Single-cell genomics studies have decoded the immune cell composition of several human prenatal organs but were limited in describing the developing immune system as a distributed network across ...tissues. We profiled nine prenatal tissues combining single-cell RNA sequencing, antigen-receptor sequencing, and spatial transcriptomics to reconstruct the developing human immune system. This revealed the late acquisition of immune-effector functions by myeloid and lymphoid cell subsets and the maturation of monocytes and T cells before peripheral tissue seeding. Moreover, we uncovered system-wide blood and immune cell development beyond primary hematopoietic organs, characterized human prenatal B1 cells, and shed light on the origin of unconventional T cells. Our atlas provides both valuable data resources and biological insights that will facilitate cell engineering, regenerative medicine, and disease understanding.
Human gut development requires the orchestrated interaction of differentiating cell types. Here, we generate an in-depth single-cell map of the developing human intestine at 6–10 weeks ...post-conception. Our analysis reveals the transcriptional profile of cycling epithelial precursor cells; distinct from LGR5-expressing cells. We propose that these cells may contribute to differentiated cell subsets via the generation of LGR5-expressing stem cells and receive signals from surrounding mesenchymal cells. Furthermore, we draw parallels between the transcriptomes of ex vivo tissues and in vitro fetal organoids, revealing the maturation of organoid cultures in a dish. Lastly, we compare scRNA-seq profiles from pediatric Crohn’s disease epithelium alongside matched healthy controls to reveal disease-associated changes in the epithelial composition. Contrasting these with the fetal profiles reveals the re-activation of fetal transcription factors in Crohn’s disease. Our study provides a resource available at www.gutcellatlas.org, and underscores the importance of unraveling fetal development in understanding disease.
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•Single-cell RNA-seq map of the developing and pediatric human intestine•Cycling BEX5+ epithelial precursors are distinct from adult LGR5+ stem cells•Human fetal intestinal organoids mature in culture•Fetal transcription factors are reactivated in the Crohn’s disease epithelium
Elmentaite and Ross et al. generated a detailed single-cell RNA-seq map of the developing human intestine. Data analyses revealed the presence of an early intestinal epithelial precursor cell and the re-activation of fetal transcription factors in the intestinal epithelium of children diagnosed with Crohn’s disease. The study provides a unique resource accessible to all researchers at www.gutcellatlas.org.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
The human immune system is composed of a distributed network of cells circulating throughout the body, which must dynamically form physical associations and communicate using interactions ...between their cell-surface proteomes
1
. Despite their therapeutic potential
2
, our map of these surface interactions remains incomplete
3,4
. Here, using a high-throughput surface receptor screening method, we systematically mapped the direct protein interactions across a recombinant library that encompasses most of the surface proteins that are detectable on human leukocytes. We independently validated and determined the biophysical parameters of each novel interaction, resulting in a high-confidence and quantitative view of the receptor wiring that connects human immune cells. By integrating our interactome with expression data, we identified trends in the dynamics of immune interactions and constructed a reductionist mathematical model that predicts cellular connectivity from basic principles. We also developed an interactive multi-tissue single-cell atlas that infers immune interactions throughout the body, revealing potential functional contexts for new interactions and hubs in multicellular networks. Finally, we combined targeted protein stimulation of human leukocytes with multiplex high-content microscopy to link our receptor interactions to functional roles, in terms of both modulating immune responses and maintaining normal patterns of intercellular associations. Together, our work provides a systematic perspective on the intercellular wiring of the human immune system that extends from systems-level principles of immune cell connectivity down to mechanistic characterization of individual receptors, which could offer opportunities for therapeutic intervention.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. Here, to ...comprehensively map cell lineages, we use single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions in the developing and up to 11 distinct anatomical regions in the healthy paediatric and adult human gut. This reveals the existence of transcriptionally distinct BEST4 epithelial cells throughout the human intestinal tract. Furthermore, we implicate IgG sensing as a function of intestinal tuft cells. We describe neural cell populations in the developing enteric nervous system, and predict cell-type-specific expression of genes associated with Hirschsprung's disease. Finally, using a systems approach, we identify key cell players that drive the formation of secondary lymphoid tissue in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. This catalogue of intestinal cells will provide new insights into cellular programs in development, homeostasis and disease.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
The function of a cell is defined by its intrinsic characteristics and its niche: the tissue microenvironment in which it dwells. Here we combine single-cell and spatial transcriptomics data to ...discover cellular niches within eight regions of the human heart. We map cells to microanatomical locations and integrate knowledge-based and unsupervised structural annotations. We also profile the cells of the human cardiac conduction system
