Biology and Life Sciences

Abstract: Gametes from several animal groups lend themselves to laboratory studies, both due to their large numbers and the ease of collection. But when it comes to some aspects of fertilization studies, care must be taken to adhere to natural conditions and not to create artifactual conditions. One such requisite is the study of the kinetics of sperm-oocyte interactions. For over 100 years scientists have arbitrarily chosen sperm-oocyte ratios in the laboratory, without considering natural conditions and in the process have created perhaps one of the greatest dogma in fertilization studies, the existence of polyspermy preventing mechanisms. The first consideration to be made when contemplating whether oocytes have evolved mechanisms to allow one spermatozoon to enter while repelling all others is to study sperm- oocyte ratios at the site of natural fertilization. High ratios may have favoured an evolutionary process by which oocytes established polyspermy preventing mechanisms, low ratios would suggest polyspermy blocks are not necessary. That oocytes change morphologically and physiologically at activation is the subject of innumerable publications, but, whether these activation events have evolved to block the entry of supernumerary spermatozoa, or are merely part and parcel of changing the inert oocyte into the dynamic zygote, is pure conjecture. Two animal groups that are amenable to laboratory experimentation, the mammals and the sea urchins, have been the focal point for the study of fertilization for several decades. Mishandling the gametes from these animals in the laboratory have led to the idea that oocytes possess mechanisms to block polyspermy and this idea was then promulgated across the animal kingdom. In this review, I will first look at the sperm-oocyte ratios at the natural site of fertilization in mammals and sea urchins and then describe and criticise the laboratory experiments that led to idea of polyspermy blocks. Finally, I will prevent an overview of sperm-oocyte interaction across the phyla identifying strategies that assure monospermy.

Abstract: Background/Objectives: Though PARP inhibition has improved the management of advanced prostate cancer, patient outcomes may be modest and progression on treatment is common. We sought to improve understanding of tumor cell response to PARP inhibition to support development of novel strategies to enhance and/or prolong PARP inhibitor (PARPi) efficacy. Methods: Cell viability assays and microscopy were used for initial characterization of PARPi response in models of advanced prostate cancer. RNA-sequencing was performed to investigate time-dependent transcriptomic changes induced by PARP inhibition. Western blots, flow cytometry, and both additional viability assays and microscopy were used to validate RNA-sequencing results and test potential therapeutic strategies. Results: Characterization of response to PARP inhibition reveals time-dependent changes which may be targeted to improve treatment efficacy. In line with expected PARPi mechanism of action, short-term treatment is largely associated with activation of ATM and the DNA damage response and cell cycle checkpoint signaling. Targeting ATM with clinical stage inhibitors significantly enhances reduction of tumor cell viability by PARP inhibition. Tumor cells exposed to longer-term treatment exhibit slug-dependent epithelial-mesenchymal transition (EMT) and evidence for altered fatty acid metabolism, both of which may be targeted to enhance PARPi anti-tumor cell effects. Conclusions: This study provides insight into both short and longer-term cellular response to PARPi treatment and provides a foundation for additional efforts to explore effective strategies to maximize the utility of PARP inhibition for managing prostate cancer.

Abstract: Warfarin is a coumarin-derived oral anticoagulant widely used for the prevention and treatment of thromboembolic disorders, particularly in patients with mechanical heart valves. The drug exerts its anticoagulant effect by inhibiting vitamin K epoxide reductase, thereby impairing γ-carboxylation of vitamin K–dependent coagulation factors. Despite its clinical efficacy, warfarin therapy is associated with a narrow therapeutic index, substantial interindividual variability in dose response, numerous drug interactions, and significant hemorrhagic risk. Maternal warfarin therapy during pregnancy is strongly associated with fetal warfarin syndrome (FWS), a characteristic pattern of embryopathy resulting from in utero exposure to the drug. This review summarizes current knowledge regarding the physicochemical properties, pharmacological mechanisms, dose variability, toxicity, and developmental effects associated with warfarin exposure. Evidence from human clinical studies and vertebrate animal models is discussed to elucidate conserved developmental and molecular mechanisms underlying warfarin teratogenicity. The review also examines signaling pathways disrupted by warfarin exposure that are involved in bone morphogenesis, vascular homeostasis, and tissue mineralization, contributing to the observed phenotypes. Collectively, this review integrates clinical, molecular, and experimental findings to provide a comprehensive understanding of warfarin-induced developmental toxicity. Current knowledge is insufficient to fully elucidate the complex mechanisms underlying warfarin-induced embryopathy and fetal toxicity. Further investigations are warranted to identify safer anticoagulant regimens during pregnancy and to inform the development of novel therapeutic strategies that minimize fetal risk while maintaining maternal anticoagulation.

