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Current Opinion in Immunology Jun 2020The mesenchymal microenvironment is increasingly recognized as a major player in immunity. Here we focus on mesenchymal cells located within or in proximity to the blood... (Review)
Review
The mesenchymal microenvironment is increasingly recognized as a major player in immunity. Here we focus on mesenchymal cells located within or in proximity to the blood vessels wall, which include pericytes, adventitial fibroblasts and mesenchymal stromal cells. We discuss recent evidence that these cells play a role in tissue homeostasis, immunity and inflammatory pathologies by multiple mechanisms, including vascular modulation, leucocyte migration, activation or survival in the perivascular space and differentiation into specialized 'effector' mesenchymal cells essential for tissue repair and immunity, such as myofibroblasts and lymphoid stromal cells. When dysregulated, these responses contribute to inflammatory and fibrotic diseases.
Topics: Cell Differentiation; Fibroblasts; Humans; Mesenchymal Stem Cells; Pericytes; Stromal Cells
PubMed: 32387900
DOI: 10.1016/j.coi.2020.03.009 -
Nature Communications May 2022Multiple pluripotent states have been described in mouse and human stem cells. Here, we apply single-cell RNA-seq to a newly established BMP4 induced mouse primed to...
Multiple pluripotent states have been described in mouse and human stem cells. Here, we apply single-cell RNA-seq to a newly established BMP4 induced mouse primed to naïve transition (BiPNT) system and show that the reset is not a direct reversal of cell fate but goes through a primordial germ cell-like cells (PGCLCs) state. We first show that epiblast stem cells bifurcate into c-Kit naïve and c-Kit trophoblast-like cells, among which, the naïve branch undergoes further transition through a PGCLCs intermediate capable of spermatogenesis in vivo. Mechanistically, we show that DOT1L inhibition permits the transition from primed pluripotency to PGCLCs in part by facilitating the loss of H3K79me2 from Gata3/6. In addition, Prdm1/Blimp1 is required for PGCLCs and naïve cells, while Gata2 inhibits PGC-like state by promoting trophoblast-like fate. Our work not only reveals an alternative route for primed to naïve transition, but also gains insight into germ cell development.
Topics: Animals; Bone Morphogenetic Protein 4; Cell Differentiation; Germ Cells; Germ Layers; Male; Mice; Stem Cells; Trophoblasts
PubMed: 35589713
DOI: 10.1038/s41467-022-30325-4 -
Development (Cambridge, England) Dec 2021Despite four decades of effort, robust propagation of pluripotent stem cells from livestock animals remains challenging. The requirements for self-renewal are unclear...
Despite four decades of effort, robust propagation of pluripotent stem cells from livestock animals remains challenging. The requirements for self-renewal are unclear and the relationship of cultured stem cells to pluripotent cells resident in the embryo uncertain. Here, we avoided using feeder cells or serum factors to provide a defined culture microenvironment. We show that the combination of activin A, fibroblast growth factor and the Wnt inhibitor XAV939 (AFX) supports establishment and continuous expansion of pluripotent stem cell lines from porcine, ovine and bovine embryos. Germ layer differentiation was evident in teratomas and readily induced in vitro. Global transcriptome analyses highlighted commonality in transcription factor expression across the three species, while global comparison with porcine embryo stages showed proximity to bilaminar disc epiblast. Clonal genetic manipulation and gene targeting were exemplified in porcine stem cells. We further demonstrated that genetically modified AFX stem cells gave rise to cloned porcine foetuses by nuclear transfer. In summary, for major livestock mammals, pluripotent stem cells related to the formative embryonic disc are reliably established using a common and defined signalling environment. This article has an associated 'The people behind the papers' interview.
Topics: Animals; Cattle; Cell Differentiation; Embryo, Mammalian; Germ Layers; Livestock; Pluripotent Stem Cells; Sheep; Species Specificity; Swine
PubMed: 34874452
DOI: 10.1242/dev.199901 -
Developmental Cell Jul 2019In this issue of Developmental Cell, Hashimoto and Sasaki (2019) explore the role of the Hippo pathway in the establishment of naive pluripotency and cell competition in...
In this issue of Developmental Cell, Hashimoto and Sasaki (2019) explore the role of the Hippo pathway in the establishment of naive pluripotency and cell competition in the epiblast. Their work gives insight into how the mouse embryo selects cells with the highest future potential, through the activity of YAP/TEAD.
