Results and Problems in Cell Differentiation最新文献

Solid organ transplantation is an established treatment method for individuals with end-stage organ dysfunction. However, despite the common perception that transplantation offers a lasting cure, transplant recipients have limited long-term treatment options for chronic rejection. Transplant vasculopathy is recognized as one of the defining pathological indicators of chronic rejection, characterized by diffuse intimal wall thickening compromising vessel function, and, in severe cases, leads to allograft failure. While the increasing number of solid organ transplants reflects the modern advancements in treating end-stage organ dysfunction, it also highlights the continuing challenge of understanding and developing effective therapies for managing chronic rejection.

Chronic rejection is a principal cause of long-term graft failure in solid organ transplantation. Characterized by progressive fibrotic remodeling, chronic rejection results from complex interactions among alloimmune responses, persistent inflammation, and dysregulated tissue repair mechanisms. This chapter provides a comprehensive overview of the cellular and molecular mechanisms underlying chronic rejection, with a focus on the roles of innate immune cells, T and B lymphocytes, profibrotic cytokines, signaling pathways, and extracellular matrix remodeling. A detailed mechanistic understanding of these pathways is critical for the identification of novel biomarkers and the development of targeted therapeutic strategies to prevent or ameliorate chronic rejection, thereby improving long-term graft survival.

Chronic rejection (CR) remains a major barrier to long-term success in facial vascularized composite allotransplantation (fVCA), particularly in facial transplants. Unlike acute rejection, CR is a gradual, progressive process marked by vasculopathy, fibrosis, and functional graft decline. Histopathologic features include intimal hyperplasia, dermal sclerosis, adnexal atrophy, and telangiectasia. Immune mechanisms driving CR involve persistent activation of Th1 and Th17 T cells, macrophages, and, to a lesser extent, B cells, which form tertiary lymphoid structures. Dysregulated cytokines and chemokines, such as IFN-γ, IL-17, and IL-6, perpetuate inflammation and fibrosis, whereas the downregulation of regulatory mediators like IL-10 impairs immune resolution. Chronic antigen exposure, complement activation, and the presence of tissue-resident memory T cells further sustain graft injury. Clinically, CR presents with tightening of facial tissue, pigmentary changes, pain, and impaired oral and facial function, which can sometimes progress to necrosis and graft failure. Diagnostic challenges persist due to heterogeneous presentation and a lack of standardized criteria. Early detection through protocol biopsies, mucosal sampling, and vascular imaging is essential. Future directions emphasize the need for molecular diagnostics, targeted immunomodulation, and antifibrotic therapies. A deeper understanding of CR pathophysiology is critical to improving graft longevity and patient quality of life in fVCA.

Acetylation of histones epigenetically mediates transcriptional dynamics of gene activation and suppression in response to physiological regulatory signals. The acetylated states of histone proteins define the activities of gene promoter and enhancer elements by contributing to competency for regulatory protein interactions and control of chromatin organization including higher-order inter and intra-chromosomal interactions. Cell transformation and tumor progression are associated with and functionally related to histone acetylation. Targeting the regulatory machinery for histone acetylation provides treatment options for cancer-compromised gene expression with specificity and reduced off-target consequences.

Epigenetic mechanisms influence early developmental events, shaping gene expression in exciting ways that go beyond the DNA blueprint. The state of chromatin is governed by an interplay between various histone modifications, variants, nucleosome remodeling complexes, and other chromatin modifiers that work in sync to prime the chromatin for specific biological outcomes. In this chapter, we explore neural crest cells (NCCs), a critical progenitor population that retains the extensive developmental potential of their blastula origins. The formation and differentiation of NCCs into diverse cell types are influenced by the regulation of their acetylation state through various epigenetic factors. This chapter delves into the intricate interplay between histone acetylases (HATs) and deacetylases (HDACs), highlighting how these enzymes modify chromatin to create a permissive environment for the induction of NCCs and steer their fate toward the melanocytic lineage. The shift in acetylation profiles during the transition from melanocytes to melanoma suggests that the transcriptional machinery may override normal regulatory mechanisms, promoting a neural crest-like state in melanoma development. Epigenetic regulation, particularly through histone acetylation, plays a pivotal role in neural crest cell development and melanoma initiation offering potential therapeutic targets.

