Cells & Development最新文献

Sarcopenia, characterized by an age-related decline in skeletal muscle mass and function, is closely associated with mitochondrial dysfunction. This study aimed to explore the role of myocyte enhancer factor 2A (MEF2A) in alleviating sarcopenia, focusing on its regulatory effect on mitochondrial homeostasis. AAV9-MEF2A was administered to 24-month-old male SAMP8 mice, and their endurance capacity and muscle histology were assessed. In vitro, MEF2A was overexpressed in C2C12 cells to examine its impact on myoblast proliferation and differentiation. Chromatin immunoprecipitation (ChIP), luciferase assays, and rescue experiments were conducted to identify downstream targets and validate the MEF2A-regulated signaling pathway. MEF2A overexpression significantly enhanced endurance performance, with a 1.17-fold increase in muscle mass, a 2.4 to 4.9-fold decrease in muscle atrophy markers compared to the AAV9-NC group, and a nearly 2 to 3-fold increase in mitochondrial biogenesis and antioxidant enzyme expression in aged mice. In C2C12 cells, MEF2A stimulated proliferation (1.8 fold increase in EdU-positive cells vs vector group) and differentiation (2 to 3-fold increase in differentiation markers vs vector group) while improving mitochondrial function through 1.5 to 2-fold increases in both OxPhos complex proteins and mitochondrial biogenesis genes compared to vector control. Mechanistically, MEF2A directly activated the PGC-1α/NRF2 axis, as validated by ChIP and reporter assays. Rescue experiments further verified the critical role of this pathway in MEF2A-mediated effects. These findings demonstrate that MEF2A mitigates sarcopenia by improving mitochondrial function and promoting muscle regeneration via activation of the PGC-1α/NRF2 signaling axis. MEF2A represents a promising therapeutic target for combating age-related muscle degeneration.

During primary neurulation in amniote embryos, the neural plate gives rise to the neural tube in a process requiring the coordination of forces at different scales throughout a geometrically complex tissue. The ways in which this process fails inform us of the complex mechanical conditions required for its correct completion. Previous results showed that the functional disruption of MARCKS, a protein which simultaneously interacts with the plasma membrane and actin filaments, resulted in neural tube closure defects with apical cell extrusion. Here, we demonstrate that this is an example of "live cell extrusion", wherein extruded cells are not undergoing apoptosis. This suggests that extrusion in this case might be due to a mechanical instability in the neural plate. Using an expanded energy-based vertex model of pseudostratified epithelia we then show that extrusion may be elicited by a reduction in the relative surface tension of apical and basal interfaces with respect to cell-cell interfaces. Finally, by considering a continuum description of a simplified epithelium we derive an approximate quantitative threshold for single-layered epithelial stability in the form of a power law relating cell density to the relative value of interfacial surface tensions. Our work serves to explain an example of how alterations in polarization and forces at the single-cell level can produce tissue-scale instabilities which not only greatly alter its morphology but can also ultimately lead to severe developmental defects.

Following fertilization, there is an initial period of rapid cell division that leads to the formation of a multicellular structure known as the blastula, or blastocyst. Within this structure, sialic acids play a key role in influencing cellular processes such as signaling, cell-to-cell contact, and adhesion. In species that develop internally, the blastocyst undergoes implantation and placentation, which depend on maternal immunomodulation facilitated by sialylated proteins and enzymes involved in the biosynthesis of sialic acids. Although research has shown that the elimination of certain initial enzymes in the sialic acid synthetic pathway can lead to reduced embryonic viability, the precise role of these enzymes remains to be further investigated, particularly in the blastula of externally developing species, which have received limited attention. Recently developed blastoid models present promising prospects for future research in this field.

The LSM (Like-Smith) family comprises RNA-binding proteins (RBPs) that are key regulators of RNA metabolism. LSM14A, a member of this family (designated Lsm14a in mice), participates in RNA processing within cytoplasmic processing bodies (P-bodies). The mouse Lsm14a gene is localized to chromosome 7qB1, spans 48.67 kilobases (kb), and encodes a 462-amino-acid protein that exhibits 94.53 % amino acid identity with human LSM14A. However, the expression profile of LSM14A in male reproductive organs and its functional relevance to male fertility remain uncharacterized. In this study, we report that LSM14A is expressed in the mouse testis and localizes to the cytoplasm of germ cells, from spermatogonia to elongating spermatids. To investigate LSM14A function, we generated germ cell-specific Lsm14a conditional knockout (cKO) mice. Lsm14a cKO male mice displayed normal growth, development, and fertility. Histological examination of Lsm14a cKO testes revealed preserved spermatogenesis and seminiferous tubule structure. Lsm14a cKO sperm exhibited normal morphology, acrosome integrity, and motility. The loss of Lsm14a in the testes did not significantly affect P-body formation, suggesting that genetic compensation by other LSM family members may have been activated upon Lsm14a knockout, thereby compensating for its loss of function. Collectively, these findings demonstrate that LSM14A is dispensable for spermatogenesis and male fertility in mice.

