Results and Problems in Cell Differentiation最新文献

While lung transplantation is a life-saving treatment option for patients with end-stage lung diseases, its long-term outcome is hampered by exceedingly high rates of chronic rejection, manifesting as chronic lung allograft dysfunction (CLAD). It has long been recognized that exposure of the lung to the external environment via the airways, coupled with its rich immune microenvironment, makes the lung uniquely susceptible to heightened alloimmunity. Extensive immunosuppressive drugs do not provide effective control of the process of chronic rejection, and so, in recent years, investigators have turned their attention toward the identification of underlying cellular mechanisms that are either inherently resistant to or evolve to escape these medications. In this review, we explore recent advances in identifying the cellular mediators of chronic lung allograft rejection, with a focus on the myeloid-T cell immune axis, which will require targeted therapeutic approaches in the future to prevent irreversible allograft fibrosis.

As a professional mechanosensor, PIEZO1 converts mechanical stimuli-such as substrate stiffness, fluid shear stress, and membrane tension-into intracellular calcium influx, which in turn regulates a wide array of immune processes. The chapter details its significance across both innate and adaptive immunity, including T cell activation and migration, macrophage polarization, dendritic cell activation, natural killer cell cytotoxicity, neutrophil extracellular trap (NET) formation, and B cell antigen discrimination and class-switching to IgA. PIEZO1 emerges as a central regulator that fine-tunes immune responses by integrating signals from the cellular microenvironment, influencing inflammation, pathogen clearance, and metabolic reprogramming. Despite these advances, key questions remain regarding its role in chronic disease, autoimmunity, and cancer immunity. Targeting PIEZO1 presents a promising therapeutic strategy for conditions driven by mechanical stress and immune dysfunction, such as fibrosis, atherosclerosis, and solid tumours, potentially inaugurating a new era of mechano-immunotherapy.

As the largest and stiffest cellular organelle, the nucleus is continuously under the influence of mechanical forces from external and internal sources. These forces trigger an adaptive response at the nuclear level that include changes in nucleocytoplasmic transport, chromatin architecture, or transcriptional activity, ultimately driving cell proliferation or differentiation. In preparation for mitosis, nuclear structure and organization is modified to ensure that chromosomes are efficiently captured and correctly separated. How these modifications impact the mechanical response of the nucleus remains a largely unexplored area. One emerging concept is that changes in the mechanical properties of the nucleus during early mitosis are required to ensure the timing and accuracy of chromosome segregation. This review will discuss the contribution of key nuclear components to nuclear mechanics and their relevance for chromosome segregation fidelity.

This chapter elucidates the fundamental role of magneto-mechanical stresses as a primary mechanism through which static and low-frequency magnetic fields influence cellular processes. We demonstrate that magnetic forces, particularly when amplified by magnetic nanoparticles (MNPs), exert precise control over cellular mechanics. At the membrane level, these forces induce subtle deformations that directly modulate the gating of mechanosensitive ion channels, such as Piezo1, thereby regulating Ca²⁺ and K⁺ fluxes and initiating downstream signaling cascades that govern gene expression, metabolism, and cytoskeletal remodeling. At higher force thresholds, magneto-mechanical stress triggers significant structural alterations, including membrane blebbing due to cortical detachment, which can act as a precursor to apoptosis-an effect with pronounced implications for cancer therapeutics. Furthermore, these magnetic stresses are transmitted through the cytoskeletal network, altering the tension in F-actin, microtubules, and intermediate filaments to remodel cell shape, motility, and adhesion, thereby influencing critical processes like cell migration and differentiation. We demonstrate that the noninvasive and selective nature of this magneto-mechanical approach offers a highly versatile and potent strategy for biomedical applications.

Chronic liver allograft rejection (CR) remains a significant cause of late graft dysfunction and failure despite advances in surgical techniques and immunosuppression. This chapter reviews the current understanding of CR, integrating diagnostic histopathological findings, atypical histological patterns of late rejection that are frequently associated with CR, and emerging diagnostic tools. CR is driven by overlapping T cell-mediated and antibody-mediated mechanisms, leading to progressive bile duct loss, vascular injury, and structural alterations. Diagnostic histopathological criteria include interlobular bile duct atrophy or loss, foam cell obliterative arteriopathy, and portal/periportal, perisinusoidal, and perivenular fibrosis. Chronic antibody-mediated rejection (cAMR) and mixed phenotypes exhibit additional vascular and sinusoidal injury, often with subtle biochemical changes. Structural sequelae such as nodular regenerative hyperplasia and variable parenchymal fibrosis underscore the heterogeneity of late graft injury. This chapter also examines late-onset rejection phenotypes, i.e., plasma cell-rich rejection, idiopathic post-transplant hepatitis, and isolated central perivenulitis and their potential to progress to chronic rejection. Future directions emphasize the integration of molecular diagnostics, digital pathology, and noninvasive biomarkers, such as donor-specific antibodies, liver stiffness measurement, and donor-derived cell-free DNA (dd-cfDNA), to complement or replace protocol biopsies, to guide personalized immunosuppression, and to enable earlier intervention. Advances in regenerative medicine and antifibrotic therapies have the potential to alter the natural history of CR, shifting toward precision medicine approaches that may extend long-term graft survival after liver transplantation.

