Cell fate

Mitotic genome-bookmarking preserves epigenetic information, re-establishing progenitor's gene expression profile through transcription factors, chromatin remodelers, and histone modifiers, thereby regulating cell fate and lineage commitment post-mitotically in progeny cells. Our recent study revealed that the constitutive association of VDR with mitotic chromatin involves its DNA-binding domain. However, amino acid residues in this domain, crucial for genome bookmarking, remain elusive. This study demonstrates that nuclear localization signal (NLS) residues between 49-55 amino acids in VDR are essential for receptor-chromatin interaction during mitosis...

Low back pain is a leading cause of disability worldwide, often attributed to intervertebral disc (IVD) degeneration with loss of the functional nucleus pulposus (NP). Regenerative strategies utilizing biomaterials and stem cells are promising for NP repair. Human NP tissue is highly viscoelastic, relaxing stress rapidly under deformation. However, the impact of tissue-specific viscoelasticity on the activities of adipose-derived stem cells (ASC) remains largely unexplored. Here, we investigated the role of matrix viscoelasticity in regulating ASC differentiation for IVD regeneration...

This review explores the nuanced role of reactive oxygen species (ROS) in cell fate, challenging the traditional view that equates ROS with cellular damage. Through significant technological advancements in detecting localized redox states and identifying oxidized cysteines, a paradigm shift has emerged: from ROS as merely damaging agents to crucial players in redox signaling. We delve into the intricacies of redox mechanisms, which, although confined, exert profound influences on cellular physiological responses...

Di-hexyl phthalate (2-ethylhexyl) (DEHP) has been confirmed to cause female reproductive toxicity in humans and model animals by affecting the survival of ovarian granulosa cells (GCs), but the interrelationships between DEHP's on autophagy, apoptosis, and inflammation in GCs are not clear. Our previous study demonstrated that DEHP exposure resulted in the disturbance of intestinal flora associated with serum LPS release, which in turn led to impaired ovarian function. LPS has also been shown to determine cell fate by modulating cellular autophagy, apoptosis, and inflammation...

H3.3 is a highly conserved nonreplicative histone variant. H3.3 is enriched in promoters and enhancers of active genes, but it is also found within suppressed heterochromatin, mostly around telomeres. Accordingly, H3.3 is associated with seemingly contradicting functions: It is involved in development, differentiation, reprogramming, and cell fate, as well as in heterochromatin formation and maintenance, and the silencing of developmental genes. The emerging view is that different cellular contexts and histone modifications can promote opposing functions for H3...

Excitatory amino acid transporters (EAATs) are responsible for excitatory amino acid transportation and are associated with auto-immune diseases in the central nervous system and peripheral tissues. However, the subcellular location and function of EAAT2 in macrophages are still obscure. In this study, we demonstrated that LPS stimulation increases expression of EAAT2 (coded by Slc1a2) via NF-κB signaling. EAAT2 is necessary for inflammatory macrophage polarization through sustaining mTORC1 activation...

The Hippo signalling pathway, an evolutionarily conserved kinase cascade, has been shown to be crucial for cell fate determination, homeostasis and tissue regeneration. Recent experimental and clinical studies have demonstrated that the Hippo signalling pathway is involved in the pathophysiology of ocular diseases. This article provides the first systematic review of studies on the regulatory and functional roles of mammalian Hippo signalling systems in eye diseases. More comprehensive studies on this pathway are required for a better understanding of the pathophysiology of eye diseases and the development of effective therapies...

Living cells actively interact biochemically and mechanically with the surrounding extracellular matrices (ECMs) and undergo dramatic morphological and dimensional transitions, concomitantly remodeling ECMs. However, there is no suitable method to quantitatively discuss the contribution of mechanical interactions in such mutually adaptive processes. We herein developed a highly deformable "living" cellular scaffold to evaluate overall mechanical energy transfer between cell and ECMs. It is based on the water-perfluorocarbon interface decorated with phospholipids bearing a cell-adhesive ligand and fluorescent tag...

Cell fate is precisely modulated by complex but well-tuned molecular signaling networks, whose spatial and temporal dysregulation commonly leads to hazardous diseases. Biomolecular condensates (BCs), as a newly emerging type of biophysical assemblies, decipher the molecular codes bridging molecular behaviors, signaling axes, and clinical prognosis. Particularly, physical traits of BCs play an important role; however, a panoramic view from this perspective toward clinical practices remains lacking. In this review, we describe the most typical five physical traits of BCs, and comprehensively summarize their roles in molecular signaling axes and corresponding major determinants...

Cellular survival hinges on a delicate balance between accumulating damages and repair mechanisms. In this intricate equilibrium, oxidants, currently considered physiological molecules, can compromise vital cellular components, ultimately triggering cell death. On the other hand, cells possess countermeasures, such as autophagy, which degrades and recycles damaged molecules and organelles, restoring homeostasis. Lysosomes and their enzymatic arsenal, including cathepsins, play critical roles in this balance, influencing the cell's fate toward either apoptosis and other mechanisms of regulated cell death or autophagy...

The improvement of in vitro embryo development is a gateway to enhance the output of assisted reproductive technologies. The Wnt and Hippo signaling pathways are crucial for the early development of bovine embryos. This study investigated the development of bovine embryos under the influence of a Hippo signaling agonist (LPA) and a Wnt signaling inhibitor (DKK1). In this current study, embryos produced in vitro were cultured in media supplemented with LPA and DKK1. We comprehensively analyzed the impact of LPA and DKK1 on various developmental parameters of the bovine embryo, such as blastocyst formation, differential cell counts, YAP fluorescence intensity and apoptosis rate...

