HuBMAP Publications

As of July 2023, HuBMAP researchers have published more than 270 scientific papers, presenting advances in software and experimental technologies, and sharing progress in creating maps of healthy human tissues at the cellular level. 
We feature a small selection of those publications below, but you can view all of our publications to learn more about the advances we are making towards creating maps of individual cells of the human body in two and three dimensions.

Featured Publications

Illustration credit: Heidi Schlehlein, Indiana University, and the HuBMAP Consortium

Thirteen scientific papers arising from HuBMAP research are featured in the July 2023 issues of the Nature family of journals, as part of a larger collection of HuBMAP publications.  We are proud to highlight those publications here. 
You can peruse the entire collection at https://hubmapconsortium.org/nature-package.

Advances and Prospects for the Human Biomolecular Atlas Program

 

Jain S, Pei L, Spraggins JM, Angelo M, Carson JP, Gehlenborg N, Ginty F, Gonçalves JP, Hagood JS, Hickey JW, Kelleher NL, Laurent LC, Lin S, Lin Y, Liu H, Naba A, Nakayasu ES, Qian WJ, Radtke A, Robson P, Stockwell BR, Van de Plas R, Vlachos IS, Zhou M; HuBMAP Consortium; Börner K, Snyder MP

 

Published in Nature Cell Biology, July 2023.

Abstract

The Human BioMolecular Atlas Program (HuBMAP) aims to create a multi-scale spatial atlas of the healthy human body at single-cell resolution by applying advanced technologies and disseminating resources to the community. As the HuBMAP moves past its first phase, creating ontologies, protocols and pipelines, this Perspective introduces the production phase: the generation of reference spatial maps of functional tissue units across many organs from diverse populations and the creation of mapping tools and infrastructure to advance biomedical research.

Grant support

NIH Award Nos. U54 HL165442, U01 HL166058, U54 DK134301, OT2 OD033753, U54 EY032442, U54 DK120058, U54 DK134302, OT2 OD033756, OT2 OD026671, UH3 CA246635, UG3 CA256967, U54 HG010426, UH3 CA246633, U54 HD104393, U54 DK127823, OT2 OD033758, UH3 CA246594, U54 EY032442, U54 DK134302, U54 HL145611, U01 HG012680, U54 DK120058, U54 EY032442, U54 DK134302, UG3 CA256959, and U54 HL165440

An atlas of healthy and injured cell states and niches in the human kidney

 

Lake BB, Menon R, Winfree S, Hu Q, Ferreira RM, Kalhor K, Barwinska D, Otto EA, Ferkowicz M, Diep D, Plongthongkum N, Knoten A, Urata S, Mariani LH, Naik AS, Eddy S, Zhang B, Wu Y, Salamon D, Williams JC, Wang X, Balderrama KS, Hoover PJ, Murray E, Marshall JL, Noel T, Vijayan A, Hartman A, Chen F, Waikar SS, Rosas SE, Wilson FP, Palevsky PM, Kiryluk K, Sedor JR, Toto RD, Parikh CR, Kim EH, Satija R, Greka A, Macosko EZ, Kharchenko PV, Gaut JP, Hodgin JB; KPMP Consortium; Eadon MT, Dagher PC, El-Achkar TM, Zhang K, Kretzler M, Jain S.

 

Published in Nature, July 2023.

Abstract

Understanding kidney disease relies on defining the complexity of cell types and states, their associated molecular profiles and interactions within tissue neighbourhoods1. Here we applied multiple single-cell and single-nucleus assays (>400,000 nuclei or cells) and spatial imaging technologies to a broad spectrum of healthy reference kidneys (45 donors) and diseased kidneys (48 patients). This has provided a high-resolution cellular atlas of 51 main cell types, which include rare and previously undescribed cell populations. The multi-omic approach provides detailed transcriptomic profiles, regulatory factors and spatial localizations spanning the entire kidney. We also define 28 cellular states across nephron segments and interstitium that were altered in kidney injury, encompassing cycling, adaptive (successful or maladaptive repair), transitioning and degenerative states. Molecular signatures permitted the localization of these states within injury neighbourhoods using spatial transcriptomics, while large-scale 3D imaging analysis (around 1.2 million neighbourhoods) provided corresponding linkages to active immune responses. These analyses defined biological pathways that are relevant to injury time-course and niches, including signatures underlying epithelial repair that predicted maladaptive states associated with a decline in kidney function. This integrated multimodal spatial cell atlas of healthy and diseased human kidneys represents a comprehensive benchmark of cellular states, neighbourhoods, outcome-associated signatures and publicly available interactive visualizations.

