66 research outputs found
Chapter 2 Genetics at the Cell Level
Image-based and sequencing-based spatial technologies can currently be used to locate cells anatomically within a tissue; the Human Vell Atlas allows its users to navigate the human body at various levels of resolution to identify patterns and interactions among its fundamental elements, zooming in and out depending on the research goals. Integrating data types or simultaneously measuring multiple modalities is invaluable when defining cell identities
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Innate Immune Mechanisms to Protect Against Infection at the Human Decidual-Placental Interface.
During pregnancy, the placenta forms the anatomical barrier between the mother and developing fetus. Infectious agents can potentially breach the placental barrier resulting in pathogenic transmission from mother to fetus. Innate immune responses, orchestrated by maternal and fetal cells at the decidual-placental interface, are the first line of defense to avoid vertical transmission. Here, we outline the anatomy of the human placenta and uterine lining, the decidua, and discuss the potential capacity of pathogen pattern recognition and other host defense strategies present in the innate immune cells at the placental-decidual interface. We consider major congenital infections that access the placenta from hematogenous or decidual route. Finally, we highlight the challenges in studying human placental responses to pathogens and vertical transmission using current experimental models and identify gaps in knowledge that need to be addressed. We further propose novel experimental strategies to address such limitations
Genetic And Epigenetic Determinants In Autoinflammatory Diseases
The concept of autoinflammation has evolved over the past 20 years, beginning with the discovery that mutations in the Mediterranean Fever (MEFV) gene were causative of Familial Mediterranean Fever. Currently, autoinflammatory diseases comprise a wide range of disorders with the common features of recurrent fever attacks, prevalence of hyperreactive innate immune cells, and signs of inflammation that can be systemic or organ specific in the absence of pathogenic infection of autoimmunity. Innate immune cells from the myeloid compartment are the main effectors of uncontrolled inflammation that is caused in great extent by the overproduction of inflammatory cytokines such as IL-1 beta and IL-18. Defects in several signaling pathways that control innate immune defense, particularly the hyperreactivity of one or more inflammasomes, are at the core of pathologic autoinflammatory phenotypes. Although many of the autoinflammatory syndromes are known to be monogenic, some of them are genetically complex and are impacted by environmental factors. Recently, epigenetic dysregulation has surfaced as an additional contributor to pathogenesis. In the present review, we discuss data that are currently available to describe the contribution of epigenetic mechanisms in autoinflammatory diseases
CellPhoneDB v5: inferring cell-cell communication from single-cell multiomics data
Cell-cell communication is essential for tissue development, regeneration and
function, and its disruption can lead to diseases and developmental
abnormalities. The revolution of single-cell genomics technologies offers
unprecedented insights into cellular identities, opening new avenues to resolve
the intricate cellular interactions present in tissue niches. CellPhoneDB is a
bioinformatics toolkit designed to infer cell-cell communication by combining a
curated repository of bona fide ligand-receptor interactions with a set of
computational and statistical methods to integrate them with single-cell
genomics data. Importantly, CellPhoneDB captures the multimeric nature of
molecular complexes, thus representing cell-cell communication biology
faithfully. Here we present CellPhoneDB v5, an updated version of the tool,
which offers several new features. Firstly, the repository has been expanded by
one-third with the addition of new interactions. These encompass interactions
mediated by non-protein ligands such as endocrine hormones and GPCR ligands.
Secondly, it includes a differentially expression-based methodology for more
tailored interaction queries. Thirdly, it incorporates novel computational
methods to prioritise specific cell-cell interactions, leveraging other
single-cell modalities, such as spatial information or TF activities (i.e.
