Human Cell最新文献

Biliary atresia (BA), resulting from abnormal development of the liver's internal or external bile ducts, can lead to liver damage and potentially fatal cirrhosis. Type I cystic biliary atresia is a relatively uncommon, but clinically significant variant of BA. It is critical to develop experimental models of BA to examine the etiology and pathogenesis, which remain elusive, and to develop future therapeutics. Here, we have successfully generated a panel of human induced pluripotent stem cells (hiPSCs) from five Japanese patients carrying type I cystic BA. These hiPSC lines exhibited characteristics of self-renewal and pluripotency. These cells held normal karyotypes mostly, but one of them carried hemizygous deletions, the clinical significance of which is unknown yet. Whole genome sequence analysis indicated that some of the mutations or single nucleotide polymorphisms (SNPs) commonly found in these patients are related to hepatobiliary abnormality. Given the limited understanding of the molecular pathogenesis of cystic BA, attributed to unknown factors of genetic and environmental causes, these cellular resources will be instrumental in replicating disease phenotypes and in advancing novel therapies for this disease.

Extensive tumor microenvironment (TME) and tumor-associated macrophages (TAMs) contribute to the initiation and progression of pancreatic cancer (PC). Cancer cell-derived exosomal miRNAs that stimulate macrophage M2 polarization might play an important role in the process. In the current study, we observed significant upregulation of miR-510 in PC cell lines in comparison to normal HPDE cell line, with PANC-1 exhibiting the highest and MIA PaCa-2 the lowest miR-510 levels. Functional assays demonstrated that miR-510 overexpression enhanced, while its inhibition reduced, PC cell viability, migration, invasion, and EMT. In vivo, miR-510 mimics promoted tumor growth and macrophage M2 polarization, whereas miR-510 inhibition had the opposite effect. Exosomes from PANC-1 and MIA PaCa-2 cells, characterized by nanoparticle tracking analysis and TEM, contained significantly higher miR-510 levels than those from HPDE cells. Macrophages incubated with conditioned media from these PC cells showed increased M2 polarization markers, a process inhibited by the exosome inhibitor GW4869. The delivery of miR-510 via PC cell-derived exosomes facilitated macrophage M2 polarization and regulated the STAT signaling pathway, suggesting that exosomal miR-510 plays a crucial role in the tumor microenvironment of PC by modulating macrophage M2 polarization.

The development of atrial fibrillation (AF) is a highly complex, multifactorial process involving pathophysiologic mechanisms, molecular pathway mechanisms and numerous genetic abnormalities. The pathophysiologic mechanisms including altered ion channels, abnormalities of the autonomic nervous system, inflammation, and abnormalities in Ca2 + handling. Molecular pathway mechanisms including, but not limited to, renin-angiotensin-aldosterone (RAAS), transforming growth factor-β (TGF-β), oxidative stress (OS). Although in clinical practice, the distinction between types of AF such as paroxysmal and persistent determines the choice of treatment options. However, it is the pathophysiologic alterations present in AF that truly determine the success of AF treatment and prognosis, but even more so the molecular mechanisms and genetic alterations that lie behind them. One tiny clue reveals the general trend, and small beginnings show how things will develop. This article will organize the development of these mechanisms and their interactions in recent years.

Tumor deposits (TDs) represent a specific form tumor metastasis observed in colorectal cancer (CRC). The lack of successfully established cell lines for TDs, as well as the molecular mechanisms by which TDs occur remain largely unknown. Here, we established paired CRC organoids, including a human primary cancer organoid and its TD organoid, from a 46-year-old male patient with CRC. Further analysis revealed that, compared with primary tumor-derived cells, TD-derived cells exhibited enhanced proliferative, invasive and metastatic capabilities, and increased expression of stemness-related proteins. Furthermore, the present findings also demonstrated that TD-derived cells were more resistant to oxaliplatin or 5-FU. Transcriptomic profiling and qPCR revealed that TD-derived cells exhibited more alterations in fatty acid metabolism signaling and enhanced lipid synthesis ability compared to primary tumor-derived cells. Inhibition of lipid synthesis markedly decreased resistance to oxaliplatin in TD-derived cells. Taken together, the paired organoids established using CRC primary tumor and its TD specimens will provide valuable tools to study tumorigenicity, metastasis and chemoresistance in CRC. Notably, these models will provide novel insights to study tumor heterogeneity and lipid metabolism in CRC.