Additional Resources

Organization of the Human Intestine at Single Cell Resolution

 

Hickey JW, Becker WR, Nevins SA, Horning A, Perez AE, Zhu C, Zhu B, Wei B, Chiu R, Chen DC, Cotter DL, Esplin ED, Weimer AK, Caraccio C, Venkataraaman V, Schürch CM, Black S, Brbić M, Cao K, Chen S, Zhang W, Monte E, Zhang NR, Ma Z, Leskovec J, Zhang Z, Lin S, Longacre T, Plevritis SK, Lin Y, Nolan GP, Greenleaf WJ, Snyder M.

 

Published in Nature, July 2023.

Abstract

The intestine is a complex organ that promotes digestion, extracts nutrients, participates in immune surveillance, maintains critical symbiotic relationships with microbiota and affects overall health1. The intesting has a length of over nine metres, along which there are differences in structure and function2. The localization of individual cell types, cell type development trajectories and detailed cell transcriptional programs probably drive these differences in function. Here, to better understand these differences, we evaluated the organization of single cells using multiplexed imaging and single-nucleus RNA and open chromatin assays across eight different intestinal sites from nine donors. Through systematic analyses, we find cell compositions that differ substantially across regions of the intestine and demonstrate the complexity of epithelial subtypes, and find that the same cell types are organized into distinct neighbourhoods and communities, highlighting distinct immunological niches that are present in the intestine. We also map gene regulatory differences in these cells that are suggestive of a regulatory differentiation cascade, and associate intestinal disease heritability with specific cell types. These results describe the complexity of the cell composition, regulation and organization for this organ, and serve as an important reference map for understanding human biology and disease.

Additional Resources

A spatially resolved timeline of the human maternal-fetal interface

 

Greenbaum S, Averbukh I, Soon E, Rizzuto G, Baranski A, Greenwald NF, Kagel A, Bosse M, Jaswa EG, Khair Z, Kwok S, Warshawsky S, Piyadasa H, Goldston M, Spence A, Miller G, Schwartz M, Graf W, Van Valen D, Winn VD, Hollmann T, Keren L, van de Rijn M, Angelo M.

 

Published in Nature, July 2023.

Abstract

Beginning in the first trimester, fetally derived extravillous trophoblasts (EVTs) invade the uterus and remodel its spiral arteries, transforming them into large, dilated blood vessels. Several mechanisms have been proposed to explain how EVTs coordinate with the maternal decidua to promote a tissue microenvironment conducive to spiral artery remodelling (SAR)1-3. However, it remains a matter of debate regarding which immune and stromal cells participate in these interactions and how this evolves with respect to gestational age. Here we used a multiomics approach, combining the strengths of spatial proteomics and transcriptomics, to construct a spatiotemporal atlas of the human maternal-fetal interface in the first half of pregnancy. We used multiplexed ion beam imaging by time-of-flight and a 37-plex antibody panel to analyse around 500,000 cells and 588 arteries within intact decidua from 66 individuals between 6 and 20 weeks of gestation, integrating this dataset with co-registered transcriptomics profiles. Gestational age substantially influenced the frequency of maternal immune and stromal cells, with tolerogenic subsets expressing CD206, CD163, TIM-3, galectin-9 and IDO-1 becoming increasingly enriched and colocalized at later time points. By contrast, SAR progression preferentially correlated with EVT invasion and was transcriptionally defined by 78 gene ontology pathways exhibiting distinct monotonic and biphasic trends. Last, we developed an integrated model of SAR whereby invasion is accompanied by the upregulation of pro-angiogenic, immunoregulatory EVT programmes that promote interactions with the vascular endothelium while avoiding the activation of maternal immune cells.

