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\"The discovery of cells--and the reframing of the human body as a cellular ecosystem--announced the birth of a new kind of medicine based on the therapeutic manipulations of cells. A hip fracture, a cardiac arrest, Alzheimer's, dementia, AIDS, pneumonia, lung cancer, kidney failure, arthritis, COVID--all could be viewed as the results of cells, or systems of cells, functioning abnormally. And all could be perceived as loci of cellular therapies. In The Song of the Cell, Mukherjee tells the story of how scientists discovered cells, began to understand them, and are now using that knowledge to create new treatments and new humans\"--Dust jacket flap.

Macrophages are the first cells of the nascent immune system to emerge during embryonic development. In mice, embryonic macrophages infiltrate developing organs, where they differentiate symbiotically into tissue-resident macrophages (TRMs) 1 . However, our understanding of the origins and specialization of macrophages in human embryos is limited. Here we isolated CD45 + haematopoietic cells from human embryos at Carnegie stages 11 to 23 and subjected them to transcriptomic profiling by single-cell RNA sequencing, followed by functional characterization of a population of CD45 + CD34 + CD44 + yolk sac-derived myeloid-biased progenitors (YSMPs) by single-cell culture. We also mapped macrophage heterogeneity across multiple anatomical sites and identified diverse subsets, including various types of embryonic TRM (in the head, liver, lung and skin). We further traced the specification trajectories of TRMs from either yolk sac-derived primitive macrophages or YSMP-derived embryonic liver monocytes using both transcriptomic and developmental staging information, with a focus on microglia. Finally, we evaluated the molecular similarities between embryonic TRMs and their adult counterparts. Our data represent a comprehensive characterization of the spatiotemporal dynamics of early macrophage development during human embryogenesis, providing a reference for future studies of the development and function of human TRMs. Single-cell RNA sequencing of haematopoietic cells from human embryos at different developmental stages sheds light on the development and specification of macrophages in different tissues.

Neuronal precursor cells in the tunicate Ciona intestinalis are shown to delaminate and undergo directed cell migration along either side of the neural tube before differentiating into bipolar neurons, suggesting that vertebrate neural-crest-derived sensory neurons have much deeper evolutionary roots. Early precursors of the vertebrate neural crest Many of the features that make vertebrates distinctive derive from an embryonic tissue called the neural crest, which starts life on the borders of the developing neural plate and migrates through the body. How did such a distinctive embryonic tissue evolve? Until recently no trace of it was known in the invertebrates closest to vertebrates such as tunicates and amphioxus. However, signs of neural plate border cells expressing cognates of vertebrate-specific neural-crest-related genes have been found. Here Lionel Christiaen and colleagues take the research a step further by showing how neuronal cells in the 'tadpole' larva of the tunicate Ciona intestinalis (the sea squirt) share features with neural-crest-derived spinal ganglia neurons in vertebrates. The precursors of these cells derive from caudal neural plate border cells and delaminate and undergo directed cell migration along either side of the neural tube before differentiating into axons, suggesting that migration — previously thought to be unique to vertebrate neural crests — has much deeper evolutionary roots. The neural crest is an evolutionary novelty that fostered the emergence of vertebrate anatomical innovations such as the cranium and jaws 1 . During embryonic development, multipotent neural crest cells are specified at the lateral borders of the neural plate before delaminating, migrating and differentiating into various cell types. In invertebrate chordates (cephalochordates and tunicates), neural plate border cells express conserved factors such as Msx, Snail and Pax3/7 and generate melanin-containing pigment cells 2 , 3 , 4 , a derivative of the neural crest in vertebrates. However, invertebrate neural plate border cells have not been shown to generate homologues of other neural crest derivatives. Thus, proposed models of neural crest evolution postulate vertebrate-specific elaborations on an ancestral neural plate border program, through acquisition of migratory capabilities and the potential to generate several cell types 5 , 6 , 7 . Here we show that a particular neuronal cell type in the tadpole larva of the tunicate Ciona intestinalis , the bipolar tail neuron, shares a set of features with neural-crest-derived spinal ganglia neurons in vertebrates. Bipolar tail neuron precursors derive from caudal neural plate border cells, delaminate and migrate along the paraxial mesoderm on either side of the neural tube, eventually differentiating into afferent neurons that form synaptic contacts with both epidermal sensory cells and motor neurons. We propose that the neural plate borders of the chordate ancestor already produced migratory peripheral neurons and pigment cells, and that the neural crest evolved through the acquisition of a multipotent progenitor regulatory state upstream of multiple, pre-existing neural plate border cell differentiation programs.