Abstract: Calpains constitute an ancient, extensive family of calcium-dependent cysteine proteases found in some bacteria and most eukaryotes. They are involved in a wide variety of developmental and cellular processes and are implicated in major human diseases, but whether they share an ancestral or broadly conserved cellular role remains unclear. Beyond their core CysPc catalytic domain, calpains contain diverse domain combinations and can be either cytosolic or membrane bound. Here, we develop the hypothesis that both cytosolic and transmembrane calpains may contribute to cytokinesis through positional anchoring and organization of microtubules (MTs). We propose that during plant cell division, the singular transmembrane calpain DEK1 play a role in localizing and organizing the array of cortical MTs from the microtubule organizing center (MTOC) and may thereby position the cell division plane, potentially affecting preprophase band placement and subsequent cell plate formation. Similarly, during cell division in animals, their cytosolic calpains may be involved in setting the point of membrane invagination via their association with membrane-bound proteins. We discuss this novel model for calpain activity in the context of data from the animal and plant literature, as well as of our discovery of putative calpain sequences in both brown and red algal genomes. These findings are consistent with the view that calpains were present early in eukaryotic evolution and diversified alongside distinct modes of cell division. Finally, we consider the possibility that early calpain functions may have been linked to the formation and function of MT arrays in flagella and cilia, from which later roles in cytokinesis might have evolved. This model is intended as a testable framework for future studies of calpain function across eukaryotes.

Abstract: Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by excessive trabeculation and deep intertrabecular recesses, yet its molecular mechanisms remain poorly understood. Here, we identify Bcl11b as a novel regulator of cardiomyocyte (CM) growth and ventricular wall maturation. CM-specific deletion of Bcl11b in mice recapitulates key LVNC features, including increased noncompact-ed-to-compacted ratio, impaired compact layer expansion, reduced CM proliferation and size, and systolic dysfunction. Mechanistically, Bcl11b deficiency leads to marked upregulation of Pou3f2, a transcriptional repressor that further suppresses Titin (TTN) expression. Loss of Bcl11b disrupts sarcomere integrity and reduces TTN protein levels, while forced Pou3f2 overexpression similarly represses TTN. Notably, heterozygous loss of Pou3f2 rescues the LVNC phenotype in Bcl11b-deficient hearts, restoring CM growth and TTN expression. Our findings establish a critical relationship among Bcl11b, Pou3f2 and TTN that governs CM proliferation and hypertrophic maturation during cardiac development. Dysregulation of this regulatory network impairs ventricular compaction and contributes to the development of LVNC, providing new insights into disease pathogenesis and potential therapeutic targets.

Abstract: Skeletal muscle is increasingly recognized as a dynamic secretory organ capable of translating contractile, metabolic, mechanical and inflammatory stimuli into systemic biological signals. Among these signals, myokines and myokine-associated exerkines mediate communication between skeletal muscle and distant organs, influencing glucose and lipid metabolism, immune regulation, bone remodeling, neuroplasticity, vascular function and tissue regeneration. However, current evidence remains fragmented across individual molecules, exercise modalities, sampling windows, assay platforms and disease contexts. This narrative mechanistic review proposes the concept of the “myokine adaptome” as an integrated, context-dependent signaling network through which skeletal muscle contributes to systemic homeostasis in health and disease. We synthesize evidence on cellular triggers of myokine release, including AMPK-PGC-1α signaling, mTORC1-dependent mechanical sensing, calcium flux, redox signaling, inflammatory pathways and extracellular vesicle-mediated communication. We further examine how exercise modality, aging, obesity, type 2 diabetes, sarcopenia, osteoporosis, cardiovascular disease, COPD, cancer/cachexia and chronic inflammation reshape myokine production and target-organ responsiveness. The central argument is that myokine biology should be interpreted not as a catalogue of isolated mediators, but as a dynamic adaptive code defined by signal amplitude, temporal pattern, molecular composition, delivery route and recipient-tissue sensitivity. This framework may improve biomarker design, disease-specific exercise prescription and therapeutic strategies aimed at restoring adaptive muscle-organ communication. The framework is further strengthened by testable predictions concerning adaptive pulsatility, modality-specific signatures, source attribution, recovery quality, disease-specific decoding and the superiority of multi-marker panels over single-molecule readouts.

