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

Abstract

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.

Isolation and characterization of hematopoietic stem cells in teleost fish

“…These niche cells express a high level of HSC maintenance factors termed "niche factors", including Angiopoietin 1 (Ang-1) (Arai et al, 2004), stem cell factor (SCF) (Heissig et al, 2002), CXCL12 (Sugiyama et al, 2006;Katayama et al, 2006;Kollet et al, 2006), thrombopoietin (Tpo) (Qian et al, 2007;Yoshihara et al, 2007), Wnt (Fleming et al, 2008), Jagged 1 (Jag1) (Calvi et al, 2003;Butler et al, 2010), TGF-β (Yamazaki et al, 2011), osteopontin (OPN) (Nilsson et al, 2005;Stier et al, 2005) CXCL4 (Bruns et al, 2014, N-cadherin (Haug et al, 2008;Hosokawa et al, 2010a;2010b), and E-selectin (Winkler et al, 2012). There are, however, still controversies in the field regarding the precise HSC niche, and a better understanding of the elements that regulate HSCs is required.…”

A network including TGFβ/Smad4, Gata2, and p57 regulates proliferation of mouse hematopoietic progenitor cells

“…Together, this data confirms previous findings of p57 as a downstream target of TGFβ but implies that p57 activation is a secondary effect dependent on the expression/activation of an additional transcriptional regulator. In HSCs (Fig 1D) p57 mRNA levels were higher than in progenitor cells (see Fig 1B) upon harvest, and unaltered by TGFβ-treatment (Fig 1D), possibly due to the previously reported HSC niche-induced TGFβ signaling activity in these cells 7 . In the presence of cycloheximide TGFβ had no effect on p57 expression in HSCs (Fig 1E).…”

“…The importance of the TGFβ pathway in HSC biology has been highlighted by observations of the Smad pathway being specifically activated in HSCs, as well as studies in genetic mouse models where deletion of TGFβRII or Smad4 results in increased proliferation and decreased self-renewal of HSCs 6,7,14 . Accordingly, recent work suggests that the physiological relevance for TGFβ in HSC biology is to keep…”

“…One of these factors is transforming growth factor-β (TGFβ), an evolutionarily conserved growth factor with a well-documented, potent inhibitory effect on hematopoietic stem and progenitor cell (HSPC) proliferation in vitro [2][3][4] , as well as a role in HSC self-renewal in vivo [5][6][7] .…”

“…Smad7), which inhibit the whole signaling pathway, as well as Smad4, which is essential for transmitting the signal into the nucleus 9 . Interestingly, it has been demonstrated that the TGFβ signaling pathway is activated in HSCs in vivo 7,12 and this activation seems to be critical for HSC maintenance as deletion of TGFβ receptor type II (TGFβRII) or Smad4 affects HSC function in vivo resulting in decreased repopulation capacity and selfrenewal 6,7 . While the mechanism mediating TGFβ signaling is well characterized, the downstream effector molecules in hematopoietic progenitors are poorly understood.…”