Cellular Fate Determination Research Articles

Exploring the interplay of intrinsic fluctuation and complexity in intracellular calcium dynamics

The concentration of intracellular calcium ion (Ca2＋) exhibits complex oscillations, including bursting and chaos, as observed experimentally. These dynamics are influenced by inherent fluctuations within cells, which serve as crucial determinants in cellular decision-making processes and fate determination. In this study, we systematically explore the interplay between intrinsic fluctuation and the complexity of various dynamic states of intracellular cytosolic Ca2＋. To investigate this interplay, we employ complexity measures such as permutation entropy and statistical complexity. Using a stochastic chemical Langevin equation, we simulate the dynamics of cytosolic Ca2＋. Our findings reveal that permutation entropy and statistical complexity effectively characterize the diverse, dynamic states of cytosolic Ca2＋ and illustrate their interactions with intrinsic fluctuation. Permutation entropy analysis elucidates that the chaotic state is more sensitive to intrinsic fluctuation than the other periodic states. Furthermore, we identify distinct states of cytosolic Ca2＋ occupying specific locations within the theoretical bounds of the complexity–entropy causality plane. These locations indicate varying complexity and information content as intrinsic fluctuation varies. When adjusting the permutation order, the statistical complexity measure for the different periodic and chaotic states exhibits peaks in an intermediate range of intrinsic fluctuation values. Additionally, we identify scale-free or fractal patterns in this intermediate range, which are further corroborated by multifractal detrended fluctuation analysis. These high-complexity states likely correspond to optimal Ca2＋ dynamics with biological significance, revealing rich and complex dynamics shaped by the interplay of intrinsic fluctuation and complexity. Our investigation enhances our understanding of the intricate regulatory mechanisms governing intracellular Ca2＋ dynamics and how intrinsic fluctuation modulates the complexity of the various dynamics that play crucial roles in biological cells.

Discovering consensus regions for interpretable identification of RNA N6-methyladenosine modification sites via graph contrastive clustering.

As a pivotal post-transcriptional modification of RNA, N6-methyladenosine (m6A) has a substantial influence on gene expression modulation and cellular fate determination. Although a variety of computational models have been developed to accurately identify potential m6A modification sites, few of them are capable of interpreting the identification process with insights gained from consensus knowledge. To overcome this problem, we propose a deep learning model, namely M6A-DCR, by discovering consensus regions for interpretable identification of m6A modification sites. In particular, M6A-DCR first constructs an instance graph for each RNA sequence by integrating specific positions and types of nucleotides. The discovery of consensus regions is then formulated as a graph clustering problem in light of aggregating all instance graphs. After that, M6A-DCR adopts a motif-aware graph reconstruction optimization process to learn high-quality embeddings of input RNA sequences, thus achieving the identification of m6A modification sites in an end-to-end manner. Experimental results demonstrate the superior performance of M6A-DCR by comparing it with several state-of-the-art identification models. The consideration of consensus regions empowers our model to make interpretable predictions at the motif level. The analysis of cross validation through different species and tissues further verifies the consistency between the identification results of M6A-DCR and the evolutionary relationships among species.

Recent advances of cellular stimulation with triboelectric nanogenerators.

Triboelectric nanogenerators (TENGs) are new energy collection devices that have the characteristics of high efficiency, low cost, miniaturization capability, and convenient manufacture. TENGs mainly utilize the triboelectric effect to obtain mechanical energy from organisms or the environment, and this mechanical energy is then converted into and output as electrical energy. Bioelectricity is a phenomenon that widely exists in various cellular processes, including cell proliferation, senescence, apoptosis, as well as adjacent cells' communication and coordination. Therefore, based on these features, TENGs can be applied in organisms to collect energy and output electrical stimulation to act on cells, changing their activities and thereby playing a role in regulating cellular function and interfering with cellular fate, which can further develop into new methods of health care and disease intervention. In this review, we first introduce the working principle of TENGs and their working modes, and then summarize the current research status of cellular function regulation and fate determination stimulated by TENGs, and also analyze their application prospects for changing various processes of cell activity. Finally, we discuss the opportunities and challenges of TENGs in the fields of life science and biomedical engineering, and propose a variety of possibilities for their potential development direction.