Abstract: The developmental basis of retroperitoneal fascial lamination remains unresolved, as classical peritoneal fusion theories cannot fully explain the consistent formation of anterior and posterior renal fasciae or their behavior in congenital renal absence. To clarify the underlying mechanobiology, we conducted a retrospective radiological analysis of unenhanced CT scans, including a rare case of unilateral renal agenesis, and interpreted fascial configurations within a framework incorporating tension‑driven lamination, orthogonal Poisson compression, and subtraction‑based reasoning. Across all cases, a continuous fascial plane was unmistakably preserved at the expected location of the retrorenal fascia despite lifelong absence of the kidney, while the renal‑vacant side consistently exhibited reduced total fascial thickness (mean 1.52 mm vs. 1.85 mm). This asymmetric thinning aligns with selective absence of the organ‑dependent inner lamina and preservation of a system‑derived outer lamina formed through mid‑gestational tension fields. These findings support a mechanobiological model in which retroperitoneal fascial lamination emerges from the interplay of geometric scaling, skeletal stiffening, and Poisson‑driven mesenchymal compression, challenging fusion‑based interpretations and providing a unified framework for understanding multilayered fascia formation.

Abstract:

Leukocyte recruitment from blood into tissues involves sequential adhesive steps, including rolling and integrin-dependent arrest. VLA-4 can support firm adhesion and, in some settings, rolling interactions, whereas CD44–hyaluronan interactions have also been implicated in leukocyte rolling. Here, we used adhesion assays and parallel-plate flow chamber experiments to analyze CD44–hyaluronan-dependent monocyte interactions on ECV304 monolayers and to compare them with α4-integrin-sensitive adhesion on endothelial monolayers. WEHI 78/24 monocytoid cells interacted with ECV304 monolayers in a CD44- and hyaluronan-dependent manner, whereas adhesion to HMEC-1 and bEnd.3 monolayers was sensitive to α4-integrin blockade. Blocking CD44, adding soluble hyaluronan, or treating ECV304 monolayers with hyaluronidase reduced adhesion and rolling. Mixed primary human monocyte preparations also showed CD44-dependent adhesion and rolling on ECV304 monolayers. ECV304 cells are interpreted here not as endothelial cells, but as T24-derived, hyaluronidase-sensitive cellular monolayers useful for functional analysis of CD44–hyaluronan-dependent interactions. These findings support a substrate-dependent functional hierarchy in which CD44–hyaluronan-dependent monocyte rolling becomes detectable when α4-integrin-dependent adhesion is not dominant, while emphasizing the cell-model-based nature of the assay.

Abstract: Foreign DNA poses a great threat to living organisms, as it can deteriorate normal cellular functions or mutate genomic sequence, consequently leading to serious health issues such as oncological conditions. About 10% of all human disorders are caused by such foreign/invader pathogenic DNAs. However, a recent study has identified a remarkable cytoplasmic strategy in eukaryotes by which organisms may deal with and get rid of such extrachromosomal DNA (ecDNA). The strategy involves the formation of a double membrane-bound novel structure in the cytoplasm called "Exclusome", that identifies and incarcerates ecDNA. Previously, the eukaryotic cells were only characterized for having their genome enclosed within the nucleus, along with certain genes carried by mitochondria and plastids. However, the discovery of an exclusome (that confines DNA fragments), has remarkably added one more name to the list of DNA-containing organelles. Exclusome is a double membrane-bound, round, spherical-shaped organelle that targets and encapsulates the ecDNA within the cytoplasm of the eukaryotic cell. The double membrane barrier of exclusome and its composition is reminiscent of the nucleus, but it lacks nuclear pore complexes (NPCs), thus averting the potential interference of confined ecDNA with the fundamental cellular functions to preserve genetic integrity. This review presents the multifaceted aspects of this newly discovered "Exclusome", elucidating its morphology and composition with a comprehensive scrutiny of the assembly mechanism and its implications in cellular defense and disease prevention.

