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Stable Changes in Mesenchymal Stromal Cells from Multiple Myeloma Patients Revealed through Their Responses to Toll-Like Receptor Ligands and Epidermal Growth Factor

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Abstract

In human multiple myeloma (MM), the tumor cells exhibit strict dependence on bone marrow (BM) stromal elements. It has been suggested that, in turn, MM cells modify multipotent stromal cells (MSCs), diverting them to support the myeloma. We investigated MM-derived MSCs by comparing their toll-like receptor (TLR) responses to those of MSCs derived from healthy controls. We now report that MM-derived MSCs manifested intact proliferation responses and IL-6 secretion and their adipose and osteogenic differentiation responses to TLR ligands were also similar to those of healthy controls, ranging from augmentation to inhibition. However, MM-derived MSCs were found to be defective in IL-8 secretion and ERK1/2 phosphorylation following TLR-2 activation. Moreover, MM-derived MSCs failed to respond to EGF by elevation of ERK1/2 phosphorylation. The persistence of these changes in extensively cultured MM-derived MSCs, suggests that these cells are stably, if not irreversibly modified.

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Acknowledgements

This study was supported by the Helen and Martin Kimmel Institute for Stem Cell Research and the M.D. Moross Institute for Cancer Research, at the Weizmann Institute, the Charles and David Wolfson Charitable Trust, grant No. 2003117 from the United States-Israel Binational Science Foundation (BSF), Jerusalem, Israel and by grants from the Gabrielle Rich Center for Transplantation Biology. We gratefully acknowledge support for this project provided by a grant from the Legacy Heritage Fund of New York.

DZ is an incumbent of the Joe and Celia Weinstein Professorial Chair at the Weizmann Institute of Science. The authors are indebted to Ms. Varda Segal for her excellent technical assistance. We thank Prof. Edna Schechtman and Dr. Yisrael Parmet for assistance with the statistical analysis and to Prof. Roni Seger for his help and advice.

Conflicts of interest

The authors declare no potential conflicts of interest

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Authors and Affiliations

  1. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel

    Meirav Pevsner-Fischer, Sarit Levin, Tal Hammer-Topaz, Yifat Cohen & Dov Zipori

  2. Department of Immunology, Weizmann Institute of Science, Rehovot, 76100, Israel

    Felix Mor & Irun Robert Cohen

  3. Department of Internal Medicine B, Rabin Medical Center, Tel Aviv University, Beilinson Campus, Ramat Aviv, Israel

    Felix Mor

  4. Department of Hematology, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands

    Gerard Wagemaker

  5. Division of Hematology, Bone Marrow Transplantation and CBB, The Chaim Sheba Medical Center, Tel-Hashomer, 52621, Israel

    Arnon Nagler

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  1. Meirav Pevsner-Fischer
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Correspondence to Dov Zipori.

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Pevsner-Fischer, M., Levin, S., Hammer-Topaz, T. et al. Stable Changes in Mesenchymal Stromal Cells from Multiple Myeloma Patients Revealed through Their Responses to Toll-Like Receptor Ligands and Epidermal Growth Factor. Stem Cell Rev and Rep 8, 343–354 (2012). https://doi.org/10.1007/s12015-011-9310-2

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