Advances in transcriptomics, epigenomics and proteomics have generated a wealth of information about the molecular components of individual cells in the human body, but it is crucial to translate this information into a better understanding of how these components function. The Human BioMolecular Atlas Program (HuBMAP), funded by the Common Fund at the National Institutes of Health, was launched in 2018 to assemble spatial maps of biomolecules, including RNA, proteins and metabolites, in human organs at single-cell resolution, and to provide an open-access data platform, enabling researchers worldwide to access and analyse the data. The ultimate goal of this initiative is to enhance our understanding of how cells work and how they interact with each other in the human body.
The collaborators involved in this initiative have worked together to develop methods, tools and standards for collecting and analysing data. These advancements enable the integration of data across various organs by research groups and consortia. By using these methods, valuable information about the transcriptome, epigenome, proteome, and metabolome across different human tissues and organs have been revealed. These findings cover a wide range of spatial scales, from subcellular resolution at approximately 100 nanometres to organ-level measurements at the centimetre scale. All the data collected by the HuBMAP consortium are freely available on the HuBMAP Data Portal. In this immersive web feature, we will highlight a sample of papers from the HuBMAP package, including three new articles published in Nature, one perspective published in Nature Cell Biology and nine additional publications across the Nature Portfolio.
HuBMAP at a glance
HuBMAP research groups come from universities and institutions both across the USA and around the world. At present, the consortium consists of more than 60 institutions and 400 researchers. These research groups have taken on various tasks within the HuBMAP initiative, including HuBMAP Infrastructure, Visualization & Engagement (HIVE), Rapid Technology Implementation (RTI), Tissue Mapping Centers (TMC), Transformative Technology Development (TTD), and Demonstration Projects (DP).
Dataset types and numbers
As of 17 June, 2023, the HuBMAP Data Portal hosts an impressive collection of 1,879 datasets. These datasets provide comprehensive coverage of 31 different organs, obtained from 189 male and female donors that represent diverse ethnic backgrounds. These valuable datasets were generated by three technological modalities. The first modality is mass spectrometry, which includes proteomics and mass spectrometry imaging techniques. The second modality primarily focuses on microscopy, specifically fluorescence in situ hybridization and antibody-based multiplexed fluorescence imaging. Sequencing-based techniques, such as single-cell/nucleus transcriptomics, chromatin accessibility mapping and spatial transcriptomics, constitute the third modality.
Two phases of HuBMAP
The HuBMAP initiative is structured into two phases: development and production. The primary objective of the development phase, which took place from 2018 to 2022, was to establish the tools and infrastructure for data acquisition, analysis and integration. A notable achievement during this phase was the development of the cross-consortium Human Reference Atlas (HRA) . In addition, the development phase generated 2D single-cell maps for several organs, such as the intestine, kidney and maternal–fetal interface, as well as 3D maps for the skin and kidney. The papers presented in this Feature primarily reflect the advances made during this phase. The production phase, spanning from 2022 to 2026, will generate more datasets from donors who vary in age, sex and race and will construct 3D bimolecular maps at single-cell resolution for individual human organs and for systems that span several organs (such as the vascular and lymphatics systems). A perspective article accompanying the research articles of HuBMAP provides further insights into the achievements and future plans of HuBMAP.
Nature Cell Biology: Advances and prospects for the Human BioMolecular Atlas Program (HuBMAP)
Building tools and infrastructure
A major goal of HuBMAP is to develop a comprehensive Human Reference Atlas (HRA) that encompasses all cells of the human body. To achieve this goal, HuBMAP has established collaborations with 16 consortia, working together to develop a unified reference framework that enables the integration of data collected from different groups across various consortia. As an example, HuBMAP has created Organ Mapping Antibody Panels (OMAPs), which consist of standardized antibody sets designed for multiplexed spatial imaging in seven human organs. Computational tools have been developed to annotate spatially resolved single-cell data (STELLAR) and to segment cells and specific structures such as functional tissue units (for example renal glomeruli and colonic crypts) out of tissue images. Notably, a reconstruction protocol has been established to generate the first 3D map of the skin. The HuBMAP project has also built the first database of the adult human blood vasculature through the creation of the HRA-Vasculature Common Coordinate Framework. Lastly, to facilitate the development and use of HRA, HuBMAP has introduced the Registration User Interface (RUI) and the Exploration User Interface (EUI) to support tissue data registration and exploration, respectively.
Communications Biology: Segmentation of human functional tissue units in support of a Human Reference Atlas
Communications Biology: Tissue registration and exploration user interfaces in support of a human reference atlas
Nature Methods: Annotation of spatially resolved single-cell data with STELLAR
Multimodal spatial maps across organs
Credit: Dr. John Hickey/Nolan Lab/Stanford University
Regional specialization of the intestine
Single-cell transcriptome and chromatin accessibility were mapped onto the spatial expression of proteins across eight different sites of human small and large intestine from nine donors. The map revealed changes in cell composition across regions, including a decrease in epithelial enterocytes and an increase in secretory enterocytes (goblet cells) when moving from the small intestine to the colon.
Cells were locally and spatially organised into neighbourhoods composed of consistent characteristic cell types, including a colon-enriched neighbourhood consisting of neutrophils associated with vasculature and innate immune cells found within stroma and smooth muscle. Neighbourhoods themselves were organised into higher order communities, which included major tissue units such as the muscularis mucosa.
Mapping cell types and neighbourhoods in healthy and diseased kidney
A collaborative study between HuBMAP and the Kidney Precision Medicine Project (KPMP) performed single-cell transcriptomics and chromatin accessibility profiling as well as spatial transcriptomics with tissues collected from 45 healthy donors and 48 patients with acute or chronic kidney diseases (CKD). It not only identified cell types and cell neighbourhoods, but also defined adaptive cell signatures associated with kidney injury that abnormally persist when kidney repair fails and relate to poor renal function in CKD.
Collecting ducts merge at the renal papilla, through which urine flows before entering the ureter. Pathological changes in renal papilla can contribute to the formation of kidney stones. Combining single-nucleus RNA sequencting, spatial transcriptomics and multiplexed imaging, an investigation defined the cellular and molecular niche of kidney papilla specimens obtained from healthy donors and individuals with kidney stones. By comparing the samples, the study revealed the potential involvement of immune activation and extracellular matrix remodelling in the development of kidney stones and identified possible urinary biomarkers that could aid in the diagnosis or monitoring of kidney stones.
Credit: Dr. Michael Angelo & Erin Soon/Stanford University
Mapping the maternal–fetal interface
The first trimester of pregnancy involves invasion of the fetal portion of the placenta into the uterus, along with the remodeling of the maternal arteries to support pregnancy. Mapping protein and transcriptional data across decidua from 66 individuals between 6 and 20 weeks of gestation provided an unprecedented view of this transformative process. Gestational age is related to the frequency of maternal immune and stromal cell types, with more tolerogenic subsets of immune cells increasing with time. The remodelling of the maternal spiral arteries correlated with placental invasion.