This is a book about the research process that led scientists to the discovery of a group of molecules that act as carriers of information among the cells of our body, which the book refers to collectively as \"body messages.\" Among the thousands of body messages, the author selected those that are part of her own research, the cytokines, adipokines, and other proteins that regulate inflammation and metabolism. She also interviewed twenty researchers who contributed significantly to the field, asking details about their discoveries while also inquiring about their life and education. Along with scientists' personal recollections, the book reconstructs the discovery process based on published reports of the original experimental findings. Though the book's main theme is the process of discovery, it devotes considerable space to the biology of body messages and the consequence of their identification for medical practice.-- Provided by publisher

The body plan of the mammalian embryo is shaped through the process of gastrulation, an early developmental event that transforms an isotropic group of cells into an ensemble of tissues that is ordered with reference to three orthogonal axes 1 . Although model organisms have provided much insight into this process, we know very little about gastrulation in humans, owing to the difficulty of obtaining embryos at such early stages of development and the ethical and technical restrictions that limit the feasibility of observing gastrulation ex vivo 2 . Here we show that human embryonic stem cells can be used to generate gastruloids—three-dimensional multicellular aggregates that differentiate to form derivatives of the three germ layers organized spatiotemporally, without additional extra-embryonic tissues. Human gastruloids undergo elongation along an anteroposterior axis, and we use spatial transcriptomics to show that they exhibit patterned gene expression. This includes a signature of somitogenesis that suggests that 72-h human gastruloids show some features of Carnegie-stage-9 embryos 3 . Our study represents an experimentally tractable model system to reveal and examine human-specific regulatory processes that occur during axial organization in early development. Human gastruloids—three-dimensional aggregates derived from human embryonic stem cells—show features of human embryos at around 19–21 days, and provide a model for the study of early human development.

Whereas the enteric nervous system of jawed vertebrates is derived largely from the vagal neural crest, that of the sea lamprey ( Petromyzon marinus ) is populated by trunk-derived neural crest cells that may be homologous to Schwann cell precursors. Evolutionary relics in the gut In gnathostomes (jawed vertebrates), the ganglia of the enteric nervous system are populated from the vagal neural crest, which invades the gut at the anterior end and makes its way to the back. In mammals, however, Schwann cell precursors also contribute to these ganglia. This second mechanism might in fact be a relic of ancient times rather than a mammalian innovation. Here, Marianne Bronner and colleagues show that the vagal neural crest plays no part in the population of the enteric nervous system in a jawless vertebrate, the sea lamprey, in which the whole gut is populated by Schwann-cell-precursor-like cells from the trunk neural crest. The enteric nervous system of jawed vertebrates arises primarily from vagal neural crest cells that migrate to the foregut and subsequently colonize and innervate the entire gastrointestinal tract. Here we examine development of the enteric nervous system in the basal jawless vertebrate the sea lamprey ( Petromyzon marinus ) to gain insight into its evolutionary origin. Surprisingly, we find no evidence for the existence of a vagally derived enteric neural crest population in the lamprey. Rather, labelling with the lipophilic dye DiI shows that late-migrating cells, originating from the trunk neural tube and associated with nerve fibres, differentiate into neurons within the gut wall and typhlosole. We propose that these trunk-derived neural crest cells may be homologous to Schwann cell precursors, recently shown in mammalian embryos to populate post-embryonic parasympathetic ganglia 1 , 2 , including enteric ganglia 3 . Our results suggest that neural-crest-derived Schwann cell precursors made an important contribution to the ancient enteric nervous system of early jawless vertebrates, a role that was largely subsumed by vagal neural crest cells in early gnathostomes.

