Frontiers in Cell and Developmental Biology最新文献

MLL4, also known as KMT2D, is a histone methyltransferase that acts as an important epigenetic regulator in various organogenesis programs. Mutations in the MLL4 gene are the major cause of Kabuki syndrome, a human developmental disorder that involves craniofacial birth defects, including anomalies in the palate. This study aimed to investigate the role of MLL4 and the underlying mechanisms in the development and growth of the palate. We generated a novel conditional knockout (cKO) mouse model with tissue-specific deletion of Mll4 in the palatal mesenchyme. Using micro-computed tomography (CT), histological analysis, cell mechanism assays, and gene expression profiling, we examined palate development and growth in the Mll4-cKO mice. Gross craniofacial examination at adult stages revealed mild midfacial hypoplasia and midline defects of the palate in Mll4-cKO mice, including a widened midpalatal suture and disrupted midline rugae pattern. Micro-CT-based time-course skeletal analysis during postnatal palatogenesis through adulthood demonstrated a transverse growth deficit in overall palate width in Mll4-cKO mice. Whole-mount and histological staining at perinatal stages identified that the midline defects in the Mll4-cKO mice emerged as early as 1 day prior to birth, presenting as a widened midpalatal suture, accompanied by increased cell apoptosis in the suture mesenchyme. Genome-wide mRNA expression analysis of the midpalatal suture tissue revealed that MLL4 is essential for the timely expression of major cartilage development genes, such as Col2a1 and Acan, at birth. Immunofluorescence staining for osteochondral differentiation markers demonstrated a marked decrease in the chondrogenic marker COL2A1, while the expression of the osteogenic marker RUNX2 remained unchanged, in the Mll4-cKO midpalatal suture. Additionally, SOX9, a master regulator of chondrogenesis, exhibited a significant decrease in protein expression. Indeed, time-course histological analysis during postnatal palate growth revealed retardation in the development of the suture cartilage in Mll4-cKO mice. Taken together, our results demonstrate that MLL4 is essential for orchestrating key cellular and molecular events that ensure proper midpalatal suture development and palate growth.

Preclinical studies have demonstrated that nanoparticles (NPs) hold significant potential for advancing cancer therapy by enhancing therapeutic efficacy while reducing side effects. Their effectiveness in solid tumors is, however, often constrained by insufficient accumulation and penetration. Understanding how the physicochemical properties of NPs - such as size, shape, and surface charge - influence their interaction with cells within the tumor is critical for optimizing NP design. In this study, we addressed the challenge of inconsistent NP behavior by systematically evaluating NP uptake in both 2D and 3D tumor models, and NP penetration in spheroids. Our results showed that larger NPs exhibited higher internalization rates in 2D models but limited penetration in 3D spheroids. Furthermore, negatively charged NPs consistently achieved superior accumulation and deeper penetration than neutral and positively charged NPs. Spherical NPs outperformed rod-shaped NPs in tumor accumulation and penetration. These findings underscore the importance of carefully tailoring NP properties to the complex tumor microenvironment for improved therapeutic outcomes in real tumors.

Exosomes, as key mediators of intercellular communication, have been increasingly recognized for their role in the oncogenic processes, particularly in facilitating drug resistance. This article delves into the emerging evidence linking exosomal lncRNAs to the modulation of drug resistance mechanisms in cancers such as ovarian, cervical, and endometrial cancer. It synthesizes current research findings on how these lncRNAs influence cancer cell survival, tumor microenvironment, and chemotherapy efficacy. Additionally, the review highlights potential therapeutic strategies targeting exosomal lncRNAs, proposing a new frontier in overcoming drug resistance. By mapping the interface of exosomal lncRNAs and drug resistance, this article aims to provide a comprehensive understanding that could pave the way for innovative treatments and improved patient outcomes in female reproductive system cancers.

Drug-induced intestinal toxicity (GIT) is a frequent dose-limiting adverse event that can impact patient compliance and treatment outcomes. In vivo, there are proliferative and differentiated cell types critical to maintaining intestinal homeostasis. Traditional in vitro models using transformed cell lines do not capture this cellular complexity, and often fail to predict intestinal toxicity. Primary tissue-derived intestinal organoids, on the other hand, are a scalable Complex in vitro Model (CIVM) that recapitulates major intestinal cell lineages and function. Intestinal organoid toxicity assays have been shown to correlate with clinical incidence of drug-induced diarrhea, however existing studies do not consider how differentiation state of the organoids impacts assay readouts and predictivity. We employed distinct proliferative and differentiated organoid models of the small intestine to assess whether differentiation state alone can alter toxicity responses to small molecule compounds in cell viability assays. In doing so, we identified several examples of small molecules which elicit differential toxicity in proliferative and differentiated organoid models. This proof of concept highlights the need to consider which cell types are present in CIVMs, their differentiation state, and how this alters interpretation of toxicity assays.