3D reconstruction of skin and spatial mapping of immune cell density, vascular distance and effects of sun exposure and aging

 

Ghose S, Ju Y, McDonough E, Ho J, Karunamurthy A, Chadwick C, Cho S, Rose R, Corwin A, Surrette C, Martinez J, Williams E, Sood A, Al-Kofahi Y, Falo LD Jr, Börner K, Ginty F.

 

Published in Communications Biology, July 2023.

Abstract

Mapping the human body at single cell resolution in three dimensions (3D) is important for understanding cellular interactions in context of tissue and organ organization. 2D spatial cell analysis in a single tissue section may be limited by cell numbers and histology. Here we show a workflow for 3D reconstruction of multiplexed sequential tissue sections: MATRICS-A (Multiplexed Image Three-D Reconstruction and Integrated Cell Spatial - Analysis). We demonstrate MATRICS-A in 26 serial sections of fixed skin (stained with 18 biomarkers) from 12 donors aged between 32–72 years. Comparing the 3D reconstructed cellular data with the 2D data, we show significantly shorter distances between immune cells and vascular endothelial cells (56 µm in 3D vs 108 µm in 2D). We also show 10–70% more T cells (total) within 30 µm of a neighboring T helper cell in 3D vs 2D. Distances of p53, DDB2 and Ki67 positive cells to the skin surface were consistent across all ages/sun exposure and largely localized to the lower stratum basale layer of the epidermis. MATRICS-A provides a framework for analysis of 3D spatial cell relationships in healthy and aging organs and could be further extended to diseased organs.

 

A spatially anchored transcriptomic atlas of the human kidney papilla identifies significant immune injury in patients with stone disease

 

Canela VH, Bowen WS, Ferreira RM, Syed F, Lingeman JE, Sabo AR, Barwinska D, Winfree S, Lake BB, Cheng YH, Gaut JP, Ferkowicz M, LaFavers KA, Zhang K, Coe FL, Worcester E; Kidney Precision Medicine Project; Jain S, Eadon MT, Williams JC Jr, El-Achkar TM.

 

Published in Nature Communications, July 2023.

Abstract

Kidney stone disease causes significant morbidity and increases health care utilization. In this work, we decipher the cellular and molecular niche of the human renal papilla in patients with calcium oxalate (CaOx) stone disease and healthy subjects. In addition to identifying cell types important in papillary physiology, we characterize collecting duct cell subtypes and an undifferentiated epithelial cell type that was more prevalent in stone patients. Despite the focal nature of mineral deposition in nephrolithiasis, we uncover a global injury signature characterized by immune activation, oxidative stress and extracellular matrix remodeling. We also identify the association of MMP7 and MMP9 expression with stone disease and mineral deposition, respectively. MMP7 and MMP9 are significantly increased in the urine of patients with CaOx stone disease, and their levels correlate with disease activity. Our results define the spatial molecular landscape and specific pathways contributing to stone-mediated injury in the human papilla and identify associated urinary biomarkers.

Anatomical structures, cell types, and biomarkers of the healthy human blood vasculature

 

Boppana A, Lee S, Malhotra R, Halushka M, Gustilo KS, Quardokus E, Herr II BW, Börner K, Weber GM.

 

Published in Scientific Data, July 2023.

Abstract

More than 150 scientists from 17 consortia are collaborating on an international project to build a Human Reference Atlas, which maps all 37 trillion cells in the healthy adult human body. The initial release of this atlas provided hierarchical lists of the anatomical structures, cell types, and biomarkers in 11 organs. Here, we describe the methods we used as part of this initiative to build the first open, computer-readable, and comprehensive database of the adult human blood vasculature, called the Human Reference Atlas-Vasculature Common Coordinate Framework (HRA-VCCF). It includes 993 vessels and their branching connections, 10 cell types, and 10 biomarkers. With this paper we are releasing additional details on vessel types and subtypes, branching sequence, anastomoses, portal systems, microvasculature, functional tissue units, mappings to regions vessels supply or drain, geometric properties of vessels, and links to 3D reference objects. Future versions will add variants and connections to the lymph vasculature; and, it will iteratively expand and improve the database as additional experimental data become available through the participating consortia.