Cancer is a significant global health threat and a leading cause of death worldwide. Effective early-stage interventions, particularly surgery, can potentially cure many solid tumors. However, the risk of postoperative cancer recurrence remains high. Recent research highlights the influence of perioperative anesthetic and analgesic choices on the fate of residual cancer cells, potentially affecting recurrence risks. Among these agents, ketamine-a well-known anesthetic and analgesic-has garnered interest due to its antitumor properties, mainly through inhibiting the N-methyl-D-aspartate (NMDA) receptor found in various cancer tissues...

Recombinant tissue-type plasminogen activator (r-tPA/Actilyse) stands as the prevailing pharmacological solution for treating ischemic stroke patients, of whom because their endogenous circulating tPA alone is not sufficient to rescue reperfusion and to promote favorable outcome. Beyond the tPA contributed by circulating endothelial cells and hepatocytes, neurons also express tPA, sparking debates regarding its impact on neuronal fate ranging from pro-survival to neurotoxic properties. In order to investigate the role of neuronal tPA during brain injuries, we developed models leading to its conditional deletion in neurons, employing AAV9-pPlat-GFP and AAV9-pPlat-Cre-GFP along with tPA floxed mice...

BIG/DARK OVEREXPRESSION OF CAB1/TRANSPORT INHIBITOR RESPONSE3 is a 0.5-MDa protein associated with multiple functions in Arabidopsis (Arabidopsis thaliana) signalling and development. However, the biochemical functions of BIG are unknown. We investigated a role for BIG in the Arg/N-degron pathways, in which substrate protein fate is influenced by the N-terminal (Nt) residue. We crossed a big loss-of-function allele to two N-degron pathway E3 ligase mutants, proteolysis6 (prt6) and prt1, and examined the stability of protein substrates...

Using 13 C6 glucose labeling coupled to gas chromatography-mass spectrometry and 2D 1 H-13 C heteronuclear single quantum coherence NMR spectroscopy, we have obtained a comparative high-resolution map of glucose fate underpinning β cell function. In both mouse and human islets, the contribution of glucose to the tricarboxylic acid (TCA) cycle is similar. Pyruvate fueling of the TCA cycle is primarily mediated by the activity of pyruvate dehydrogenase, with lower flux through pyruvate carboxylase. While the conversion of pyruvate to lactate by lactate dehydrogenase (LDH) can be detected in islets of both species, lactate accumulation is 6-fold higher in human islets...

The germline provides the genetic and non-genetic information that passes from one generation to the next. Given this important role in species propagation, egg and sperm precursors, called primordial germ cells (PGCs), are one of the first cell types specified during embryogenesis. In fact, PGCs form well before the bipotential somatic gonad is specified. This common feature of germline development necessitates that PGCs migrate through many tissues to reach the somatic gonad. During their journey, PGCs must respond to select environmental cues while ignoring others in a dynamically developing embryo...

RNA interference (RNAi) is a biological process that evolved to protect eukaryotic organisms from foreign genes delivered by viruses. This process has been adapted as a powerful tool to treat numerous diseases through the delivery of small-interfering RNAs (siRNAs) to target cells to alter aberrant gene expression.Antibody-oligonucleotide conjugates (AOCs) are monoclonal antibodies with complexed siRNA or antisense oligonucleotides (ASOs) that have emerged to address some of the challenges faced by naked or chemically conjugated siRNA, which include rapid clearance from systemic circulation and lack of selective delivery of siRNA to target cells...

Pulmonary neuroendocrine (NE) cells are rare airway epithelial cells. The balance between Achaete-scute complex homolog 1 (ASCL1) and hairy and enhancer of split 1, one of the target molecules of the Notch signaling pathway, is crucial for NE differentiation. Small cell lung cancer (SCLC) is a highly aggressive lung tumor, characterized by rapid cell proliferation, a high metastatic potential, and the acquisition of resistance to treatment. The subtypes of SCLC are defined by the expression status of NE cell-lineage transcription factors, such as ASCL1, which roles are supported by SRY-box 2, insulinoma-associated protein 1, NK2 homeobox 1, and wingless-related integration site signaling...

(1) Background: Our previous data indicated that disturbance of the Transforming Growth Factor beta (TGFB) signaling pathway via its Type-2 Receptor (TGFBR2) can cause a Corneal Ectasia (CE)-like phenotype. The purpose of this study is to elucidate whether the SMAD4-dependent signaling pathway is involved in the TGFBR2-related CE-like pathogenesis. (2) Methods: Smad4 was designed to be conditionally knocked out from keratocytes. Novel triple transgenic mice, KerartTA ; Tet-O-Cre; Smad4flox/flox ( Smad4kera-cko ), were administered with doxycycline (Dox)...

Controlling mesenchymal stem cells (MSCs) differentiation remains a critical challenge in their therapeutic application. Numerous biophysical and mechanical stimuli influence stem cell fate, however, their relative efficacy and specificity in mechanically directed differentiation remain unclear. Yes-associated protein (YAP) is one key mechanosensitive protein that controls MSC differentiation. Previous studies have related nuclear mechanics with YAP activity, but we still lack an understanding of what nuclear deformation specifically regulates YAP, and its relationship with mechanical stimuli...