Mapping the cellular biogeography of human bone marrow niches using single-cell transcriptomics and proteomic imaging.
Shovik Bandyopadhyay, Michael P Duffy, Kyung Jin Ahn, Jonathan H Sussman, Minxing Pang, David Smith, Gwendolyn Duncan, Iris Zhang, Jeffrey Huang, Yulieh Lin, Barbara Xiong, Tamjid Imtiaz, Chia-Hui Chen, Anusha Thadi, Changya Chen, Jason Xu, Melissa Reichart, Zachary Martinez, Caroline Diorio, Chider Chen, Vinodh Pillai, Oraine Snaith, Derek Oldridge, Siddharth Bhattacharyya, Ivan Maillard, Martin Carroll, Charles Nelson, Ling Qin, Kai Tan
Author Information
Shovik Bandyopadhyay: Cellular and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Michael P Duffy: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Kyung Jin Ahn: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Jonathan H Sussman: Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Minxing Pang: Applied Mathematics & Computational Science Graduate Group, University of Pennsylvania, Philadelphia, PA, USA.
David Smith: Center for Single Cell Biology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Gwendolyn Duncan: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
Iris Zhang: Department of Computer and Information Science, University of Pennsylvania, Philadelphia, PA, USA.
Jeffrey Huang: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
Yulieh Lin: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Barbara Xiong: Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Tamjid Imtiaz: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
Chia-Hui Chen: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Anusha Thadi: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Changya Chen: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Jason Xu: Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Melissa Reichart: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Zachary Martinez: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Caroline Diorio: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Chider Chen: Department of Oral and Maxillofacial Surgery/Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Vinodh Pillai: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Oraine Snaith: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Derek Oldridge: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Siddharth Bhattacharyya: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Ivan Maillard: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Martin Carroll: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Charles Nelson: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Ling Qin: Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: qinling@pennmedicine.upenn.edu.
Kai Tan: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Center for Single Cell Biology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: tank1@chop.edu.
Non-hematopoietic cells are essential contributors to hematopoiesis. However, heterogeneity and spatial organization of these cells in human bone marrow remain largely uncharacterized. We used single-cell RNA sequencing (scRNA-seq) to profile 29,325 non-hematopoietic cells and discovered nine transcriptionally distinct subtypes. We simultaneously profiled 53,417 hematopoietic cells and predicted their interactions with non-hematopoietic subsets. We employed co-detection by indexing (CODEX) to spatially profile over 1.2 million cells. We integrated scRNA-seq and CODEX data to link predicted cellular signaling with spatial proximity. Our analysis revealed a hyperoxygenated arterio-endosteal neighborhood for early myelopoiesis, and an adipocytic localization for early hematopoietic stem and progenitor cells (HSPCs). We used our CODEX atlas to annotate new images and uncovered mesenchymal stromal cell (MSC) expansion and spatial neighborhoods co-enriched for leukemic blasts and MSCs in acute myeloid leukemia (AML) patient samples. This spatially resolved, multiomic atlas of human bone marrow provides a reference for investigation of cellular interactions that drive hematopoiesis.
