Identification of a Novel Stem Cell Subtype for Clear Cell Renal Cell Carcinoma Based on Stem Cell Gene Profiling

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer and is characterized by high rates of metastasis. Cancer stem cell is a vital cause of renal cancer metastasis and recurrence. However, little is known regarding the change and the roles of stem cells during the development of renal cancer. To clarify this problem, we developed a novel stem cell clustering strategy. Based on The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) genomic datasets, we used 19 stem cell gene sets to classify each dataset. A machine learning method was used to perform the classification. We classified ccRCC into three subtypes—stem cell activated (SC-A), stem cell dormant (SC-D), and stem cell excluded (SC-E)—based on the expressions of stem cell-related genes. Compared with the other subtypes, C2(SC-A) had the highest degree of cancer stem cell concentration, the highest level of immune cell infiltration, a distinct mutation landscape, and the worst prognosis. Moreover, drug sensitivity analysis revealed that subgroup C2(SC-A) had the highest sensitivity to immunotherapy CTLA-4 blockade and the vascular endothelial growth factor receptor (VEGFR) inhibitor sunitinib. The identification of ccRCC subtypes based on cancer stem cell gene sets demonstrated the heterogeneity of ccRCC and provided a new strategy for its treatment.

Magnetic iron oxide nanoparticles have potential on gene therapy effectiveness and biocompatibility

Recent breakthroughs in employing magnetic iron oxide nanoparticles (IONPs) to improve gene transmission to stem cells are outlined in this study, which highlights IONPs' unique properties as biocompatible metal-based gene delivery vectors. The physicochemical characteristics of IONPs, as discussed in this study, have a major effect on gene transmission effectiveness and biocompatibility with stem cells. Regulated syntheses of homogeneous IONPs are preferable for successful, reproducible gene delivery. In addition, synthesizing or assembling IONPs with higher ARs can boost cell absorption, enhancing the effectiveness of gene transmission to stem cells. In addition, magnetofection technology has a substantial influence on stem cell gene transmission. An unoptimized transfection approach resulted in severe cytotoxicity and a significant reduction in levels of gene expression. Gene delivery using IONPs and external magnetic force, on the other hand, has demonstrated excellent results in overcoming serum interference and boosting target gene transmission to 3D cell cultures. Notably, serum-resistant and 3D gene transfer are beneficial for maintaining stem cell survival and stem after magnetofection.However, considerable challenges remain in the way IONP-assisted gene trafficking to stem cells, including the unknown bioeffects of IONPs on stem cell behavior and the large-scale fabrication of controlled size and shape monodispersed IONPs. Used at appropriate concentrations for gene delivery, IONPs exhibit no deleterious influence on stem cell survival, proliferation, and differentiation capacity. However, the dose-dependent toxicity of IONPs and the potential hazards associated with using transfection agents such as PEI require extra attention. Moreover, the potential bio-influences of IONPs and ionized ions on stem cell biological behaviors should be thoroughly examined and studies of new undiscovered bio-effects should continue. Meanwhile, another issue worth addressing for the real use of IONPs as a powerful and omnipresent platform tool to transport target genes to stem cells for medicinal reasons is the large-scale synthesis of homogeneous IONPs with low interbatch variations. IONPs have shown their extraordinary ability to increase the effectiveness of gene transport to stem cells, making them superior to other gene delivery techniques in terms of multifunctional stem cell engineering, paired with their high biocompatibility and promising functionality. However, the challenges of using IONPs to deliver genes to stem cells involve chemistry, physics, material science, pharmaceutics, and cell biology and require more multidisciplinary collaborations to achieve breakthroughs and translate this promising stem cell gene delivery strategy into medical practice.

DNMT3A-dependent DNA methylation is required for spermatogonial stem cells to commit to spermatogenesis

DNA methylation plays a critical role in spermatogenesis, as evidenced by the male sterility of DNA methyltransferase (DNMT) mutant mice. Here, we report a striking division of labor in the establishment of the methylation landscape of male germ cells and its functions in spermatogenesis: while DNMT3C is essential for preventing retrotransposons from interfering with meiosis, DNMT3A broadly methylates the genome - at the exception of DNMT3C-dependent retrotransposons - and controls spermatogonial stem cell (SSC) plasticity. By reconstructing developmental trajectories through single-cell RNA-seq and by profiling chromatin states, we found that Dnmt3A mutant SSCs can only self-renew and no longer differentiate due to spurious enhancer activation that enforces an irreversible stem cell gene program. We therefore provide a novel function for DNA methylation in male fertility: the epigenetic programming of SSC commitment to differentiation and to life-long spermatogenesis supply.