Abstract: The Drosophila midgut serves as a powerful model system for studying the mechanisms under-lying stem cell hyperproliferation during aging and tissue regeneration. Two distinct pathways, the nutrient-sensing Insulin signaling axis and the growth-regulating Hippo pathway, are known to mediate intestinal stem cell (ISC) hyperproliferation in response to stress; however, the coor-dination between these two pathways remains unclear. Here, we show that Homeodo-main-interacting protein kinase (Hipk), recently identified as a nutrient transducer in progenitors, links Insulin signaling to Yorkie (Yki) activation in progenitor cells. Progeni-tor-specific hipk knockdown or knockout abolished gut hyperplasia induced by aging, dextran sulfate sodium (DSS)-mediated injury, and Yki overexpression. Mechanistically, Hipk promotes Yki protein stability and nuclear accumulation in progenitors. This regulation is specific to wild-type Yki, as the constitutively active Yki^S168A mutant, which escapes Warts-mediated inhi-bition, is insensitive to Hipk depletion. Together, these findings identify Hipk as an integrator that couples Insulin signaling to the Hippo pathway to drive stress-induced ISC hyperprolifera-tion and intestinal regeneration.

Abstract: m⁶A is a ubiquitous reversible post-transcriptional RNA methylation modification in eukaryotic cells, which has been positive effect on regulating follicles development in animals. However, the role of m⁶A modification profiling in regulating the development of healthy and atresia small yellow follicle have not yet been studied in poultry. In this study, we conducted a comparative analysis of the m⁶A methylation profiles of healthy and atresia follicles Zi goose during the period of peak egg-laying. Here, we discovered that 23,342 and 25,552 m⁶A peak between healthy small yellow follicles group (HSYF) and atresia small yellow follicle groups (ASYF), which were mainly enriched in 3'-UTR and stop codon regions. We found that 1174 differential upregulated peaks and 1250 differential downregulated peaks were identified in ASYF group, these differential peaks were covered 1141 and 1233 genes, including METTL14, WTAP, IGF2BP3 and CYTB. Motif analysis demonstrated that these m⁶A peaks exhibit the RRACH and DRACH conserved consensus sequence. Importantly, Zi goose follice transcriptome was extensively methylated and a positive correlation between the m⁶A peak and gene expression levels. The combined analysis of MeRIP-seq and RNA-seq revealed that a total of 78 DMGs were shared in HSYF and ASYF groups, such as BMP5, PPARGC1A, NGF, SCD5, which were mainly involved in TGFβ signaling pathway, MAPK signaling pathway, PPAR signaling pathway and ECM receptor interaction. Furthermore, METTL14 plays a regulatory role in Zi goose granulosa cell development, which was verified by in vitro experiments. We found that knockdown of METTL14 dramatically prevented GCs apoptosis, promoted GCs proliferation, increased the production and secretion of steriod hormone, enhanced the expression levels of genes related to steroid hormone synthesis in granulosa cell. Conversely, overexpression of METTL14 resulted in opposite outcomes. Additionally, we also observed that knockdown of METTL14 increased the activities of antioxidant enzyme (SOD, GSH and CAT), decreased the activities of MDA in goose GCs. Conversely, overexpression of METTL14 inhibited the activities of antioxidant enzymes, increased the activities of MDA. In summary, these data collectively demonstrated that m⁶A methylation was widely distributed in the process of geese follicle growth and development, and futher confirm the significant role of METTL14 influences on granulosa cell development of Zi geese. These findings can be a considerable efficient way to faciliate the laying egg performance of Zi goose through molecular marker assisted breeding technology.