Mitochondrial Dysfunction and Their Management by Antioxidants

For normal cell functioning generation of ATP is very important, and it is produced by mitochondria, and they also an important organelle. When sometimes mitochondrial dysfunction occur produces high energy will be demanded, and it is critical for cells such as signal transmission between neuronal cells and also affects cardiomyocytes. Mitochondria and their role to act as power house of the cell and through reactive oxygen species they transmit signaling between molecule and also determination of cellular fate. But sometimes the reactive oxygen species generated more that time, for maintaining normal homeostatic mitochondrial function rapid activation of antioxidant defense system that is required by mitochondrial electron transport. But that time antioxidant defense system is not responded properly or absent that cause mitochondrial dysfunction is occurred at that time they produce degenerative diseases in human beings that is nervous system, and they significantly contribute to produce a cardiac pathology because mitochondria are more abundant in cardiac tissues due to mitochondrial dysfunction, and also they are involved in lung related diseases that is asbestos, lung cancer, chronic airway disease and lung fibrosis. When compared to nuclear DNA the mitochondrial DNA is more sensitive to oxidants because they encode the mitochondrial proteins. When damages to mitochondrial DNA, that case impairment occurs in electron transport chain and potential loss in mitochondrial membrane. In this review I concluded that by, oxidative stress induced mitochondrial dysfunction produced lung related heart related and neurological related disease and their one of the way of prevention is by antioxidant induced mitochondrial biogenesis.

Heparinized Gelatin-Based Hydrogels for Differentiation of Induced Pluripotent Stem Cells.

Chemically defined hydrogels are increasingly utilized to define the effects of extracellular matrix (ECM) components on cellular fate determination of human embryonic and induced pluripotent stem cell (hESC and hiPSCs). In particular, hydrogels cross-linked by orthogonal click chemistry, including thiol-norbornene photopolymerization and inverse electron demand Diels–Alder (iEDDA) reactions, are explored for 3D culture of hESC/hiPSCs owing to the specificity, efficiency, cytocompatibility, and modularity of the cross-linking reactions. In this work, we exploited the modularity of thiol-norbornene photopolymerization to create a biomimetic hydrogel platform for 3D culture and differentiation of hiPSCs. A cell-adhesive, protease-labile, and cross-linkable gelatin derivative, gelatin-norbornene (GelNB), was used as the backbone polymer for constructing hiPSC-laden biomimetic hydrogels. GelNB was further heparinized via the iEDDA click reaction using tetrazine-modified heparin (HepTz), creating GelNB-Hep. GelNB or GelNB-Hep was modularly cross-linked with either inert macromer poly(ethylene glycol)-tetra-thiol (PEG4SH) or another bioactive macromer-thiolated hyaluronic acid (THA). The formulations of these hydrogels were modularly tuned to afford biomimetic matrices with similar elastic moduli but varying bioactive components, enabling the understanding of each bioactive component on supporting hiPSC growth and ectodermal, mesodermal, and endodermal fate commitment under identical soluble differentiation cues.

Midline represses Dpp signaling and target gene expression in Drosophila ventral leg development.

ABSTRACTVentral leg patterning in Drosophila is controlled by the expression of the redundant T-box Transcription factors midline (mid) and H15. Here, we show that mid represses the Dpp-activated gene Daughters against decapentaplegic (Dad) through a consensus T-box binding element (TBE) site in the minimal enhancer, Dad13. Mutating the Dad13 DNA sequence results in an increased and broadening of Dad expression. We also demonstrate that the engrailed-homology-1 domain of Mid is critical for regulating the levels of phospho-Mad, a transducer of Dpp-signaling. However, we find that mid does not affect all Dpp-target genes as we demonstrate that brinker (brk) expression is unresponsive to mid. This study further illuminates the interplay between mechanisms involved in determination of cellular fate and the varied roles of mid.

A review on Tsukushi: mammalian development, disorders, and therapy.

Tsukushi (TSK), a leucine-rich peptidoglycan in the extracellular compartment, mediates multiple signaling pathways that are critical for development and metabolism. TSK regulates signaling pathways that eventually control cellular communication, proliferation, and cell fate determination. Research on TSK has become more sophisticated in recent years, illustrating its involvement in the physiology and pathophysiology of neural, genetic, and metabolic diseases. In a recent study, we showed that TSK therapy reversed the pathophysiological abnormalities of the hydrocephalic (a neurological disorder) brain in mice. This review summarizes the roles of TSK in key signaling processes in the mammalian development, disorders, and evaluating its possible therapeutic and diagnostic potential.

In vivo macromolecular crowding is differentially modulated by aquaporin 0 in zebrafish lens: Insights from a nanoenvironment sensor and spectral imaging.

