal-ventral axis within 3D culture systems. Although efforts have been made to solve these problems, unfortunately, there is no ideal method. Teratoma, which has been frequently studied in pathological conditions, was recently discovered as a new
in vivo
model for developmental studies. In contrast to organoids, teratomas have vascularized 3D structures and regions of complex tissue-like organization. Studies have demonstrated that teratomas can be used to mimic multilineage human development, enrich specific somatic progenitor/stem cells, and even generate brain organoids. These results provide unique opportunities to promote our understanding of the vascularization and maturation of organoids. In this review, we first summarize the basic characteristics, applications, and limitations of both organoids and teratomas and further discuss the possibility that
in vivo
teratoma systems can be used to promote the vascularization and maturation of organoids within an
in vitro
3D culture system.
Prenatal alcohol exposure‐induced fetal alcohol syndrome (FAS) can lead to serious maldevelopment in many organ systems, including the eyes. In the present study, the effects of alcohol exposure on ...early development of the human retina and the therapeutic effects of resveratrol on alcohol‐induced neural retinal damage were observed for the first time in an in vitro retinal organoid model. We report that the number of proliferating and apoptotic cells decreased and increased, respectively, following ethanol treatment. In addition, the number of PAX6+ cells and migrating TUJ1+ cells decreased after ethanol exposure. However, pretreatment with resveratrol prevented all of these negative effects. Using RNA sequencing and immunofluorescence, we identified activation of the PI3K‐AKT signalling pathway as the possible mechanism through which resveratrol protects the retina from alcohol‐induced damage. These results suggest that while ethanol exposure can restrict the growth of the human retina and impede the development of specific retinal cells, pretreatment with resveratrol may be a feasible method for preventing these effects.
Pluripotent stem cell‐derived organoids in vitro can be widely used in disease modelling and drug screening. Based on a retinal organoid model, we found that alcohol significantly inhibited retinal cell proliferation and promoted cell apoptosis. Furthermore, pretreatment with resveratrol can reduce alcohol‐induced retinal cell damage by activating the PI3K‐AKT signalling pathway.
Abstract
Objective
The aim of this study was to investigate the effect of lymph node micrometastasis on the prognosis of patients with gastric cancer and the necessity of integrating it into the ...gastric cancer staging system.
Methods
In total, 241 patients with gastric cancer were included. Hematoxylin and eosin staining of lymph nodes was performed, and negative lymph nodes were evaluated by immunohistochemistry to detect micrometastases. Differences in survival rates between stages were evaluated.
Results
(1) A total of 78 patients (32.4%) had lymph node micrometastases. Compared with the group without micrometastases, the overall recurrence rate, lymph infiltration, vascular invasion, and nerve invasion rate in the micrometastasis group were significantly higher (
P
< 0.05). (2) According to the standard N staging system, the rates of disease-free survival (DFS) for the N0, N1, N2, N3a, and N3b groups were 96.0%, 84.0%, 67.6%, 59.0%, and 21.7%, respectively. There was no significant difference in survival between N2 and N3a. The cumulative survival curves for N2 and N3a intersected. (3) The N stage of 38 patients (15.8%) differed between the traditional system and the new N staging system reflecting micrometastasis. The DFS for N0, N1, N2, N3a, and N3b were 97.0%, 86.3%, 74.2%, 65.4%, and 29.2%, respectively. There was no significant difference in survival between N2 and N3a, but the cumulative survival curves for N2 and N3a did not intersect. (4) Based on a Cox multivariate analysis, various independent risk factors for recurrence were identified (
P
< 0.05).
Conclusion
Lymph node micrometastasis is an important risk factor for gastric cancer recurrence. Lymph node micrometastasis should be considered in TNM staging to determine prognosis and optimal treatment strategies.
The lens is a relatively special and simple organ. It has become an ideal model to study the common developmental characteristics among different organic systems. Lens development is a complex ...process influenced by numerous factors, including signals from the intracellular and extracellular environment. Reactive oxygen species (ROS) are a group of highly reactive and oxygen-containing molecules that can cause endoplasmic reticulum stress in lens cells. As an adaptive response to ER stress, lens cells initiate the unfolded protein response (UPR) to maintain normal protein synthesis by selectively increasing/decreasing protein synthesis and increasing the degradation of misfolded proteins. Generally, the UPR signaling pathways have been well characterized in the context of many pathological conditions. However, recent studies have also confirmed that all three UPR signaling pathways participate in a variety of developmental processes, including those of the lens. In this review, we first briefly summarize the three stages of lens development and present the basic profiles of ROS and the UPR. We then discuss the interconnections between lens development and these two mechanisms. Additionally, the potential adoption of human pluripotent stem-cell-based lentoids in lens development research is proposed to provide a novel perspective on future developmental studies.