Abstract: Discoidin domain receptor 1 (DDR1) has been implicated in fibrotic progression in multiple organs, including the kidney; however, its role in regulating cytoskeletal organization and matrix remodeling in renal fibroblasts remains unclear. Here, we investigated how DDR1 expression is regulated by profibrotic stimulation and extracellular matrix stiffness, and how DDR1 influences cytoskeletal organization and collagen remodeling. Single-cell RNA sequencing of murine kidneys subjected to unilateral ureteral obstruction (UUO) revealed enrichment of Ddr1 expression in transitional fibroblast populations during early activation. In vitro, transforming growth factor-β1 (TGF-β1) increased DDR1 expression, but DDR1 depletion did not affect canonical myofibroblast marker expression. Instead, DDR1 depletion suppressed stress fiber assembly while promoting actin-rich podosome formation associated with matrix degradation. Functionally, DDR1-deficient cells exhibited impaired focal adhesion maturation, enhanced collagen degradation, reduced gel contraction, and decreased collagen matrix stiffness as measured by atomic force microscopy. Furthermore, extracellular matrix stiffness dynamically regulated DDR1 expression, suggesting a bidirectional relationship between DDR1 expression and matrix mechanics. Together, these findings identify DDR1 as a modulator of cytoskeletal remodeling that governs the balance between matrix-degradative and contractile remodeling programs in renal fibroblasts.

Abstract: The Developmental Origins of Health and Disease framework proposes that environmental exposures during critical periods of development can shape physiological systems and influence the risk of chronic diseases later in life, including diabetes and metabolic syndrome. Most research on metabolic programming has focused on classical metabolic organs such as the liver, pancreas, and adipose tissue. However, skeletal muscle plays a central role in systemic glucose homeostasis and metabolic flexibility, accounting for the majority of insulin-stimulated glucose uptake in the body. Because muscle metabolism is closely regulated by neural activity through the organization of motor units, the development of the motor neuromuscular axis may represent an underexplored dimension of metabolic programming. This review examines evidence linking early-life metabolic environments to neuromuscular development and discusses how alterations in the maturation of motor neurons, neuromuscular junctions, and muscle fiber phenotype may influence long-term metabolic outcomes. Evidence from epidemiological studies, experimental models, and mechanistic research suggests that maternal metabolic disturbances, including hyperglycemia, obesity, and systemic inflammation, can influence fetal development through metabolic and inflammatory pathways affecting both neural and muscular components of the motor system. These findings support the hypothesis that the motor neuromuscular axis may represent a structural interface linking early developmental exposures to long-term metabolic regulation and risk of metabolic syndrome.

Abstract: Extracellular lipid-containing particles are usually interpreted as extracellular vesicles, lipoproteins, soluble lipid mediators, or carriers of molecular cargo. This article proposes the lipid-state exchange hypothesis (LSE), a falsifiable framework in which cellular or tissue lipid states can be externalized, partially retained, remodeled by biological fluids, and sampled by target cells or clearance systems as functional state inputs. LSE reframes lipid state as a causal variable in extracellular particle biology, linking lipid composition, interfacial organization, carrier presentation, and fluid-phase identity to biological function.LSE is developed in weak, intermediate, and strong forms. Weak LSE places lipid-state function within known extracellular vesicle and lipoprotein biology. Intermediate LSE emphasizes that carrier form, interfacial presentation, and fluid-phase identity can reshape lipid function. Strong LSE predicts a lipid-state-dependent functional layer beyond established extracellular particle classes and cargo-centered mechanisms.The key empirical prediction of strong LSE is the existence of non-classical lipid-state exchange particles (non-classical LSEPs). Operationally, these candidates are expected to appear as extracellular lipid-dominant particle-like or complex-like components with low canonical extracellular-vesicle and classical apolipoprotein markers. Functionally, they are defined by source-state association, lipid-state-dependent activity, and positive causal residuality when conventional particle-, cargo-, and artifact-based frameworks cannot sufficiently explain their effects. Thus, non-classical LSEPs are not proposed as a marker-defined particle class, but as a lipid-state-dominant functional entity.At a broader level, LSE shifts extracellular lipid biology from particle identity and cargo attribution to state causality. It opens a conceptual space in which membrane-derived lipid organization itself may act as a transferable, fluid-edited, and biologically sampleable state-bearing interface for homeostatic regulation, injury interpretation, and disease-relevant extracellular communication.