CLN3 mutation causes Juvenile neuronal ceroid lipofuscinosis (JNCL, also known as Batten disease), an early onset neurodegenerative disorder. Patients who suffer from Batten disease often die at an early age. However, the mechanisms underlying how CLN3 loss develops Batten disease remain largely unclear. Here, using Drosophila midgut system, we demonstrate that Drosophila Cln3 has no effect on midgut homeostasis maintaince, including cellular component, intestinal stem cells (ISCs) proliferation and differentiation, but is necessary for ISC activation upon tissue damage. Cell type-specific Gal4 screening reveals that the failure of ISC activation during regeneration caused by Cln3 loss is ISC-autonomous. Through genetic analyses, we elucidate that JAK/STAT signaling in ISCs is not activated with Cln3 depletion upon tissue damage, and functions downstream of Cln3. Our study provides a potential mechanism underlying the development of CLN3-mediated Batten disease at cellular level.

Pyroptosis, a form of programmed cell death induced by inflammasome with a mechanism distinct from that of apoptosis, occurs via one of the three pathway types: classical, non-classical, and granzyme A/B-dependent pyroptosis pathways. Pyroptosis is implicated in various diseases, notably exhibiting a dual role in liver diseases. It facilitates the clearance of damaged hepatocytes, preventing secondary injury, and triggers immune responses to eliminate pathogens and damaged cells. Conversely, excessive pyroptosis intensifies inflammatory responses, exacerbates hepatocyte damage and promotes the activation and proliferation of hepatic stellate cells, accelerating liver fibrosis. Furthermore, by sustaining an inflammatory state, impacts the survival and proliferation of cancer cells. This review comprehensively summarizes the dual role of pyroptosis in liver diseases and its therapeutic strategies, offering new theoretical foundations and practical guidance for preventing and treating of liver diseases.

The spindle assembly checkpoint (SAC) is a surveillance mechanism that prevents uneven segregation of sister chromatids between daughter cells during anaphase. This essential regulatory checkpoint prevents aneuploidy which can lead to various congenital defects observed in newborns. Many studies have been carried out to elucidate the role of proteins involved in the SAC as well as the function of the checkpoint during gametogenesis and embryogenesis. In this review, we discuss the role of SAC proteins in regulating both meiotic and mitotic cell division along with several factors that influence the SAC strength in various species. Finally, we outline the role of SAC proteins and the consequences of their absence or insufficiency on proper gametogenesis and embryogenesis in vivo.

Background: Diabetic kidney disease (DKD) is the leading risk factor for end-stage renal disease (ESRD). Hydroxyurea (HU), a sickle cell disease (SCD) drug approved by FDA, shows protective effect in nephropathy. This study aims to understand whether the application of HU could be effective to treat DKD.

Methods: The streptozotocin (STZ)-induced diabetic mice, and high glucose (HG)-treated human renal mesangial cells (HRMCs) were used to investigate the effect of HU on DKD. Serum creatinine and blood urea nitrogen levels reflecting renal function were evaluated. Histology was used to evaluate pathological changes. Indicators of inflammation and apoptosis were detected. Lastly, the mTOR-S6K pathway was explored by detecting the protein expression of S6K and phosphorylated S6K.

Results: In STZ-induced diabetic mice, administration of HU (20 mg/kg) in drinking water for 16 weeks resulted in significant reductions in creatinine and urea nitrogen levels, alongside mitigating histopathological damage. Additionally, HU effectively suppressed the inflammatory response and apoptosis within the kidneys. HRMC cells were cultivated in HG conditions, and HU effectively attenuated the HG-induced inflammation and apoptosis. Moreover, HU treatment significantly inhibited the mTOR signaling pathway in both in both in vivo and in vitro experiments.

Conclusion: This study unveils a new role of HU in alleviating diabetic kidney disease by modulating inflammation and apoptosis through the mTOR-S6K pathway. However, since HU did not significantly affect blood glucose levels, its therapeutic potential may be best realized when used in combination with standard antidiabetic therapies. Such a combination approach could simultaneously address hyperglycemia and renal dysfunction, offering a more comprehensive management strategy for DKD.

The generation of myogenic progenitors from iPSCs (iMPs) with therapeutic potential for in vivo tissue regeneration has long been a goal in the skeletal muscle community. Today, protocols enable the production of potent, albeit immature, iMPs that resemble Pax7+ adult muscle stem cells. While muscular dystrophies are often the primary therapeutic target for these cells, an underexplored application is their use in treating traumatic muscle injuries. Notably absent from recent reviews on iMPs is the concept of engineering these cells to perform functions post-transplantation that non-transgenic cells cannot. Here, we highlight protocols to enhance the generation, purification, and maturation of iMPs, and introduce the idea of engineering these cells to perform functions beyond their normal capacities, envisioning novel therapeutic applications.