Additional Resources

Organ Mapping Antibody Panels (OMAPs): A community resource for standardized multiplexed tissue imaging

 

Quardokus EM, Saunders DC, McDonough E, Hickey JW, Werlein C, Surrette C, Rajbhandari P, Casals AM, Tian H, Lowery L, Neumann EK, Björklund F, Neelakantan TV, Croteau J, Wiblin AE, Fisher J, Livengood AJ, Dowell KG, Silverstein JC, Spraggins JM, Pryhuber GS, Deutsch G, Ginty F, Nolan GP, Melov S, Jonigk D, Caldwell MA, Vlachos IS, Muller W, Gehlenborg N, Stockwell BR, Lundberg E, Snyder MP, Germain RN, Camarillo JM, Kelleher NL, Börner K, Radtke AJ

 

Published in Nature Methods, July 2023.

Abstract

Multiplexed antibody-based imaging enables the detailed characterization of molecular and cellular organization in tissues. Advances in the field now allow high-parameter data collection (>60 targets); however, considerable expertise and capital are needed to construct the antibody panels employed by these methods. Organ mapping antibody panels are community-validated resources that save time and money, increase reproducibility, accelerate discovery and support the construction of a Human Reference Atlas.

Additional Resources

Segmentation of human functional tissue units in support of a Human Reference Atlas

 

Jain Y, Godwin LL, Ju Y, Sood N, Quardokus EM, Bueckle A, Longacre T, Horning A, Lin Y, Esplin ED, Hickey JW, Snyder MP, Patterson NH, Spraggins JM, Börner K.

 

Published in Commun. Biol., July 2023.

Abstract

The Human BioMolecular Atlas Program (HuBMAP) aims to compile a Human Reference Atlas (HRA) for the healthy adult body at the cellular level. Functional tissue units (FTUs), relevant for HRA construction, are of pathobiological significance. Manual segmentation of FTUs does not scale; highly accurate and performant, open-source machine-learning algorithms are needed. We designed and hosted a Kaggle competition that focused on development of such algorithms and 1200 teams from 60 countries participated. We present the competition outcomes and an expanded analysis of the winning algorithms on additional kidney and colon tissue data, and conduct a pilot study to understand spatial location and density of FTUs across the kidney. The top algorithm from the competition, Tom, outperforms other algorithms in the expanded study, while using fewer computational resources. Tom was added to the HuBMAP infrastructure to run kidney FTU segmentation at scale-showcasing the value of Kaggle competitions for advancing research.

Additional Resources

Specimen, biological structure, and spatial ontologies in support of a Human Reference Atlas

 

Herr BW 2nd, Hardi J, Quardokus EM, Bueckle A, Chen L, Wang F, Caron AR, Osumi-Sutherland D, Musen MA, Börner K.

 

Published in Sci Data, March 2023.

Abstract

The Human Reference Atlas (HRA) is defined as a comprehensive, three-dimensional (3D) atlas of all the cells in the healthy human body. It is compiled by an international team of experts who develop standard terminologies that they link to 3D reference objects, describing anatomical structures. The third HRA release (v1.2) covers spatial reference data and ontology annotations for 26 organs. Experts access the HRA annotations via spreadsheets and view reference object models in 3D editing tools. This paper introduces the Common Coordinate Framework (CCF) Ontology v2.0.1 that interlinks specimen, biological structure, and spatial data, together with the CCF API that makes the HRA programmatically accessible and interoperable with Linked Open Data (LOD). We detail how real-world user needs and experimental data guide CCF Ontology design and implementation, present CCF Ontology classes and properties together with exemplary usage, and report on validation methods. The CCF Ontology graph database and API are used in the HuBMAP portal, HRA Organ Gallery, and other applications that support data queries across multiple, heterogeneous sources.

Additional Resources

Tissue registration and exploration user interfaces in support of a human reference atlas

 

Börner K, Bueckle A, Herr BW 2nd, Cross LE, Quardokus EM, Record EG, Ju Y, Silverstein JC, Browne KM, Jain S, Wasserfall CH, Jorgensen ML, Spraggins JM, Patterson NH, Weber GM

 

Published in Commun Biol., December 2022.

