Nonmyelinating Schwann Cells Maintain Hematopoietic Stem Cell Hibernation in the Bone Marrow Niche

• Published in: Cell Vol. 147; no. 5; pp. 1146 - 1158
• Main Authors: Yamazaki, Satoshi, Ema, Hideo, Karlsson, Göran, Yamaguchi, Tomoyuki, Miyoshi, Hiroyuki, Shioda, Seiji, Taketo, Makoto M., Karlsson, Stefan, Iwama, Atsushi, Nakauchi, Hiromitsu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.11.2011
• Subjects: Animals; Antigens, CD34 - metabolism; Bone marrow; Bone Marrow - physiology; Clinical Medicine; Denervation; Dormancy; genes; Glial cells; Hematologi; Hematology; hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - physiology; Hibernation; Humans; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; nerve tissue; Nerves; Neuroglia - metabolism; Schwann cells; Schwann Cells - cytology; Schwann Cells - physiology; Smad protein; Stem cells; Sympathectomy; transforming growth factor beta; Transforming Growth Factor beta3 - metabolism
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2011.09.053

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. [Display omitted] ► The TGF-β/Smad signaling pathway is active in dormant hematopoietic stem cells (HSCs) ► Loss of the TGF-β type II receptor reduces long-term repopulating activity in HSCs ► Nonmyelinating Schwann (glial) cells maintain HSC dormancy by activating latent TGF-β ► Autonomic nerve denervation causes glial cell death and rapid loss of HSCs Glial cells ensheathing sympathetic nerves in the bone marrow enable the maintenance of hematopoietic stem cells by activating TGF-β signaling