Factors of the bone marrow microniche that support human plasma cell survival and immunoglobulin secretion/CORRECTION

• Type of Material: Article
• Authors: Doan C. Nguyen, Emory University; Swetha Garimalla, Georgia Institute of Technology; Haopeng Xiao, Georgia Institute of Technology; Shuya Kyu, Emory University; Igor Albizua, Emory University; Jacques Galipeau, Emory University; Kuang-Yueh Chiang, University of Toronto; Edmund Waller, Emory University; Ronghu Wu, Georgia Institute of Technology; Greg Gibson, Georgia Institute of Technology; James Roberson, Emory University; Frances E. Lund, University of Alabama Birmingham; Troy D. Randall, University of Alabama Birmingham; Ignacio Sanz, Emory University; Frances Lee, Emory University
• Language: English
• Date: 2018-09-12
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2018, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-018-05853-7
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 9
• Issue: 1
• Start Page: 3698
• End Page: 3698
• Grant/Funding Information: This work was supported by: NIH: NIAID: 1R01AI121252, R21Al094218, R21AI109601, 1P01AI125180, P01A1078907, R37AI049660, U01AI045969, HHSN266200500030C (N01-AI50029), U19AI109962, NIH/NCATS UL1 TR000454, R01DK109508.
• Keywords: MESENCHYMAL STEM-CELLS; MEMORY B-CELLS; APRIL; IDENTIFICATION; 14-3-3 PROTEINS; Science & Technology; MAINTENANCE; DATABASE; STROMAL CELLS; Science & Technology - Other Topics; HYPOXIA; MATRIX METALLOPROTEINASE-1; Multidisciplinary Sciences
• Research Categories: Health Sciences, Oncology; Biology, Cell; Chemistry, Biochemistry

Abstract

Human antibody-secreting cells (ASC) in peripheral blood are found after vaccination or infection but rapidly apoptose unless they migrate to the bone marrow (BM). Yet, elements of the BM microenvironment required to sustain long-lived plasma cells (LLPC) remain elusive. Here, we identify BM factors that maintain human ASC > 50 days in vitro. The critical components of the cell-free in vitro BM mimic consist of products from primary BM mesenchymal stromal cells (MSC), a proliferation-inducing ligand (APRIL), and hypoxic conditions. Comparative analysis of protein–protein interactions between BM-MSC proteomics with differential RNA transcriptomics of blood ASC and BM LLPC identify two major survival factors, fibronectin and YWHAZ. The MSC secretome proteins and hypoxic conditions play a role in LLPC survival utilizing mechanisms that downregulate mTORC1 signaling and upregulate hypoxia signatures. In summary, we identify elements of the BM survival niche critical for maturation of blood ASC to BM LLPC.