Ascidian embryos highlight the importance of cell lineages in animal development. As simple proto-vertebrates, they also provide insights into the evolutionary origins of cell types such as cranial placodes and neural crest cells. Here we have determined single-cell transcriptomes for more than 90,000 cells that span the entirety of development—from the onset of gastrulation to swimming tadpoles—in Ciona intestinalis . Owing to the small numbers of cells in ascidian embryos, this represents an average of over 12-fold coverage for every cell at every stage of development. We used single-cell transcriptome trajectories to construct virtual cell-lineage maps and provisional gene networks for 41 neural subtypes that comprise the larval nervous system. We summarize several applications of these datasets, including annotating the synaptome of swimming tadpoles and tracing the evolutionary origin of cell types such as the vertebrate telencephalon. Comprehensive single-cell transcriptomes in the proto-vertebrate Ciona intestinalis identified provisional gene networks for 41 different neural subtypes, providing insights into the swimming circuit of tadpoles and the evolution of the vertebrate telencephalon.

Direct lineage reprogramming involves the conversion of cellular identity. Single-cell technologies are useful for deconstructing the considerable heterogeneity that emerges during lineage conversion. However, lineage relationships are typically lost during cell processing, complicating trajectory reconstruction. Here we present ‘CellTagging’, a combinatorial cell-indexing methodology that enables parallel capture of clonal history and cell identity, in which sequential rounds of cell labelling enable the construction of multi-level lineage trees. CellTagging and longitudinal tracking of fibroblast to induced endoderm progenitor reprogramming reveals two distinct trajectories: one leading to successfully reprogrammed cells, and one leading to a ‘dead-end’ state, paths determined in the earliest stages of lineage conversion. We find that expression of a putative methyltransferase, Mettl7a1 , is associated with the successful reprogramming trajectory; adding Mettl7a1 to the reprogramming cocktail increases the yield of induced endoderm progenitors. Together, these results demonstrate the utility of our lineage-tracing method for revealing the dynamics of direct reprogramming. Combinatorial tagging of single cells using expressed DNA barcodes, delivered by a lentiviral vector, is used to track individual cells and reconstruct their lineages and trajectories during cell fate reprogramming.

During reproduction, multiple species such as insects and all mammals undergo extensive physiological and morphological adaptions to ensure health and survival of the mother and optimal development of the offspring. Here we report that the intestinal epithelium undergoes expansion during pregnancy and lactation in mammals. This enlargement of the intestinal surface area results in a novel geometry of expanded villi. Receptor activator of nuclear factor-κΒ (RANK, encoded by TNFRSF11A ) and its ligand RANKL were identified as a molecular pathway involved in this villous expansion of the small intestine in vivo in mice and in intestinal mouse and human organoids. Mechanistically, RANK–RANKL protects gut epithelial cells from cell death and controls the intestinal stem cell niche through BMP receptor signalling, resulting in the elongation of villi and a prominent increase in the intestinal surface. As a transgenerational consequence, babies born to female mice that lack Rank in the intestinal epithelium show reduced weight and develop glucose intolerance after metabolic stress. Whereas gut epithelial remodelling in pregnancy/lactation is reversible, constitutive expression of an active form of RANK is sufficient to drive intestinal expansion followed by loss of villi and stem cells, and prevents the formation of Apc min -driven small intestinal stem cell tumours. These data identify RANK–RANKL as a pathway that drives intestinal epithelial expansion in pregnancy/lactation, one of the most elusive and fundamental tissue remodelling events in mammalian life history and evolution. The RANK–RANKL pathway drives intestinal epithelial expansion in pregnancy and lactation.