CellSign module). Finally, we provide CellPhoneDBViz, a module to interactively
visualise and share results amongst users. Altogether, CellPhoneDB v5 elevates
the precision of cell-cell communication inference, ushering in new
perspectives to comprehend tissue biology in both healthy and pathological
states.Comment: 30 pages, 3 figures and 2 tables. Added previously missing figures
and tables; Updated the reference for 'An integrated single-cell reference
atlas of the human endometrium' pape
Single-Cell RNA Sequencing Reveals a Dynamic Stromal Niche That Supports Tumor Growth
Here, using single-cell RNA sequencing, we examine the stromal compartment in murine melanoma and draining lymph nodes (LNs) at points across tumor development, providing data at http://www.teichlab.org/data/. Naive lymphocytes from LNs undergo activation and clonal expansion within the tumor, before PD1 and Lag3 expression, while tumor-associated myeloid cells promote the formation of a suppressive niche. We identify three temporally distinct stromal populations displaying unique functional signatures, conserved across mouse and human tumors. Whereas "immune" stromal cells are observed in early tumors, "contractile" cells become more prevalent at later time points. Complement component C3 is specifically expressed in the immune population. Its cleavage product C3a supports the recruitment of C3aR(+) macrophages, and perturbation of C3a and C3aR disrupts immune infiltration, slowing tumor growth. Our results highlight the power of scRNA-seq to identify complex interplays and increase stromal diversity as a tumor develops, revealing that stromal cells acquire the capacity to modulate immune landscapes from early disease.Peer reviewe
DMRT1 regulates human germline commitment
Germline commitment following primordial germ cell (PGC) specification during early human development establishes an epigenetic programme and competence for gametogenesis. Here we follow the progression of nascent PGC-like cells derived from human embryonic stem cells in vitro. We show that switching from BMP signalling for PGC specification to Activin A and retinoic acid resulted in DMRT1 and CDH5 expression, the indicators of migratory PGCs in vivo. Moreover, the induction of DMRT1 and SOX17 in PGC-like cells promoted epigenetic resetting with striking global enrichment of 5-hydroxymethylcytosine and locus-specific loss of 5-methylcytosine at DMRT1 binding sites and the expression of DAZL representing DNA methylation-sensitive genes, a hallmark of the germline commitment programme. We provide insight into the unique role of DMRT1 in germline development for advances in human germ cell biology and in vitro gametogenesis
Acute response to pathogens in the early human placenta at single-cell resolution
The placenta is a selective maternal-fetal barrier that provides nourishment and protection from infections. However, certain pathogens can attach to and even cross the placenta, causing pregnancy complications with potential lifelong impacts on the child's health. Here, we profiled at the single-cell level the placental responses to three pathogens associated with intrauterine complicationsâPlasmodium falciparum, Listeria monocytogenes, and Toxoplasma gondii. We found that upon exposure to the pathogens, all placental lineages trigger inflammatory responses that may compromise placental function. Additionally, we characterized the responses of fetal macrophages known as Hofbauer cells (HBCs) to each pathogen and propose that they are the probable niche for T. gondii. Finally, we revealed how P. falciparum adapts to the placental microenvironment by modulating protein export into the host erythrocyte and nutrient uptake pathways. Altogether, we have defined the cellular networks and signaling pathways mediating acute placental inflammatory responses that could contribute to pregnancy complications.</p
Acute response to pathogens in the early human placenta at single-cell resolution
The placenta is a selective maternal-fetal barrier that provides nourishment and protection from infections. However, certain pathogens can attach to and even cross the placenta, causing pregnancy complications with potential lifelong impacts on the child's health. Here, we profiled at the single-cell level the placental responses to three pathogens associated with intrauterine complicationsâPlasmodium falciparum, Listeria monocytogenes, and Toxoplasma gondii. We found that upon exposure to the pathogens, all placental lineages trigger inflammatory responses that may compromise placental function. Additionally, we characterized the responses of fetal macrophages known as Hofbauer cells (HBCs) to each pathogen and propose that they are the probable niche for T. gondii. Finally, we revealed how P. falciparum adapts to the placental microenvironment by modulating protein export into the host erythrocyte and nutrient uptake pathways. Altogether, we have defined the cellular networks and signaling pathways mediating acute placental inflammatory responses that could contribute to pregnancy complications.</p
NF-ÎșB-direct activation of microRNAs with repressive effects on monocyte-specific genes is critical for osteoclast differentiation
Monocyte-to-osteoclast conversion is a unique terminal differentiation process that is exacerbated in rheumatoid arthritis and bone metastasis. The mechanisms implicated in upregulating osteoclast-specific genes involve transcription factors, epigenetic regulators and microRNAs (miRNAs). It is less well known how downregulation of osteoclast-inappropriate genes is achieved. RESULTS: In this study, analysis of miRNA expression changes in osteoclast differentiation from human primary monocytes revealed the rapid upregulation of two miRNA clusters, miR-212/132 and miR-99b/let-7e/125a. We demonstrate that they negatively target monocyte-specific and immunomodulatory genes like TNFAIP3, IGF1R and IL15. Depletion of these miRNAs inhibits osteoclast differentiation and upregulates their targets. These miRNAs are also upregulated in other inflammatory monocytic differentiation processes. Most importantly, we demonstrate for the first time the direct involvement of Nuclear Factor kappa B (NF-ÎșB) in the regulation of these miRNAs, as well as with their targets, whereby NF-ÎșB p65 binds the promoters of these two miRNA clusters and NF-ÎșB inhibition or depletion results in impaired upregulation of their expression. CONCLUSIONS:Our results reveal the direct involvement of NF-ÎșB in shutting down certain monocyte-specific genes, including some anti-inflammatory activities, through a miRNA-dependent mechanism for proper osteoclast differentiation
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