Abstract

Seventeen international consortia are collaborating on a human reference atlas (HRA), a comprehensive, high-resolution, three-dimensional atlas of all the cells in the healthy human body. Laboratories around the world are collecting tissue specimens from donors varying in sex, age, ethnicity, and body mass index. However, harmonizing tissue data across 25 organs and more than 15 bulk and spatial single-cell assay types poses challenges. Here, we present software tools and user interfaces developed to spatially and semantically annotate ("register") and explore the tissue data and the evolving HRA. A key part of these tools is a common coordinate framework, providing standard terminologies and data structures for describing specimen, biological structure, and spatial data linked to existing ontologies. As of April 22, 2022, the "registration" user interface has been used to harmonize and publish data on 5,909 tissue blocks collected by the Human Biomolecular Atlas Program (HuBMAP), the Stimulating Peripheral Activity to Relieve Conditions program (SPARC), the Human Cell Atlas (HCA), the Kidney Precision Medicine Project (KPMP), and the Genotype Tissue Expression project (GTEx). Further, 5,856 tissue sections were derived from 506 HuBMAP tissue blocks. The second "exploration" user interface enables consortia to evaluate data quality, explore tissue data spatially within the context of the HRA, and guide data acquisition. A companion website is at https://cns-iu.github.io/HRA-supporting-information/ .

Additional Resources

Annotation of Spatially Resolved Single-cell Data with STELLAR

 

Brbić M, Cao K, Hickey JW, Tan Y, Snyder MP, Nolan GP, Leskovec J.

 

Published in Nature Methods, November 2022.

Abstract

Accurate cell-type annotation from spatially resolved single cells is crucial to understand functional spatial biology that is the basis of tissue organization. However, current computational methods for annotating spatially resolved single-cell data are typically based on techniques established for dissociated single-cell technologies and thus do not take spatial organization into account. Here we present STELLAR, a geometric deep learning method for cell-type discovery and identification in spatially resolved single-cell datasets. STELLAR automatically assigns cells to cell types present in the annotated reference dataset and discovers novel cell types and cell states. STELLAR transfers annotations across different dissection regions, different tissues and different donors, and learns cell representations that capture higher-order tissue structures. We successfully applied STELLAR to CODEX multiplexed fluorescent microscopy data and multiplexed RNA imaging datasets. Within the Human BioMolecular Atlas Program, STELLAR has annotated 2.6 million spatially resolved single cells with dramatic time savings.

A user-friendly tool for cloud-based whole slide image segmentation with examples from renal histopathology

 

Lutnick B, Manthey D, Becker JU, Ginley B, Moos K, Zuckerman JE, Rodrigues L, Gallan AJ, Barisoni L, Alpers CE, Wang XX, Myakala K, Jones BA, Levi M, Kopp JB, Yoshida T, Zee J, Han SS, Jain S, Rosenberg AZ, Jen KY, Sarder P; Kidney Precision Medicine Project.

 

Published in Commun. Med., August 2022.

Abstract

Background: Image-based machine learning tools hold great promise for clinical applications in pathology research. However, the ideal end-users of these computational tools (e.g., pathologists and biological scientists) often lack the programming experience required for the setup and use of these tools which often rely on the use of command line interfaces.

Methods: We have developed Histo-Cloud, a tool for segmentation of whole slide images (WSIs) that has an easy-to-use graphical user interface. This tool runs a state-of-the-art convolutional neural network (CNN) for segmentation of WSIs in the cloud and allows the extraction of features from segmented regions for further analysis.

Results: By segmenting glomeruli, interstitial fibrosis and tubular atrophy, and vascular structures from renal and non-renal WSIs, we demonstrate the scalability, best practices for transfer learning, and effects of dataset variability. Finally, we demonstrate an application for animal model research, analyzing glomerular features in three murine models.

Conclusions: Histo-Cloud is open source, accessible over the internet, and adaptable for segmentation of any histological structure regardless of stain.