Understanding heterogeneity of human bone marrow plasma cell maturation and survival pathways by single-cell analyses

• Authors: Meixue Duan, Georgia Institute of Technology, Atlanta; Doan C Nguyen, Emory University; Chester J Joyner, Emory University; Celia L Saney, Emory University; Christopher M Tipton, Emory University; Joel Andrews, Emory University; Sagar Lonial, Emory University; Caroline Kim, Emory University; Ian Hentenaar, Emory University; Astrid Kosters, Emory University; Eliver Ghosn, Emory University; Annette Jackson, Duke University; Stuart Knechtle, Emory University; Stalinraja Maruthamuthu, University of California San Francisco; Sindhu Chandran, University of California San Francisco; Tom Martin, University of California San Francisco; Raja Rajalingam, University of California San Francisco; Flavio Vincenti, University of California San Francisco; Cynthia Breeden, Emory University; Ignacio Sanz, Emory University; Greg Gibson, Georgia Institute of Technology, Atlanta; F. Eun-Hyung Lee, Emory University
• Journal Title: CELL REPORTS
• Volume: Volume 42, Number 7
• Publisher: CELL PRESS | 2023-06-24, Pages 112682-112682
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1016/j.celrep.2023.112682
• Subjects: Biology, Cell; Health Sciences, Public Health; Health Sciences, Immunology; Health Sciences, Oncology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cell Biology; MEMORY B-CELLS; TRANSMEMBRANE ACTIVATOR; ANTIBODY-RESPONSES; MULTIPLE-MYELOMA; EXPRESSION; GENE; DIFFERENTIATION; BINDING; BLOOD; FOXP1

Abstract

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.