Understanding heterogeneity of human bone marrow plasma cell maturation and survival pathways by single-cell analyses
Meixue Duan,
Doan C. Nguyen,
Chester J. Joyner,
Celia L. Saney,
Christopher M. Tipton,
Joel Andrews,
Sagar Lonial,
Caroline Kim,
Ian Hentenaar,
Astrid Kosters,
Eliver Ghosn,
Annette Jackson,
Stuart Knechtle,
Stalinraja Maruthamuthu,
Sindhu Chandran,
Tom Martin,
Raja Rajalingam,
Flavio Vincenti,
Cynthia Breeden,
Ignacio Sanz,
Greg Gibson,
F. Eun-Hyung Lee
Affiliations
Meixue Duan
School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA
Doan C. Nguyen
Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, GA, USA
Chester J. Joyner
Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, GA, USA
Celia L. Saney
Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, GA, USA
Christopher M. Tipton
Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, GA, USA; Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
Joel Andrews
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
Sagar Lonial
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
Caroline Kim
Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, GA, USA
Ian Hentenaar
Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, GA, USA
Astrid Kosters
Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
Eliver Ghosn
Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
Annette Jackson
Departments of Immunology, Duke University, Durham, NC, USA; Department of Surgery, Duke University, Durham, NC, USA
Stuart Knechtle
Department of Surgery, Duke University, Durham, NC, USA
Stalinraja Maruthamuthu
Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, USA
Sindhu Chandran
Department of Medicine, University of California San Francisco, San Francisco, CA, USA
Tom Martin
Department of Medicine, University of California San Francisco, San Francisco, CA, USA
Raja Rajalingam
Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, USA
Flavio Vincenti
Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
Cynthia Breeden
Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
Ignacio Sanz
Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
Greg Gibson
School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA
F. Eun-Hyung Lee
Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, GA, USA; Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA; Corresponding author
Summary: Human bone marrow (BM) plasma cells are heterogeneous, ranging from newly arrived antibody-secreting cells (ASCs) to long-lived plasma cells (LLPCs). We provide single-cell transcriptional resolution of 17,347 BM ASCs from five healthy adults. Fifteen clusters are identified ranging from newly minted ASCs (cluster 1) expressing MKI67 and high major histocompatibility complex (MHC) class II that progress to late clusters 5–8 through intermediate clusters 2–4. Additional ASC clusters include the following: immunoglobulin (Ig) M predominant (likely of extra-follicular origin), interferon responsive, and high mitochondrial activity. Late ASCs are distinguished by G2M checkpoints, mammalian target of rapamycin (mTOR) signaling, distinct metabolic pathways, CD38 expression, utilization of tumor necrosis factor (TNF)-receptor superfamily members, and two distinct maturation pathways involving TNF signaling through nuclear factor κB (NF-κB). This study provides a single-cell atlas and molecular roadmap of LLPC maturation trajectories essential in the BM microniche. Altogether, understanding BM ASC heterogeneity in health and disease enables development of new strategies to enhance protective ASCs and to deplete pathogenic ones.