Antibody-mediated rejection (AMR) is now recognized as the primary cause of the decline of functional integrity and ultimately, graft failure in kidney transplants. Evolving understanding of effectors responsible for B-cell activation and plasma cell biology has led to the informed design of new therapeutics. Currently, several novel agents with varying mechanisms of action have emerged. These include imlifidase, FcRn inhibitors, anti-cytokine (IL-6/IL-6R) therapies, and plasma cell-directed therapies, especially anti-CD38s. As our understanding of critical effector pathways responsible for ARM grows, we now know that no single agent can control all facets of antibody generation and injury. The future of antibody-directed therapeutics will require protocols consisting of multiple agents positioned in a logical sequence to rapidly and durably remove pathogenic DSAs and block their re-emergence.

There is no cure for chronic rejection of transplanted organs. Macrophages are heavily involved in chronic rejection. Macrophages' movement into the graft depends on the actin cytoskeleton and its regulators the GTPase RhoA and its effector ROCK kinase. In this chapter, we describe how the interference with macrophage RhoA/ROCK pathway disrupts macrophage actin cytoskeleton, impairing their functions and migration to the allograft, and preventing the development of chronic rejection, and how such interference can be applied to clinical therapies.

Understanding the mechanotransduction mechanisms underlying the tactile dimension of skin aging remains an underexplored aspect of dermatological and neurosciences. This investigation introduces a novel mechanosensory responsiveness index, tactile acuity index (TAI), derived from a time-frequency analysis of friction-induced vibrations recorded during controlled touch interactions utilizing the wearable tactile acquisition device (WTAD). By decomposing tactile signals across frequency bands specific to Merkel, Meissner, Ruffini, and Pacinian mechanoreceptors, TAI quantifies both the amplitude and spectral organization of vibrational energy transmitted through the skin.In a first experimental phase, TAI exhibited a clear monotonic decline across seven grades of paper textures, confirming that smoother surfaces produce weaker and spectrally narrower mechanical stimulation, thereby reducing mechanoreceptor recruitment. The strongest correlations were observed for Ruffini (R² = 0.89) and Pacinian (R² = 0.95) receptors, reflecting their sensitivity to macroscopic strain and high-frequency vibration. In an ensuing aging study involving 40 women aged 20-65, TAI revealed a pronounced reduction in mechanosensory activity across all receptor types, with the largest declines in deep mechanotransductive pathways. The associated time-frequency spectrograms further highlighted shorter, lower-amplitude bursts and restricted spectral bandwidths in older skin, indicating a progressive simplification of tactile encoding with age.Together, these findings validate TAI as a quantitative biomarker of tactile vitality, capable of distinguishing between textural and biological sources of sensory decline. By providing receptor-specific insights into mechanotransduction efficiency, this approach establishes a novel framework for diagnosing, monitoring, and potentially restoring tactile function through targeted cosmetic or therapeutic interventions.

Over the past decade, theoretical and experimental work in mechanobiology has become increasingly interdependent, with modeling now serving as an essential tool for interpreting experiments and guiding measurements. Cellular mechanosensation, the conversion of mechanical cues into biochemical signals, governs essential processes such as migration, polarization, lineage specification, and tissue homeostasis, and its dysregulation contributes to disease. Quantitative models of mechanosensation have been central to clarifying how cells detect and respond to force across multiple scales, from ion channels and molecular bonds to adhesions, cytoskeletal dynamics, nuclear deformation, and transcriptional regulators such as YAP/TAZ (Yes-associated protein and transcriptional coactivator with PDZ-binding motif). In this chapter, we survey both experimental and theoretical advances in mechanosensation, emphasizing how mathematical and computational models complement experiments, expose limitations, and generate testable hypotheses and conceptual frameworks.

The myelin sheath is a multilayered glial membrane that surrounds axons providing insulation and rapid propagation of action potentials and contributing to structural support in both the central nervous system (CNS) and the peripheral nervous system (PNS). Therefore, myelin formation plays a crucial role in maintaining the integrity, connectivity, and functionality of the nervous system, as well as neuronal regeneration after injury or damage. Myelination in early developmental stages requires the molecular and mechanical exogenous cues provided mainly by the axons of the neurons, coupling the myelin-generating oligodendrocytes in the CNS and Schwann cells in the PNS. Complementary to early development, adaptive myelination dynamically regulates myelin remodeling in response to neuronal activity, ensuring optimal synaptic function and plasticity. Adaptive myelination is shown to be extremely mechanosensitive, requiring strict spatial constraints, stiffness, and topography for cell plasticity and myelination. Consequently, myelin regeneration is limited after traumatic injury and in demyelinating neurodegenerative diseases such as multiple sclerosis (MS). In addition to the inflammatory niche created around damaged myelin sheath, it is often overlooked that altered mechanical properties of the surrounding tissue are also pivotal in the inhibition of remyelination.This review focuses on the effects of mechanical cues on the polarization and plasticity of myelin generating cells, as well as on the induction of the myelin sheath during normal development and in pathological conditions. It also aims to give insights into potential mechanoepigenetic therapeutic approaches for demyelinating conditions.