Macromolecular crowding is crucial for cellular homeostasis. In vivo studies of macromolecular crowding and water dynamics are needed to understand their roles in cellular physiology and fate determination. Macromolecular crowding in the lens is essential for normal optics, and an understanding of its regulation will help prevent cataract and presbyopia. Here, we combine the use of the nanoenvironmental sensor [6-acetyl-2-dimethylaminonaphthalene (ACDAN)] to visualize lens macromolecular crowding with in vivo studies of aquaporin 0 zebrafish mutants that disrupt its regulation. Spectral phasor analysis of ACDAN fluorescence reveals water dipolar relaxation and demonstrates that mutations in two zebrafish aquaporin 0s, Aqp0a and Aqp0b, alter water state and macromolecular crowding in living lenses. Our results provide in vivo evidence that Aqp0a promotes fluid influx in the deeper lens cortex, whereas Aqp0b facilitates fluid efflux. This evidence reveals previously unidentified spatial regulation of macromolecular crowding and spatially distinct roles for Aqp0 in the lens.

Bioactive lipid: A novel diagnostic approach for retinoblastoma in clinical management

Bioactive lipids, presumably lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), play a critical role in regulating an array of cellular functions ranging from cellular fate determination, inflammation, immunity, and cancer. Epidemiological evidence suggests that both the metabolites play a prominent role in the development and progression of oncogenic phenotype in a variety of cancers including breast, colorectal, pancreatic, and lymphoma. Previous studies have demonstrated the possible association of LPA, S1P and their receptor in regulating the pathogenesis of retinoblastoma, however, the exact mechanism involved in this event has not been studied in detail. Importantly, understating the mechanistic basis of LPA and S1P regulation is of utmost significance, as far the phenotypical complexity of retinoblastoma (RB) is concerned. Findings from the recent investigations elucidate the prospective role of S1P in provoking the chemoresistant behavior of RB cells for etoposide. In this context, the current paper will enable the identification of novel diagnostic biomarkers and therapeutic targets for better treatment and clinical efficacy in children with RB.

Arsenene-mediated multiple independently targeted reactive oxygen species burst for cancer therapy

The modulation of intracellular reactive oxygen species (ROS) levels is crucial for cellular homeostasis and determination of cellular fate. A sublethal level of ROS sustains cell proliferation, differentiation and promotes tumor metastasis, while a drastic ROS burst directly induces apoptosis. Herein, surface-oxidized arsenene nanosheets (As/AsxOy NSs) with type II heterojunction are fabricated with efficient ·O2− and 1O2 production and glutathione consumption through prolonging the lifetime of photo-excited electron-hole pairs. Moreover, the portion of AsxOy with oxygen vacancies not only catalyzes a Fenton-like reaction, generating ·OH and O2 from H2O2, but also inactivates main anti-oxidants to cut off the “retreat routes” of ROS. After polydopamine (PDA) and cancer cell membrane (M) coating, the engineered As/AsxOy@PDA@M NSs serve as an intelligent theranostic platform with active tumor targeting and long-term blood circulation. Given its narrow-band-gap-enabled in vivo fluorescence imaging properties, As/AsxOy@PDA@M NSs could be applied as an imaging-guided non-invasive and real-time nanomedicine for cancer therapy.

The role of transthyretin in cell biology: impact on human pathophysiology.

Transthyretin (TTR) is an extracellular protein mainly produced in the liver and choroid plexus, with a well-stablished role in the transport of thyroxin and retinol throughout the body and brain. TTR is prone to aggregation, as both wild-type and mutated forms of the protein can lead to the accumulation of amyloid deposits, resulting in a disease called TTR amyloidosis. Recently, novel activities for TTR in cell biology have emerged, ranging from neuronal health preservation in both central and peripheral nervous systems, to cellular fate determination, regulation of proliferation and metabolism. Here, we review the novel literature regarding TTR new cellular effects. We pinpoint TTR as major player on brain health and nerve biology, activities that might impact on nervous systems pathologies, and assign a new link between TTR and angiogenesis and cancer. We also explore the molecular mechanisms underlying TTR activities at the cellular level, and suggest that these might go beyond its most acknowledged carrier functions and include interaction with receptors and activation of intracellular signaling pathways.

Approaches to characterize the transcriptional trajectory of human myogenesis.

Human pluripotent stem cells (hPSCs) have attracted considerable interest in understanding the cellular fate determination processes and modeling a number of intractable diseases. In vitro generation of skeletal muscle tissues using hPSCs provides an essential model to identify the molecular functions and gene regulatory networks controlling the differentiation of skeletal muscle progenitor cells. Such a genetic roadmap is not only beneficial to understanding human myogenesis but also to decipher the molecular pathology of many skeletal muscle diseases. The combination of established human in vitro myogenesis protocols and newly developed molecular profiling techniques offers extensive insight into the molecular signatures for the development of normal and disease human skeletal muscle tissues. In this review, we provide a comprehensive overview of the current progress of in vitro skeletal muscle generation from hPSCs and relevant examples of the transcriptional landscape and disease-related transcriptional aberrations involving signaling pathways during the development of skeletal muscle cells.