Abstract: While the pathological impact of reactive oxygen species (ROS) in the aetiology of human infertility has received much attention, this review explores the counterproposal that these highly reactive metabolites play an essential role in mediating reproductive success. The physiological importance of ROS in biological systems can be distilled into three main categories of influence: (1) ROS can oxidize thiols to generate either the corresponding sulfenic acid or disulfide bridges. This oxidizing capacity is critical for several reproductive processes including the cross linking of sperm chromatin during epididymal maturation, formation of the mitochondrial sheath, and the activation of proteolytic zymogens involved in such processes as ovulation, menstruation, implantation and parturition. Thiol oxidation is also involved in the suppression of phosphatase activity and the resulting promotion of phosphorylation-dependent signal transduction pathways, that are involved in virtually every aspect of reproduction from sperm capacitation to parturition; (2) The destructive properties of ROS are also biologically significant in the defence against genital tract infections and in mediating such processes as autophagy, apoptosis and ferroptosis, which are fundamental to the reproductive process; (3) Finally, ROS are involved in controlling the redox status of transition metals (particularly iron and copper) in the active site of many enzymes that are of fundamental importance to reproduction. Given the biological importance of ROS to procreation, we should use antioxidants with care in managing both male and female infertility and avoid the induction of reductive stress.

Abstract: Taste buds are continuously renewed sensory organs in which development, adult maintenance, and repair share overlapping molecular circuitry. During embryogenesis, WNT/β-catenin signaling promotes taste placode formation and placodal Shh expression, whereas SHH refines papilla spacing and restricts neighboring papilla formation. SOX2 functions as a taste-competence and progenitor-maintenance factor. In adults, LGR5/LGR6-RSPO-WNT signaling sustains progenitor activity, and gustatory neurons provide RSPO2 as a niche signal that maintains epithelial renewal. HH signaling from epithelial and neuronal sources further supports SOX2-dependent progenitor homeostasis. Lineage allocation is controlled by transcriptional programs that include POU2F3/SKN-1a for sweet, umami, and bitter type II taste receptor cells and ASCL1 with posterior-field NKX2-2 for type III presynaptic/sour cells. After denervation or irradiation, regeneration depends primarily on LGR5+/KRT14+ progenitors and may be supplemented, in specific injury contexts, by plasticity of a subset of K8-lineage taste receptor cells that acquire KRT14/SOX2/PCNA progenitor-like features. Key unresolved issues include the direct chromatin targets of taste lineage regulators (which remain to be defined by ChIP-seq in native taste progenitors), the identity of the type I cell selector, the contribution of dedifferentiation across injury models, and the extent to which mouse-derived networks are conserved in human taste biology.

Abstract: Mid-stage embryos of different species often look more alike than early embryos or adults. Early and late development diverge, leading to a broad-narrow-broad hourglass pattern. I propose that mid-embryogenesis coincides with protocol waists, narrow interfaces that standardize communication between otherwise distinct processes. For example, continuous spatial geometry is translated into a morphogen gradient protocol readable by gene regulatory networks. This architecture arises because the physical space-time geometry of early development cannot directly instruct late gene regulatory programs. They require a translator. The need for domain translation distinguishes protocols from generic canalization and bottlenecks. Translation protocols explain the hourglass: a protocol screens off upstream inputs, allowing early diversification, and decouples downstream responses, enabling late radiation. A protocol waist often remains evolutionarily frozen as the essential common language that keeps these diverging halves compatible. Perturbations of protocol waists tend to cause widespread system failure, concentrating fragility. Protocol waists provide a framework to interpret domain translators, such as morphogen gradients for geometry-to-molecules, Notch/Delta lateral inhibition for topology-to-fates, the vertebrate segmentation clock for time-to-space, and Hox axial patterning for position-to-identity. Sequential domain translators form a protocol stack, matching the common architecture of robust complex systems in engineering.