Topics: Animals; Germ Layers; Mice; Protein Serine-Threonine Kinases; Signal Transduction; Transcription Factors
PubMed: 31336094
DOI: 10.1016/j.devcel.2019.07.005 -
Anatomical Record (Hoboken, N.J. : 2007) Aug 2022The process by which upper respiratory tract structures have changed over deep evolutionary time is, in part, reflected in the process of embryologic development. The...
The process by which upper respiratory tract structures have changed over deep evolutionary time is, in part, reflected in the process of embryologic development. The nasopharynx in particular is a centrally located space bounded by components of the respiratory portion of the nasal cavity, cranial base, soft palate, and Eustachian tube. The development of these components can be understood both in terms of embryologic structures such as the branchial arches and paraxial mesoderm and through fossil evidence dating as far back as the earliest agnathan fish of the Cambrian Period. Understanding both the evolution and development of these structures has been an immeasurable benefit to the otolaryngologist seeking to model disease etiology of both common and rare conditions. This discussion is a primer for those who may be unfamiliar with the central importance of the nasopharynx both in terms of our evolutionary history and early embryological development of vital cranial and upper respiratory tract structures.
Topics: Animals; Biological Evolution; Branchial Region; Developmental Biology; Mesoderm; Nasopharynx; Skull
PubMed: 35665451
DOI: 10.1002/ar.24950 -
Nature Communications Sep 2023Understanding of the molecular drivers of lineage diversification and tissue patterning during primary germ layer development requires in-depth knowledge of the dynamic...
Understanding of the molecular drivers of lineage diversification and tissue patterning during primary germ layer development requires in-depth knowledge of the dynamic molecular trajectories of cell lineages across a series of developmental stages of gastrulation. Through computational modeling, we constructed at single-cell resolution, a spatio-temporal transcriptome of cell populations in the germ-layers of gastrula-stage mouse embryos. This molecular atlas enables the inference of molecular network activity underpinning the specification and differentiation of the germ-layer tissue lineages. Heterogeneity analysis of cellular composition at defined positions in the epiblast revealed progressive diversification of cell types. The single-cell transcriptome revealed an enhanced BMP signaling activity in the right-side mesoderm of late-gastrulation embryo. Perturbation of asymmetric BMP signaling activity at late gastrulation led to randomization of left-right molecular asymmetry in the lateral mesoderm of early-somite-stage embryo. These findings indicate the asymmetric BMP activity during gastrulation may be critical for the symmetry breaking process.
Topics: Animals; Mice; Gastrulation; Functional Laterality; Gastrula; Germ Layers; Mesoderm
PubMed: 37709743
DOI: 10.1038/s41467-023-41482-5 -
Nature Communications Jul 2023Biomechanical cues are instrumental in guiding embryonic development and cell differentiation. Understanding how these physical stimuli translate into transcriptional...
Biomechanical cues are instrumental in guiding embryonic development and cell differentiation. Understanding how these physical stimuli translate into transcriptional programs will provide insight into mechanisms underlying mammalian pre-implantation development. Here, we explore this type of regulation by exerting microenvironmental control over mouse embryonic stem cells. Microfluidic encapsulation of mouse embryonic stem cells in agarose microgels stabilizes the naive pluripotency network and specifically induces expression of Plakoglobin (Jup), a vertebrate homolog of β-catenin. Overexpression of Plakoglobin is sufficient to fully re-establish the naive pluripotency gene regulatory network under metastable pluripotency conditions, as confirmed by single-cell transcriptome profiling. Finally, we find that, in the epiblast, Plakoglobin was exclusively expressed at the blastocyst stage in human and mouse embryos - further strengthening the link between Plakoglobin and naive pluripotency in vivo. Our work reveals Plakoglobin as a mechanosensitive regulator of naive pluripotency and provides a paradigm to interrogate the effects of volumetric confinement on cell-fate transitions.
Topics: Animals; Mice; Humans; gamma Catenin; Cell Differentiation; Germ Layers; Embryonic Development; Gene Expression Profiling; Blastocyst; Mammals
PubMed: 37419903
DOI: 10.1038/s41467-023-39515-0 -
Communications Biology May 2023Mesenchymal stem/Stromal cells (MSCs) have great therapeutic potentials, and they have been isolated from various tissues and organs including definitive endoderm (DE)...
