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Non-myelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche

Cell 147, 1146-1158, November 23, 2011
Satoshi Yamazaki1, Hideo Ema3, Göran Karlsson4, Tomoyuki Yamaguchi1, 3, Hiroyuki Miyoshi5, 6, Seiji Shioda7, Makoto M. Taketo5, Stefan Karlsson4, Atsushi Iwama2, 8, and Hiromitsu Nakauchi1, 3
1Japan Science and Technology Agency (JST), ERATO and 2CREST, Sanbancho, Chiyoda-ku, Tokyo 102-0075, Japan. 3Division of Stem Cell Therapy, Center for Stem Cell Biology and Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. 4Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University Hospital, BMC A12, 221 84, Lund, Sweden. 5 Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan. 6 Present address: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. 7 Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. 8Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.

Hematopoietic stem cells (HSCs) reside and self-renew in the bone marrow (BM) niche. Overall, the signaling that regulates stem cell dormancy in the HSC niche remains controversial. Here, we demonstrate that TGF-β type II receptor-deficient HSCs show low-level Smad activation and impaired long-term repopulating activity, underlining the critical role of TGF-β/Smad signaling in HSC maintenance. TGF-β is produced as a latent form by a variety of cells, so we searched for those that express activator molecules for latent TGF-β. Nonmyelinating Schwann cells in BM proved responsible for activation. These glial cells ensheathed autonomic nerves, expressed HSC niche factor genes, and were in contact with a substantial proportion of HSCs. Autonomic nerve denervation reduced the number of these active TGF-β-producing cells and led to rapid loss of HSCs from BM. We propose that glial cells are components of a BM niche and maintain HSC hibernation by regulating activation of latent TGF-β.