Thanks to progress in the development of three‐dimensional (3D) culture technologies, human central nervous system (CNS) development and diseases have been gradually deciphered by using organoids ...derived from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs). Selforganized neural organoids (NOs) have been used to mimic morphogenesis and functions of specific organs in vitro. Many NOs have been reproduced in vitro, such as those mimicking the human brain, retina, and spinal cord. However, NOs fail to capitulate to the maturation and complexity of in vivo neural tissues. The persistent issues with current NO cultivation protocols are inadequate oxygen supply and nutrient diffusion due to the absence of vascular networks. In vivo, the developing CNS is interpenetrated by vasculature that not only supplies oxygen and nutrients but also provides a structural template for neuronal growth. To address these deficiencies, recent studies have begun to couple NO culture with bioengineering techniques and methodologies, including genetic engineering, coculture, multidifferentiation, microfluidics and 3D bioprinting, and transplantation, which might promote NO maturation and create more functional NOs. These cutting‐edge methods could generate an ever more reliable NO model in vitro for deciphering the codes of human CNS development, disease progression, and translational application. In this review, we will summarize recent technological advances in culture strategies to generate vascularized NOs (vNOs), with a special focus on cerebral‐ and retinal‐organoid models.
Endocrine disrupting chemicals (EDCs) are a group of chemical compounds that present a considerable public health problem due to their pervasiveness and associations with chronic diseases. EDCs can ...interrupt the endocrine system and interfere with hormone homeostasis, leading to abnormalities in human physiology. Much attention has been focused on the adverse effects EDCs have on the reproductive system, neurogenesis, neuroendocrine system, and thyroid dysfunction. The eye is usually directly exposed to the surrounding environment; however, the influences of EDCs on the eye have received comparatively little attention. Ocular diseases, such as ocular surface diseases and retinal diseases, have been implicated in hormone deficiency or excess. Epidemiologic studies have shown that EDC exposure not only causes ocular surface disorders, such as dry eye, but also associates with visual deficits and retinopathy. EDCs can pass through the human blood-retinal barrier and enter the neural retina, and can then accumulate in the retina. The retina is an embryologic extension of the central nervous system, and is extremely sensitive and vulnerable to EDCs that could be passed across the placenta during critical periods of retinal development. Subtle alterations in the retinal development process usually result in profound immediate, long-term, and delayed effects late in life. This review, based on extensive literature survey, briefly summarizes the current knowledge about the impact of representative manufactured EDCs on retinal toxicity, including retinal structure alterations and dysfunction. We also highlight the potential mechanism of action of EDCs on the retina, and the predictive retinal models of EDC exposure.
Display omitted
•EDCs can pass through the placenta and can then accumulate in the retina.•EDC exposure associated with visual deficits and retinopathy.•EDC exposure caused retinal structure and dysfunction.•EDCs exert actions through binding NHRs, biotransformation or disrupting retinoid signaling.•Novel in vivo and in vitro testing models applied to test retinal toxicity.
Fibrotic cataracts, including anterior subcapsular cataract (ASC) as well as posterior capsule opacification (PCO), are a common vision-threatening cause worldwide. Still, little is known about the ...underlying mechanisms. Here, we demonstrate a miRNA-based pathway regulating the pathological fibrosis process of lens epithelium.
Gain- and loss-of-function approaches, as well as multiple fibrosis models of the lens, were applied to validate the crucial role of two miR-1225 family members in the TGF-β2 induced PCO model of human LECs and injury-induced ASC model in mice.
Both miR-1225-3p and miR-1225-5p prominently stimulate the migration and EMT process of lens epithelial cells (LECs)
as well as lens fibrosis
. Moreover, we demonstrated that the underlying mechanism for these effects of miR-1225-5p is
directly targeting Keap1 to regulate Keap1/Nrf2 signaling. In addition, evidence showed that Keap1/Nrf2 signaling is activated in the TGF-β2 induced PCO model of human LECs and injury-induced ASC model in mice, and inhibition of the Nrf2 pathway can significantly reverse the process of LECs EMT as well as lens fibrosis.
These results suggest that blockade of miR-1225-5p prevents lens fibrosis
targeting Keap1 thereby inhibiting Nrf2 activation. The 'miR-1225-Keap1-Nrf2' signaling axis presumably holds therapeutic promise in the treatment of fibrotic cataracts.
