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

doi:10.1016/j.celrep.2023.112682

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

Cell Rep. 2023 Jul 25;42(7):112682. doi: 10.1016/j.celrep.2023.112682. Epub 2023 Jun 24.

Authors

Meixue Duan¹, Doan C Nguyen², Chester J Joyner², Celia L Saney², Christopher M Tipton³, Joel Andrews⁴, Sagar Lonial⁴, Caroline Kim², Ian Hentenaar², Astrid Kosters⁵, Eliver Ghosn⁵, Annette Jackson⁶, Stuart Knechtle⁷, Stalinraja Maruthamuthu⁸, Sindhu Chandran⁹, Tom Martin⁹, Raja Rajalingam⁸, Flavio Vincenti¹⁰, Cynthia Breeden¹¹, Ignacio Sanz⁵, Greg Gibson¹, F Eun-Hyung Lee¹²

Affiliations

¹ School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA.
² Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, GA, USA.
³ 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.
⁴ Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
⁵ Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA.
⁶ Departments of Immunology, Duke University, Durham, NC, USA; Department of Surgery, Duke University, Durham, NC, USA.
⁷ Department of Surgery, Duke University, Durham, NC, USA.
⁸ Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, USA.
⁹ Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
¹⁰ Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
¹¹ Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA.
¹² 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. Electronic address: f.e.lee@emory.edu.

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.

Keywords: CP: Immunology; TNF signaling through NFKB; heterogeneity and maturation; human bone marrow; long-lived plasma cell; single-cell sequencing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Antibody-Producing Cells / metabolism
Bone Marrow Cells
Bone Marrow*
Histocompatibility Antigens Class II / metabolism
Humans
Plasma Cells*
Single-Cell Analysis

Substances

Histocompatibility Antigens Class II

Abstract

Publication types

MeSH terms

Substances

Grants and funding