Current Topics in Developmental Biology最新文献

The increasing incidence of kidney diseases has highlighted the need for in vitro experimental models to mimic disease development and to test new therapeutic approaches. Traditional two-dimensional in vitro experimental models are not fully able to recapitulate renal diseases. Instead, kidney organoids represent three-dimensional models that better mimic the human organ from both structural and functional points of view. Human pluripotent stem cells (PSCs), both embryonic and induced, are ideal sources for generating renal organoids. These organoids contain all renal cell types and the protocols to differentiate PSCs into renal organoids consist of three different stages that recapitulate embryonic development: mesodermal induction, nephron progenitor formation, and nephron differentiation. Recently it has been establish a renal organoid model where collecting ducts are also present. In this case, the presence of ureteric bud progenitor cells is essential. Renal organoids are particularly useful for studying genetic diseases, by introducing the specific mutations in PSCs by genome editing or generating organoids from patient-derived PSCs. Moreover, renal organoids represent promising models in toxicology studies and testing new therapeutic approaches. Renal organoids can be established also from adult stem cells. This type of organoid, named tubuloid, is composed only of epithelial cells and recapitulates the tissue repair process. The tubuloids can be generated from adult stem or progenitor cells, obtained from renal biopsies or urine, and are promising in vitro models for studying tubular functions, diseases, and regeneration. Tubuloids can be derived from patients and permit the study of genetic diseases, performing personalized drug screening and modeling renal pathologies.

The neural crest is a highly migratory and multipotent cell population that contributes to many defining features of vertebrates. As a uniquely vertebrate cell type, the neural crest is an excellent model for studying cell lineage and diversification during embryonic development because of its multipotency, motility, and capacity to form a plethora of derivatives. Neural crest cells migrate extensively throughout the body and contribute to many of the defining features of vertebrate embryos, including the craniofacial skeleton, most of the peripheral nervous system and pigmentation of the skin. What guides their migration and subsequent formation of discrete structures? Interactions between neural crest cells and their environment, including other cell types like placode cells, play a major role in guiding their migration and condensation into numerous derivatives. In this review, we discuss aspects of neural crest induction, migration and axial level differences, highlighting what is currently known regarding molecular cues that govern their formation, migratory behavior, and differentiation as they reach their final destinations. We particularly focus on formation of cranial sensory ganglia. New technologies are playing an important role in furthering our understanding of the molecular mechanisms underlying neural crest migration and what leads to cessation of their movement and onset of differentiation.

"No cell is an island" - highlights the interconnectedness of cellular behavior and the extracellular matrix (ECM). Cell migration is inherently contextual, as cells navigate and adapt to their environments, reshaping the ECM while being influenced by its properties. This review focuses on the mechanical characteristics of the ECM-specifically its architecture, porosity, dynamics, and stiffness-and how these attributes affect cell behavior and migration strategies. We discuss how the mechanical properties are modulated by the composition and arrangement of ECM components and the role of enzymatic activities, including crosslinking and matrix metalloproteinases. By presenting examples from vertebrate and invertebrate developmental models, we demonstrate how ECM mechanics dictate cell migration at various biological scales. Additionally, we examine the importance of cell-matrix adhesions in regulating migration speed and direction. While in vitro studies have advanced our understanding of the molecular mechanisms at play, significant questions persist regarding the regulation of cell migration by ECM mechanics in vivo. Ultimately, this synthesis aims to illuminate the complexities of cell-ECM mechanical interactions, pointing the way for future research that may unveil novel insights into how ECM mechanics influences cell migration during development and disease.

Primordial germ cells (PGCs) migrate to associate with somatic cells to form the gonad, generate gametes and thereby ensure fertility. This chapter presents the mechanisms underlying single-cell migration performed by PGCs in various organisms, such as zebrafish, Drosophila, and the mouse models. This review introduces the principles of cell motility, factors controlling directed migration, and the effects of interactions between migrating cells and their environment. Specifically, it discusses passive and active migration mechanisms, the roles of guidance cues, and of interactions with different tissues that influence PGC migration. Comparative analysis of the process in different organisms reveals conserved and distinct strategies for motility and directed migration. The presented mechanisms contribute to broader understanding of cell migration, highlighting PGCs as a useful in vivo model for studying the principles governing the movement of cells within tissues.

Although mature oocytes are arrested in a differentiated state, they are provisioned with maternally-derived macromolecules that will start embryogenesis. The transition to embryogenesis, called 'egg activation', occurs without new transcription, even though it includes major cell changes like completing stalled meiosis, translating stored mRNAs, cytoskeletal remodeling, and changes to nuclear architecture. In most animals, egg activation is triggered by a rise in free calcium in the egg's cytoplasm, but we are only now beginning to understand how this induces the egg to transition to totipotency and proliferation. Here, we discuss the model that calcium-dependent protein kinases and phosphatases modify the phosphorylation landscape of the maternal proteome to activate the egg. We review recent phosphoproteomic mass spectrometry analyses that revealed broad phospho-regulation during egg activation, both in number of phospho-events and classes of regulated proteins. Our interspecies comparisons of these proteins pinpoints orthologs and protein families that are phospho-regulated in activating eggs, many of which function in hallmark events of egg activation, and others whose regulation and activity warrant further study. Finally, we discuss key phospho-regulating enzymes that may act apically or as intermediates in the phosphorylation cascades during egg activation. Knowing the regulators, targets, and effects of phospho-regulation that cause an egg to initiate embryogenesis is crucial at both fundamental and applied levels for understanding female fertility, embryo development, and cell-state transitions.

