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

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.
Competing Interests: Declaration of interests F.E.L. is the founder of Micro-Bplex, Inc., serves on the scientific board of Be Biopharma, and is a recipient of grants from the BMGF and Genentech, Inc. I.S. has consulted for GSK, Pfizer, Kayverna, Johnson & Johnson, Celgene, Bristol Myer Squibb, and Visterra. F.E.L, D.C.N., and I.S. are inventors of the issued patents: 9/21/21 US 11,124766 B2 PCT/US2016/036650 and 9/21/21 US 11, 125757 B2 for the PC survival media.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)