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Author Notes:

Correspondence and requests for materials should be addressed to F.-H.L. (email: f.e.lee@emory.edu)

These authors contributed equally: Doan C. Nguyen, Swetha Garimalla

D.C.N. conceived the experimental design, carried out the experiments and wrote the manuscript.

S.G. carried out the experiments and wrote the manuscript.

H.X. and R.W. carried out the proteomics experiments.

S.K. and I.A. helped with the experiments.

J.G. helped develop the MSC isolation.

K.-Y.C. and E.K.W. helped obtain the human BM aspirates.

G.G. supervised the bioinformatics analysis.

J.R. helped obtain human BM specimens.

F.E.L. helped conceive the experimental design.

T.D.R. and I.S. helped conceive the experimental design.

F.E.-H.L. conceived the experimental design and wrote the manuscript.

We thank Jennifer Scantlin, Claudine Nkurunziza, Anna Stephens, Hinel Patel, Maya Lindsay, Sonia Ros, and Sang N. Le for their dedication to human subject recruitment for this study.

We also thank Raghavan Chinnadurai and Holly Lewis for his initial MSC lines; Wayne Harris and Ernestine Mahar in Department of Hematology and Medical Oncology; Aaron Rae in the Children’s Healthcare of Atlanta & Emory University’s Pediatric Flow Cytometry Core; and Robert E. Karaffa and Kametha T. Fife in the Emory Flow Cytometry Core (EFCC; one of the Emory Integrated Core Facilities (EICF)), for their assistance.

We thank Vivien Warren for her technical assistance.

We also thank the Atlanta Clinical & Translational Science Institute (ACTSI) for their assistance in obtaining BM aspirates.

F.E.-H.L. is the founder of MicroBplex, Inc., J.R. received grants from Stryker.

A patent has been applied for by Emory University with F.E.L, I.S. and D.C. N. as named inventors; the patent application number is PCT/US2016/036650.

The remaining authors declare no competing interests.

Subjects:

Research Funding:

This work was supported by: NIH: NIAID: 1R01AI121252, R21Al094218, R21AI109601, 1P01AI125180, P01A1078907, R37AI049660, U01AI045969, HHSN266200500030C (N01-AI50029), U19AI109962, NIH/NCATS UL1 TR000454, R01DK109508.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • MESENCHYMAL STEM-CELLS
  • MEMORY B-CELLS
  • STROMAL CELLS
  • MATRIX METALLOPROTEINASE-1
  • 14-3-3 PROTEINS
  • APRIL
  • IDENTIFICATION
  • DATABASE
  • HYPOXIA
  • MAINTENANCE

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

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Journal Title:

Nature Communications

Volume:

Volume 9, Number 1

Publisher:

, Pages 3698-3698

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2018, The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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