Synovial sarcoma (SS) is identified as a sarcoma with monomorphic blue spindle cells that display variable epithelial differentiation and is characterized by the SS18::SSX fusion gene. SS accounts for approximately 5-10% of all soft tissue sarcomas, making it a relatively common type within this group of tumors. Since SS is generally sensitive to chemotherapy, the standard treatment for SS includes extensive surgical resection, complemented by neoadjuvant chemotherapy with several approved anticancer drugs. However, in advanced and metastatic cases, the efficacy of these drugs is limited, resulting in poor prognoses. This underscores the need for innovative therapeutic strategies. Patient-derived cancer cell lines are essential tools for basic and preclinical research, yet only four SS cell lines are publicly available. To facilitate the studies of SS, we have developed a novel SS cell line, named NCC-SS6-C1, derived from surgically excised tumor tissue of an SS patient. NCC-SS6-C1 cells preserve the SS18::SSX1 fusion gene, consistent with the genetic characteristics of the original tumor. The cells exhibit continuous proliferation, invasiveness, and the ability to form spheroids. Additionally, we confirmed that this cell line was useful for evaluating the efficacy of anticancer drugs. Our results suggest that NCC-SS6-C1 is a useful tool for basic and pre-clinical studies of SS.

Oral bacteria naturally secrete extracellular vesicles (EVs), which have attracted attention for their promising biomedical applications including cancer therapeutics. However, our understanding of EV impact on tumor progression is hampered by limited in vivo models. In this study, we propose a facile in vivo platform for assessing the effect of EVs isolated from different bacterial strains on oral cancer growth and dissemination using the larval zebrafish model. EVs were isolated from: wild-type Aggregatibacter actinomycetemcomitans and its mutant strains lacking the cytolethal distending toxin (CDT) or lipopolysaccharide (LPS) O-antigen; and wild-type Porphyromonas gingivalis. Cancer cells pretreated with EVs were xenotransplanted into zebrafish larvae, wherein tumor growth and metastasis were screened. We further assessed the preferential sites for the metastatic foci development. Interestingly, EVs from the CDT-lacking A. actinomycetemcomitans resulted in an increased tumor growth, whereas EVs lacking the lipopolysaccharide O-antigen reduced the metastasis rate. P. gingivalis-derived EVs showed no significant effects. Cancer cells pretreated with EVs from the mutant A. actinomycetemcomitans strains tended to metastasize less often to the head and tail compared to the controls. In sum, the proposed approach provided cost- and labor-effective yet efficient model for studying bacterial EVs in oral carcinogenesis, which can be easily extended for other cancer types. Furthermore, our results support the notion that these nanosized particles may represent promising targets in cancer therapeutics.

As periodontal progenitor cells, human dental follicle stem cells (hDFCs) play an important role in regenerative medicine research. Mechanical stimuli exert different regulatory effects on various functions of stem cells. Mechanosensitive ion channels can perceive and transmit mechanical signals. Piezo1 is a novel mechanosensitive cation channel dominated by Ca²⁺ permeation. The yes-associated protein 1 (YAP1) and mitogen-activated protein kinase (MAPK) pathways can respond to mechanical stimuli and play important roles in cell growth, differentiation, apoptosis, and cell cycle regulation. In this study, we demonstrated that Piezo1 was able to transduce cyclic tension stress (CTS) and promote the osteogenic differentiation of hDFCs by applying CTS of 2000 μstrain to hDFCs. Further investigation of this mechanism revealed that CTS activated Piezo1 in hDFCs and resulted in increased levels of intracellular Ca²⁺, YAP1 nuclear translocation, and phosphorylated protein expression levels of extracellular signalling-associated kinase 1/2 (ERK 1/2) and Jun amino-terminal kinase 1/2/3 (JNK 1/3) of the MAPK pathway family. However, when Piezo1 was knocked down in the hDFCs, all these increases disappeared. We conclude that CTS activates Piezo1 expression and promotes its osteogenesis via Ca²⁺/YAP1/MAPK in hDFCs. Appropriate mechanical stimulation promotes the osteogenic differentiation of hDFCs via Piezo1. Targeting Piezo1 may be an effective strategy to regulate the osteogenic differentiation of hDFCs, contributing to MSC-based therapies in the field of bone tissue engineering.