Healing of ear holes made in early postnatal mice represents an accessible model for the study of the regeneration of multiple tissues in mammals. This regenerative process involves three phases: wound healing, blastema formation, and re-differentiation. Classical models for regeneration studies have implicated macrophages as key cells for regeneration progression. In this study macrophage distribution and macrophage depletion experiments were conducted to evaluate whether these cells have a role during ear hole regeneration in early postnatal mice. Using the pan-macrophage markers CD68 and F4/80, we discriminate infiltrating from tissue-resident macrophages. In addition to expressing F4/80, tissue-resident macrophages also showed the presence of iNOS, a marker of pro-inflammatory macrophages. Unexpectedly, depletion of macrophages by clodronate liposomes administration during the wound healing stage of ear hole regeneration of early postnatal-age mice resulted in an increased number of infiltrating CD68+ cells and a deletion of F4/80+ macrophages with the subsequent delay in re-epithelialization and blastema formation. Under this experimental condition, IL10 was not affected during the wound healing phase, but its levels decreased when the re-population of F4/80+ tissue-resident macrophages was evident in the regenerating tissues. In addition, the administration of clodronate liposomes during the re-differentiation stage accelerated the maturation of regenerating elastic cartilage. These results indicate that F4/80+ tissue-resident macrophages control the infiltration of determined immune cells and are the main macrophage subpopulation that contributes to the regeneration of ear holes made in early postnatal mice.

Communication between cells is an inescapable feature of every multicellular organism, from the coordination of development during embryogenesis to the maintenance of homeostasis throughout adulthood. Extracellular vesicles (EVs) are new and central players in intercellular communication processes, by carrying multiple signals at once and acting in concert with well-described soluble effectors released in the environment. These membrane-enclosed particles are released by all cells in their environment. Their lipid bilayer protects their internal content while exposing surface determinants, allowing EVs to interact with target cells and/or surrounding extracellular matrix. EVs can also escape to blood or lymph circulation and reach further away organs. By carrying multiple signals, locally or at a distance, EVs are increasingly considered as players in the coordination of physiological processes within and across tissues. Here, we briefly summarize the many studies describing physiological functions of EVs, and discuss their actual demonstration in vivo. In addition, we discuss this knowledge in light of our current understanding on the heterogeneity of EVs, the complex composition of EV-containing preparations and the consequences to unravel the specific activities of EVs, including subtypes of EVs such as exosomes, and of other extracellular particles (EPs).

Tissue repair is an intricate biological process involving cellular and molecular mechanisms. These mechanisms coordinate the repair of damaged tissue, relying on the function of several signalling molecules. Growth factors, cytokines, and hormones perform a fundamental role in tissue regeneration, especially in skin regeneration. On the other hand, in case of diabetes or chronic wounds, the synthesis and regulation of these signalling molecules may be disrupted. Despite advances in medical science, chronic, non-healing wounds remain a continuous challenge, often characterized by reduced angiogenesis, impaired epithelialization, irregular granulation tissue formation, and elevated inflammation. This highlights the need to explore their therapeutic applications and the possibility of external production or stimulation for improved healing. The cellular intricacies are revealed within the wounded environment, explaining the functions of each signalling molecule, thus providing a roadmap for therapeutic exploration. It scrutinizes the complexities of venous and arterial ulcers, diabetic wounds, and complex burn wounds, which indicates the urgency of coming up with innovative interventions. From the modulation of wound microenvironments will arise new treatment modalities that spur tissue restoration with efficacy. Scientists have explored the wound healing properties of Vascular Endothelial Growth Factor, Platelet Derived Growth Factor, Transforming Growth Factor-β, granulocyte-macrophage colony-stimulating factor, estradiol benzoate, thyroxine, and erythropoietin. This review article acts as a guide for better treatments that can improve wound healing.