Myelin plasticity is a key process for acquiring new motor skills and preventing neurodegeneration during ageing. Neural precursor cells (NPCs) and parenchymal oligodendrocyte precursor cells (OPCs) play a key role in myelin plasticity in the central nervous system (CNS), being specialized in reconstituting the myelin sheath upon damage. Reversible acetylation, regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) activity, controls these stem cells' differentiation in myelinating oligodendrocytes (mOLs) during their proliferation and remyelination processes. By modulating cytosolic protein activity and precisely orchestrating the spatial and timely regulated activity of the transcription factors participating in the NPC and OPC differentiation process, these enzymes play a vital role in preserving the adult brain's cognitive capacity during ageing. This review highlights the role of reversible acetylation in the regulation of stem cell differentiation during remyelination, as disruptions in this process contribute to severe neurodegenerative impairments and accelerated ageing.

Post-translational modifications (PTM) involve chemical modifications of amino acid residues within histone and non-histone proteins and are chemically diverse. PTM plays a vital role in regulating the chromatin structure in the nucleus, thus gene regulation. Among the various PTM, reversible acetylation of histone non-histone proteins has fundamental functions in various cellular processes. In all organisms, histone acetylation of lysine residues is connected with transcription activation. Acetyltransferases and deacetylases are well-known enzymes in the acetylation of the histone and non-histone proteins. This chapter will review the latest progress in histone and non-histone reversible acetylation epigenetic alterations and mechanisms and summarize how they affect development, aging, and diseases.

Microtubule (MT) acetylation has emerged as a critical regulator of cellular stress responses, integrating mechanical and oxidative stimuli to support cellular adaptability and survival. This post-translational modification (PTM) enhances MT flexibility and resilience, enabling cells to withstand mechanical challenges such as changes in extracellular matrix stiffness and applied forces. Through its impact on MT physical properties, acetylation minimizes cytoskeletal breakage, reducing the need for constant remodeling and supporting cellular integrity under mechanical stress. Furthermore, tubulin acetylation regulates intracellular trafficking by modulating interactions with molecular motors, allowing for efficient cargo transport and precise spatial organization without disrupting the MT network. In the context of oxidative stress, tubulin acetylation responds to redox imbalances by stabilizing MTs and influencing cellular pathways that regulate reactive oxygen species (ROS). This modification is linked to enhanced antioxidant responses, autophagy regulation, and mitochondrial dynamics, highlighting its role in maintaining cellular homeostasis under oxidative conditions. The dual function of tubulin acetylation, responding to and integrating signals from mechanical and oxidative stress, acts as a bridging mechanism between physical and chemical signaling pathways. Consequently, it has the potential to be a therapeutic target in diseases characterized by dysregulated stress responses, including neurodegenerative disorders, cancer, and cardiovascular conditions. Despite significant progress has been made, unanswered questions persist, particularly regarding the molecular mechanisms by which acetylated MTs encode spatial and functional information and their interplay with other tubulin PTMs.

The cytoskeleton of eukaryotic cells undergoes a reorganization in response to intracellular and extracellular cues, which plays an essential role in orchestrating various cell functions including migration, development, differentiation, tissue homeostasis, contractility, proliferation, gene expression, cancer cell invasion, and airway/vascular remodeling. Acetylation occurs on the cytoskeletal components, such as microtubules, actin, and vimentin, which regulate cellular functions. Moreover, remodeling of the cytoskeleton is regulated by acetylation and deacetylation of regulatory proteins, including adapter proteins and protein kinases. Therefore, protein acetylation and deacetylation are critical mechanisms for cytoskeletal reorganization in response to changes of intracellular and extracellular environments.

Viruses are acellular organisms and part of our ecosystem but exist at the interface of living and non-living. Furthermore, viruses are obligate intracellular parasites hence require the machinery of other organisms to multiply. Consequently, most viral infections result into a viral disease. Broadly, viruses cause two types of infection-acute and persistent (latent and chronic), in humans and other mammals that could lead to various lethal and non-lethal viral diseases. Acetylation is now known to be a ubiquitous protein (and nucleic acid) modification and is critical for cellular metabolism. An imbalance in acetylation has been associated with various cancers and diseases in humans. Likewise, the association of acetylation with viral infection and disease was observed soon after its discovery in twentieth century. Now, the literature accumulated in this space shows that acetylation promotes the infection of many viruses causing both acute and persistent infections. Furthermore, reduction in the acetylation level reduces viral clearance from the host and promotes viral persistency. The latter can be interrupted by increasing the acetylation level by using deacetylase inhibitors. Indeed, this approach has become a therapeutic tool to treat and clear the persistent viral infections as well as boost the oncolytic virus-mediated cancer therapy.