Cannabinoid Type 1 Receptor is Undetectable in Rodent and Primate Cerebral Neural Stem Cells but Participates in Radial Neuronal Migration.

Cannabinoid type 1 receptor (CB1R) is expressed and participates in several aspects of cerebral cortex embryonic development as demonstrated with whole-transcriptome mRNA sequencing and other contemporary methods. However, the cellular location of CB1R, which helps to specify molecular mechanisms, remains to be documented. Using three-dimensional (3D) electron microscopic reconstruction, we examined CB1R immunolabeling in proliferating neural stem cells (NSCs) and migrating neurons in the embryonic mouse (Mus musculus) and rhesus macaque (Macaca mulatta) cerebral cortex. We found that the mitotic and postmitotic ventricular and subventricular zone (VZ and SVZ) cells are immunonegative in both species while radially migrating neurons in the intermediate zone (IZ) and cortical plate (CP) contain CB1R-positive intracellular vesicles. CB1R immunolabeling was more numerous and more extensive in monkeys compared to mice. In CB1R-knock out mice, projection neurons in the IZ show migration abnormalities such as an increased number of lateral processes. Thus, in radially migrating neurons CB1R provides a molecular substrate for the regulation of cell movement. Undetectable level of CB1R in VZ/SVZ cells indicates that previously suggested direct CB1R-transmitted regulation of cellular proliferation and fate determination demands rigorous re-examination. More abundant CB1R expression in monkey compared to mouse suggests that therapeutic or recreational cannabis use may be more distressing for immature primate neurons than inferred from experiments with rodents.

Untangling early embryo development using single cell genomics

The zygote undergoes five cell divisions prior to the first signs of lineage segregation. Blastocyst formation requires segregation of the trophectoderm, needed for implantation, and the inner cell mass, which differentiate towards the major lineages of the fetus. This process is broadly conserved in mammals, however, in recent years investigations using high throughput single cell transcriptomics have provided new insights on the gene regulatory networks and epigenetic mechanisms controlling these processes in different species, highlighting novel unique evolutionary adaptations. Although analysis of single cell datasets is inherently challenging due to stochastic gene expression in single cells, continuous development of novel computational tools have contributed to improving the quality of these datasets. Single cell -omics provides detailed information on discrete cellular states, and when combined with spatial transcriptomics it can inform on the relationship between cellular compartments and fate determination. This technology has recently been used to shed new light into the progression of lineage segregation, establishment of pluripotency, epigenetic regulation and signalling pathways participating in mammalian pre-gastrulation development. The adoption of these new technologies for generating high-resolution maps of embryogenesis will readily translate into biotechnological applications that will have significant impact in livestock production.

Inhibition of the lncRNA SAF drives activation of apoptotic effector caspases in HIV-1–infected human macrophages

Long noncoding RNAs (lncRNAs) impart significant regulatory functions in a diverse array of biological pathways and manipulation of these RNAs provides an important avenue to modulate such pathways, particularly in disease. Our knowledge about lncRNAs' role in determination of cellular fate during HIV-1 infection remains sparse. Here, we have identified the impact of the lncRNA SAF in regulating apoptotic effector caspases in macrophages, a long-lived cellular reservoir of HIV-1, that are largely immune to virus-induced cell death. Expression of SAF is significantly up-regulated in HIV-1-infected human monocyte-derived macrophages (MDM) compared with bystander and virus-nonexposed cells. A similar enhancement in SAF RNA expression is also detected in the HIV-1-infected airway macrophages obtained by bronchoalveolar lavage of HIV-1-infected individuals. Down-regulation of SAF with siRNA treatment increases caspase-3/7 activity levels in virus-infected MDMs. This induction of apoptotic caspases occurs exclusively in HIV-1-infected macrophages and not in bystander cells, leading to a significant reduction in HIV-1 replication and overall viral burden in the macrophage culture. This study identifies targeting of the lncRNA SAF as a potential means to specifically induce cell death in HIV-1-infected macrophages.

A Review on the Genetic Regulation of Myogenesis and Muscle Development

Myogenesis of muscle tissues is known as a very complex and delicate process including many cellular differentiation and development events in animals. Here, the courses of cellular fate determination and terminal differentiation of muscle cells are systematically elaborated and the genetic regulatory network of muscle genesis is well conceived in animal organic growth and development through literature retrieval. Furthermore, the principal roles of myogenic regulatory factors, Myostatin, fibroblast growth factor, insulin-like growth factor and other muscular regulatory factors interrelated and reported in the myogenesis relevant studies are also reviewed. In addition, the interactions of these muscular specific factors and their possible relevant regulative pathways and interactions among them are included and developed too.