Microglia are immune cells in the central nervous system (CNS) that originate from the yolk sac in an embryo. The renewal of the microglia pool in the adult eye consists of two components. In ...addition to the self-proliferation of resident cells, microglia in the CNS also derive from the bone marrow (BM). BM-derived cells pass through the blood–brain barrier (BBB) or blood–retina barrier (BRB) and differentiate into microglia under specific conditions which involves a complex mechanism. Recent studies have widely investigated the role of resident microglia and BM-derived microglia in the retinal degenerative disease. Both two cell types play dual roles and share many similar functions. However, resident microglia tend to polarize to the M1 phenotype which is pro-inflammatory and neurotoxic, whereas BM-derived microglia mainly polarize to the neuroprotective M2 phenotype in retinal degeneration. The molecular mechanism that underlines the invasion of peripheral cells has led to extensive discussions. In addition to the BBB and BRB disruption, many signaling pathways are involved in this process. Based on these studies, we discuss the roles of these two types of microglia in retinal degeneration disease and the potential clinical application of BM-derived microglia, which may benefit future therapies.
A previous study reported that intravitreal injection of αA-crystallin inhibits glial scar formation after optic nerve traumatic injury. The purpose of this study was to investigate the effect of ...αA-crystallin on optic nerve astrocytes induced by oxygen glucose deprivation (OGD) in vitro.
Optic nerve astrocytes from newborn Long Evans rats were cultured with αA-crystallin (10−4 g/l) to detect the effects of αA-crystallin on astrocytes. Using a scratch assay, the effect of αA-crystallin treatment on astrocyte migration was assessed. Astrocytes were exposed to OGD and glucose reintroduction/reoxygenation culture for 24 h and 48 h. The expression of glial fibrillary acidic protein (GFAP) and neurocan were subsequently evaluated via immunocytochemistry and western blot. BMP2/4, BMPRIa/Ib and Smad1/5/8 mRNA expression levels were detected by RT-PCR.
The results showed that αA-crystallin slowed the migration of astrocytes in filling the scratch gaps. GFAP and neurocan expression in astrocytes was increased after OGD. However, after treatment with αA-crystallin, GFAP and neurocan expression levels clearly decreased. Furthermore, RT-PCR showed that BMP2 and BMP4 mRNA expression levels decreased significantly.
These results suggest that αA-crystallin inhibits the activation of astrocytes after OGD injury in vitro. Inhibition of the BMP/Smad signaling pathway might be the mechanism underlying this effect.
•We observed the inhibition of αA-crystallin in astrocyte activation in vitro.•αA-crystallin inhibited the migration of astrocytes in scratch assay.•αA-crystallin inhibited astrocyte GFAP and neurocan expression after oxygen glucose deprivation.•αA-crystallin inhibited astrocyte BMPs mRNA expression after oxygen glucose deprivation.
This study investigated the protective effect of carbon monoxide releasing molecule-3 (CORM-3), the classical donor of carbon monoxide, on selenite-induced cataract in rats and explore its possible ...mechanism.
Sprague-Dawley rat pups treated with sodium selenite (Na
2
SeO
3
) were chosen as the cataract model. Fifty rat pups were randomly divided into 5 groups: Control group, Na
2
SeO
3
(3.46 mg/kg) group, low-dose CORM-3 (8 mg/kg/d) + Na
2
SeO
3
group, high-dose CORM-3 (16 mg/kg/d) + Na
2
SeO
3
group, and inactivated CORM-3 (iCORM-3) (8 mg/kg/d) + Na
2
SeO
3
group. The protective effect of CORM-3 was tested by lens opacity scores, hematoxylin and eosin staining, TdT-mediated dUTP nick-end labeling assay, and enzyme-linked immunosorbent assay. Besides, quantitative real-time PCR and western blotting were used for mechanism validation.
Na
2
SeO
3
induced nuclear cataract rapidly and stably, and the achievement ratio of Na
2
SeO
3
group was 100%. CORM-3 alleviated lens opacity of selenite-induced cataract and attenuated the morphological changes of the rat lens. The levels of antioxidant enzymes GSH and SOD in rat lens were also increased by CORM-3 treatment. CORM-3 significantly reduced the ratio of apoptotic lens epithelial cells, besides, CORM-3 decreased the expression of Cleaved Caspase-3 and Bax induced by selenite and increased the expression of Bcl-2 in rat lens inhibited by selenite. Moreover, Nrf-2 and HO-1 were upregulated and Keap1 was downregulated after CORM-3 treatment. While iCORM-3 did not exert the same effect as CORM-3.
Exogenous CO released from CORM-3 alleviates oxidative stress and apoptosis in selenite-induced rat cataract via activating Nrf2/HO-1 pathway. CORM-3 may serve as a promising preventive and therapeutic strategy for cataract.
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