Abstract: Human language continuously generates patterned mechanical vibrations, yet the cellular consequences of such structured sound remain largely unexplored. Here, we investigate whether acoustic vibration with different degrees of temporal and spectral organization modulates actin cable architecture and polarity in the non auditory eukaryote Saccharomyces cerevisiae. Using a direct contact stimulation setup, yeast cells expressing ABP140- GFP were exposed to sustained tonal sound, broadband white noise, or brief consonant like acoustic bursts designed to isolate speech relevant temporal structures without semantic content. Sustained tonal stimulation, characterized by rhythmic continuity and harmonic coherence similar to vowel like components of speech, increased ABP140- GFP signal intensity,actin branching and actin length and significantly enhanced shmoo formation. In contrast, broadband noise disrupted actin organization and suppressed shmooing, while transient consonant like bursts produced no measurable structural effects. These results indicate that language related acoustic structure, specifically sustained and coherent mechanical vibration, can modulate cytoskeletal organization in yeast, supporting the view of sound and speech as biologically active mechanical inputs rather than purely communicative signals.

Abstract: The retina and optic nerve rely on a tightly regulated neurovascular unit that sustains the highly dynamic and metabolically demanding neural tissues required for vision. Adequate oxygen and nutrient delivery are essential for maintaining tissue function and cellular survival. Over the past decades, extensive research within and beyond the field of ophthalmology has sought to elucidate the mechanisms that govern neurovascular regulation in health and disease. Growing evidence indicates that neurovascular dysfunction plays an important role in both the initiation and progression of glaucoma, a leading cause of irreversible blindness worldwide. Alterations in vascular architecture and blood flow may compromise the metabolic support required by retinal ganglion cells, increasing their vulnerability to injury and degeneration. While neurons possess limited regenerative capacity, the vascular system retains a remarkable degree of plasticity and is therefore amenable to repair. This vascular plasticity presents an opportunity to develop therapeutic strategies aimed at restoring vascular architecture and improving blood flow, complementing existing approaches focused on intraocular pressure reduction, neuroprotection, axonal regeneration, and/or neuronal transplantation. In this review, we summarize the current understanding of neurovascular function in the healthy eye, discuss mechanisms that contribute to vascular compromise in glaucoma, and highlight emerging avenues for promoting vascular regeneration and blood flow recovery. By identifying key knowledge gaps and future research priorities, we aim to outline promising directions for targeting the ocular neurovasculature to preserve retinal ganglion cell function and slow or stop progressive vision loss.

Abstract:

Background: Mesangiogenic Progenitor cells (MPCs) were first described in 2008 in cultures of human bone marrow mononuclear cells (hBM-MNCs) aimed at isolating mesenchymal stromal cells (MSCs) using human autologous serum. A selective culture method was subsequently developed to isolate MPCs with a high degree of purity, yielding approximately 1% of the total plated cells. Since their initial description, MPCs have demonstrated the ability to differentiate into highly clonogenic MSCs while retaining early vasculogenic potential. Gene expression profiling of MPCs revealed constitutive expression of pluripotency-associated transcription factors such as OCT-4 and NANOG, as well as SOX15 instead of SOX2, suggesting a possible molecular mechanism that sustains MPC plasticity, defined as the “adult Oct-4 circuit”. Although the expression of these pluripotency-associated markers has been hypothesized to represent a distinctive adult molecular circuit, concerns regarding the tumorigenic potential of MPCs are reasonable and have not yet explored. Methods: Here, we present data from the tumorigenicity test in partial compliance with WHO recommendations of two different MPC-derived cell products in athymic nude mice. Results: Histomorphometric analysis of nodules excised from animals at 6, 8, or 12 weeks post-cell transplantation excluded tumor formation and demonstrated the ability of MPCs to generate homogeneous and organized tissue through distinct phases: an “early” vasculogenic phase, followed by remodeling of the newly formed microvascular network and the deposition of structured, aligned collagen fibers. Conclusions: MPCs do not possess intrinsic tumorigenic potential and spontaneously form vascularized xenogenic tissue four weeks after injection into the subcutaneous space.