How can a binary switch within the pars tuberalis control seasonal timing of reproduction?

Life in seasonally changing environments is challenging. Biological systems have to not only respond directly to the environment, but also schedule life history events in anticipation of seasonal changes. The cellular and molecular basis of how these events are scheduled is unknown. Cellular decision-making processes in response to signals above certain thresholds regularly occur i.e. cellular fate determination, apoptosis and firing of action potentials. Binary switches, the result of cellular decision-making processes, are defined as a change in phenotype between two stable states. A recent study presents evidence of a binary switch operating in the pars tuberalis (PT) of the pituitary, seemingly timing seasonal reproduction in sheep. Though, how a binary switch would allow for anticipation of seasonal environmental changes, not just direct responsiveness, is unclear. The purpose of this review is to assess the evidence for a binary switching mechanism timing seasonal reproduction and to hypothesize how a binary switch would allow biological processes to be timed over weeks to years. I draw parallels with mechanisms used in development, cell fate determination and seasonal timing in plants. I propose that the adult PT is a plastic tissue, showing a seasonal cycle of cellular differentiation, and that the underlying processes are likely to be epigenetic. Therefore, considering the mechanisms behind adult cellular plasticity offers a framework to hypothesize how a long-term timer functions within the PT.

Mitochondrial respiratory dysfunction disturbs neuronal and cardiac lineage commitment of human iPSCs

Mitochondrial diseases are genetically heterogeneous and present a broad clinical spectrum among patients; in most cases, genetic determinants of mitochondrial diseases are heteroplasmic mitochondrial DNA (mtDNA) mutations. However, it is uncertain whether and how heteroplasmic mtDNA mutations affect particular cellular fate-determination processes, which are closely associated with the cell-type-specific pathophysiology of mitochondrial diseases. In this study, we established two isogenic induced pluripotent stem cell (iPSC) lines each carrying different proportions of a heteroplasmic m.3243A>G mutation from the same patient; one exhibited apparently normal and the other showed most likely impaired mitochondrial respiratory function. Low proportions of m.3243A>G exhibited no apparent molecular pathogenic influence on directed differentiation into neurons and cardiomyocytes, whereas high proportions of m.3243A>G showed both induced neuronal cell death and inhibited cardiac lineage commitment. Such neuronal and cardiac maturation defects were also confirmed using another patient-derived iPSC line carrying quite high proportion of m.3243A>G. In conclusion, mitochondrial respiratory dysfunction strongly inhibits maturation and survival of iPSC-derived neurons and cardiomyocytes; our presenting data also suggest that appropriate mitochondrial maturation actually contributes to cellular fate-determination processes during development.

Molecular Interactions of lncRNAs: Cellular Fate Determination and Tissue Regeneration

LncRNAs (long non-coding RNAs) are responsible to control the degradation process, RNA stability, orchestration, inhibition, transcription and histone modification etc. These RNAs have been termed as the key agents of several mechanisms such as development, organogenesis and regeneration of damaged tissues etc. They interact with a number of partner molecules either protein, RNAs or DNAs and control the cellular behaviour while differentiation or maintaining the stem cell status. This editorial is discussing the significance of lncRNAs as therapeutic target in stem cell therapy field.

USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder

Endosomal protein recycling is a fundamental cellular process important for cellular homeostasis, signaling, and fate determination that is implicated in several diseases. WASH is an actin-nucleating protein essential for this process, and its activity is controlled through K63-linked ubiquitination by the MAGE-L2-TRIM27 ubiquitin ligase. Here, we show that the USP7 deubiquitinating enzyme is an integral component of the MAGE-L2-TRIM27 ligase and is essential for WASH-mediated endosomal actin assembly and protein recycling. Mechanistically, USP7 acts as a molecular rheostat to precisely fine-tune endosomal F-actin levels bycounteracting TRIM27 auto-ubiquitination/degradation and preventing overactivation of WASH through directly deubiquitinating it. Importantly, we identify de novo heterozygous loss-of-function mutations of USP7 in individuals with a neurodevelopmental disorder, featuring intellectual disability and autism spectrum disorder. These results provide unanticipated insights into endosomal trafficking, illuminate the cooperativity between an ubiquitin ligase and a deubiquitinating enzyme, and establish a role for USP7 in human neurodevelopmental disease.