. The results revealed their distinctive repertoire of ion channels, G-protein-coupled receptors (GPCRs) and regulatory networks, and implicated FOXP2 in the pacemaker phenotype. We show that the sinoatrial node is compartmentalized, with a core of pacemaker cells, fibroblasts and glial cells supporting glutamatergic signalling. Using a custom CellPhoneDB.org module, we identify trans-synaptic pacemaker cell interactions with glia. We introduce a druggable target prediction tool, drug2cell, which leverages single-cell profiles and drug-target interactions to provide mechanistic insights into the chronotropic effects of drugs, including GLP-1 analogues. In the epicardium, we show enrichment of both IgG
and IgA
plasma cells forming immune niches that may contribute to infection defence. Overall, we provide new clarity to cardiac electro-anatomy and immunology, and our suite of computational approaches can be applied to other tissues and organs.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Single-cell transcriptomics has allowed unprecedented resolution of cell types/states in the human lung, but their spatial context is less well defined. To (re)define tissue architecture of lung and ...airways, we profiled five proximal-to-distal locations of healthy human lungs in depth using multi-omic single cell/nuclei and spatial transcriptomics (queryable at lungcellatlas.org ). Using computational data integration and analysis, we extend beyond the suspension cell paradigm and discover macro and micro-anatomical tissue compartments including previously unannotated cell types in the epithelial, vascular, stromal and nerve bundle micro-environments. We identify and implicate peribronchial fibroblasts in lung disease. Importantly, we discover and validate a survival niche for IgA plasma cells in the airway submucosal glands (SMG). We show that gland epithelial cells recruit B cells and IgA plasma cells, and promote longevity and antibody secretion locally through expression of CCL28, APRIL and IL-6. This new 'gland-associated immune niche' has implications for respiratory health.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
This chapter focuses on a financial institution that had to operate in a new, democratic South Africa amid exposure to both the macro- and micro-challenges. It explores the development of an ...Assessment Development Centre (ADC) using computer-based simulations (CBSs) and exercises, and provides insight into the development phases of both the CBSs and the ADC exercises. The primary purpose of the ADC was to identify individuals who fitted the profile of the newly created role of a service advisor (SA) and to redeploy individuals who did not fit the profile within the financial institution. Transformation from ADC exercises to integrated business-process business simulations calls for more than mere assessment of the traditional behavioural competencies. The CBS ADC adopts a holistic approach to the management of talent by employing a series of interlinked strategies. The Business Analysis Phase is the most important phase in the development of CBSs and entails meeting and consulting with the client's project team.
When you look back on the history of conservation it's easier to understand the mind- set underpinning these evictions. Aristocrat hunters established the Society for the Preservation of the Fauna of ...the Empire (SPFE, now Flora and Fauna International) in 1903. This was a starting point for the conservation movement, resulting in huge international NGOs that dominate the scene today. At the time SPFE was founded, hunting was an important part of élite society and hunters were becoming concerned that their game was being wiped out. Ironically, the colonialists apparently also felt they were needed to protect Africa and its extraordinary wildlife. The attitudes of these conservationists haven't changed much since. It's very much a colonial, imperialist, racist attitude where the white man is the great saviour, where he knows better than the people who have lived in the forests for generations, where he's a 'sportsman' and indigenous people 'poachers'; where killing for a trophy is noble and killing for food is a waste; where mining, timber, agriculture and tourism infrastructure are necessary but wood fuel for local people is destructive. 1 Survival International, 'Cameroon: WWF complicit in tribal people's abuse', October 2014. nin.tl/WWFBaka 2 M Dowie, Conservation Refugees. The Hundred-Year Conflict between Global Conservation and Native Peoples, The MIT Press, 2009.3 W Fluismann, PandaLeaks, 2014; www.pandaleaks.org 4 C Nichonghaile and D Smith, 'Kenya's Samburu people 'violently evicted'after US charities buy land', The Guardian, 14 December 2011. nin.tl/Samburu-eviction 5 M Dowie, Conservation Refugees. The Hundred-Year Conflict between Global Conservation and Native Peoples, The MIT Press, 2009.6 R P Neumann, 'The Postwar Conservation Boom in British Colonial Africa' in Environmental History, Vol 7, No 1, January 2002.7 Global Witness, Pandering to the Loggers: Why WWF's Global Forest and Trade Network isn't Working, 2011. nin.tl/pandering-to-loggers 8 Greenpeace, 'World Bank ditches shares in Congo-trashing company', 10 December 2007. nin.tl/WB-Olam 9 Forest Peoples Program, nin.tl/sengwer-eviction; M Grainger and K Geary, The New Forests Company and its Uganda Plantations, Oxfam, 2011.10 REDD Monitor, 2012, nin.tl/wwfscandal-tanzania; REDD+ in Madagascar: You can't see the Wood for the Carbon, Amis de la Terre and Basta!, 2013.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
...it can be a tool for social transformation. The Gates Foundation, to pick on the 'elephant in the room,' runs the largest philanthropy in the world through a board that consists of three members ...of the Gates family plus Warren Buffet.
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