Embryonic skeletal muscle growth is contingent upon a population of somite derived satellite cells, however, the contribution of these cells to early postnatal skeletal muscle growth remains relatively high. As prepubertal postnatal development proceeds, the activity and contribution of satellite cells to skeletal muscle growth diminishes. Eventually, at around puberty, a population of satellite cells escapes terminal commitment, continues to express the paired box transcription factor Pax7, and reside in a quiescent state orbiting the myofiber periphery adjacent to the basal lamina. After adolescence, some satellite cell contributions to muscle maintenance and adaptation occur, however, their necessity is reduced relative to embryonic, early postnatal, and prepubertal growth.

The skeletal muscle is well known for its remarkable ability to regenerate after injuries. The regeneration is a complex and dynamic process that involves muscle stem cells (also called muscle satellite cells, MuSCs), fibro-adipogenic progenitors (FAPs), immune cells, and other muscle-resident cell populations. The MuSCs are the myogenic cell populaiton that contribute nuclei directly to the regenerated myofibers, while the other cell types collaboratively establish a microenvironment that facilitates myogenesis of MuSCs. The myogenic process includes activation, proliferation and differentiationof MuSCs, and subsequent fusion their descendent mononuclear myocytes into multinuclear myotubes. While the contributions of FAPs and immune cells to this microenvironment have been well studied, the influence of MuSCs on other cell types remains poorly understood. This review explores recent evidence supporting the potential role of MuSCs as immunomodulators during muscle regeneration, either through cytokine production or ligand-receptor interactions.

During development, macrophage subpopulations derived from hematopoietic progenitors take up residence in the developing heart. Embryonic macrophages are detectable at the early stages of heart formation in the nascent myocardium, valves and coronary vasculature. The specific subtypes of macrophages present in the developing heart reflect the generation of hematopoietic progenitors in the yolk sac, aorta-gonad-mesonephros, fetal liver, and postnatal bone marrow. Ablation studies have demonstrated specific requirements for embryonic macrophages in valve remodeling, coronary and lymphatic vessel development, specialized conduction system maturation, and myocardial regeneration after neonatal injury. The developmental origins of macrophage lineages change over time, with embryonic lineages having more reparative and remodeling functions in comparison to the bone marrow derived myeloid lineages of adults. Here we review the contributions and functions of cardiac macrophages in the developing heart with potential regenerative and reparative implications for cardiovascular disease.

The heart is the first organ to form during embryonic development, establishing the circulatory infrastructure necessary to sustain life and enable downstream organogenesis. Critical to the heart's function is its ability to initiate and propagate electrical impulses that allow for the coordinated contraction and relaxation of its chambers, and thus, the movement of blood and nutrients. Several specialized structures within the heart, collectively known as the cardiac conduction system (CCS), are responsible for this phenomenon. In this review, we discuss the discovery and scientific history of the mammalian cardiac conduction system as well as the key genes and transcription factors implicated in the formation of its major structures. We also describe known human diseases related to CCS development and explore existing challenges in the clinical context.

The regulation of ploidy in cardiomyocytes is a complex and tightly regulated aspect of cardiac development and function. Cardiomyocyte ploidy can range from diploid (2N) to 8N or even 16N, and these states change during key stages of development and disease progression. Polyploidization has been associated with cellular hypertrophy to support normal growth of the heart, increased contractile capacity, and improved stress tolerance in the heart. Conversely, alterations to ploidy also occur during cardiac pathogenesis of diseases, such as ischemic and non-ischemic heart failure and arrhythmia. Therefore, understanding which genes control and modulate cardiomyocyte ploidy may provide mechanistic insight underlying cardiac growth, regeneration, and disease. This chapter summarizes the current knowledge regarding the genes involved in the regulation of cardiomyocyte ploidy. We discuss genes that have been directly tested for their role in cardiomyocyte polyploidization, as well as methodologies used to identify ploidy alterations. These genes encode cell cycle regulators, transcription factors, metabolic proteins, nuclear scaffolding, and components of the sarcomere, among others. The general physiological and pathological phenotypes in the heart associated with the genetic manipulations described, and how they coincide with the respective cardiomyocyte ploidy alterations, are further discussed in this chapter. In addition to being candidates for genetic-based therapies for various cardiac maladies, these genes and their functions provide insightful evidence regarding the purpose of widespread polyploidization in cardiomyocytes.