Mesenchymal stem/Stromal cells (MSCs) have great therapeutic potentials, and they have been isolated from various tissues and organs including definitive endoderm (DE) organs, such as the lung, liver and intestine. MSCs have been induced from human pluripotent stem cells (hPSCs) through multiple embryonic lineages, including the mesoderm, neural crest, and extraembryonic cells. However, it remains unclear whether hPSCs could give rise to MSCs in vitro through the endodermal lineage. Here, we report that hPSC-derived, SOX17 definitive endoderm progenitors can further differentiate to cells expressing classic MSC markers, which we name definitive endoderm-derived MSCs (DE-MSCs). Single cell RNA sequencing demonstrates the stepwise emergence of DE-MSCs, while endoderm-specific gene expression can be elevated by signaling modulation. DE-MSCs display multipotency and immunomodulatory activity in vitro and possess therapeutic effects in a mouse ulcerative colitis model. This study reveals that, in addition to the other germ layers, the definitive endoderm can also contribute to MSCs and DE-MSCs could be a cell source for regenerative medicine.
Topics: Animals; Mice; Humans; Cell Differentiation; Mesenchymal Stem Cells; Pluripotent Stem Cells; Liver; Mesoderm
PubMed: 37127734
DOI: 10.1038/s42003-023-04810-5 -
EMBO Reports Sep 2022Pluripotent cells in mouse embryos, which first emerge in the inner cell mass of the blastocyst, undergo gradual transition marked by changes in gene expression,... (Review)
Review
Pluripotent cells in mouse embryos, which first emerge in the inner cell mass of the blastocyst, undergo gradual transition marked by changes in gene expression, developmental potential, polarity, and morphology as they develop from the pre-implantation until post-implantation gastrula stage. Recent studies of cultured mouse pluripotent stem cells (PSCs) have clarified the presence of intermediate pluripotent stages between the naïve pluripotent state represented by embryonic stem cells (ESCs-equivalent to the pre-implantation epiblast) and the primed pluripotent state represented by epiblast stem cells (EpiSCs-equivalent to the late post-implantation gastrula epiblast). In this review, we discuss these recent findings in light of our knowledge on peri-implantation mouse development and consider the implications of these new PSCs to understand their temporal sequence and the feasibility of using them as model system for pluripotency.
Topics: Animals; Blastocyst; Cell Differentiation; Embryonic Stem Cells; Germ Layers; Mice; Pluripotent Stem Cells
PubMed: 35903955
DOI: 10.15252/embr.202255010 -
Cell Research Feb 2023Acute liver failure (ALF) is a life-threatening disease that occurs secondary to drug toxicity, infection or a devastating immune response. Orthotopic liver...
Acute liver failure (ALF) is a life-threatening disease that occurs secondary to drug toxicity, infection or a devastating immune response. Orthotopic liver transplantation is an effective treatment but limited by the shortage of donor organs, the requirement for life-long immune suppression and surgical challenges. Stem cell transplantation is a promising alternative therapy for fulminant liver failure owing to the immunomodulatory abilities of stem cells. Here, we report that when transplanted into the liver, human endoderm stem cells (hEnSCs) that are germ layer-specific and nontumorigenic cells derived from pluripotent stem cells are able to effectively ameliorate hepatic injury in multiple rodent and swine drug-induced ALF models. We demonstrate that hEnSCs tune the local immune microenvironment by skewing macrophages/Kupffer cells towards an anti-inflammatory state and by reducing the infiltrating monocytes/macrophages and inflammatory T helper cells. Single-cell transcriptomic analyses of infiltrating and resident monocytes/macrophages isolated from animal livers revealed dramatic changes, including changes in gene expression that correlated with the change of activation states, and dynamic population heterogeneity among these cells after hEnSC transplantation. We further demonstrate that hEnSCs modulate the activation state of macrophages/Kupffer cells via cystatin SN (CST1)-mediated inhibition of interferon signaling and therefore highlight CST1 as a candidate therapeutic agent for diseases that involve over-activation of interferons. We propose that hEnSC transplantation represents a novel and powerful cell therapeutic treatment for ALF.
Topics: Animals; Humans; Endoderm; Inflammation; Liver; Liver Failure, Acute; Pluripotent Stem Cells; Salivary Cystatins; Swine; Interferons
PubMed: 36670290
DOI: 10.1038/s41422-022-00760-5