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Blood Cells Need Glia, Too: A New Role for the Nervous System in the Bone Marrow Niche

2011; Elsevier BV; Volume: 9; Issue: 6 Linguagem: Inglês

10.1016/j.stem.2011.11.016

1934-5909

Katja Brückner,

Neurogenesis and neuroplasticity mechanisms

Regulation of hematopoietic stem cell (HSC) dormancy by specific cell types in the hematopoietic niche remains poorly understood. Yamazaki et al., 2011Yamazaki S. Ema H. Karlsson G. Yamaguchi T. Miyoshi H. Shioda S. Taketo M.M. Karlsson S. Iwama A. Nakauchi H. Cell. 2011; 147: 1146-1158Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar now report that nerve-associated nonmyelinating Schwann cells activate TGF-β to maintain dormant HSCs, suggesting that glia are novel players in the bone marrow niche. Regulation of hematopoietic stem cell (HSC) dormancy by specific cell types in the hematopoietic niche remains poorly understood. Yamazaki et al., 2011Yamazaki S. Ema H. Karlsson G. Yamaguchi T. Miyoshi H. Shioda S. Taketo M.M. Karlsson S. Iwama A. Nakauchi H. Cell. 2011; 147: 1146-1158Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar now report that nerve-associated nonmyelinating Schwann cells activate TGF-β to maintain dormant HSCs, suggesting that glia are novel players in the bone marrow niche. Hematopoietic stem cells (HSCs) reside in specialized microenvironments, or niches, that ensure their localization, survival, controlled proliferation, and differentiation. Components of the bone marrow (BM) hematopoietic niche include mesenchymal stem cells (MSCs), which secrete HSC homing and maintenance factors; osteoblasts, which derive from MSCs and line the surface of the endosteum on the inside of the bone cavity; and sympathetic nerve fibers, which coordinate hematopoietic responses with systemic cues and central nervous system inputs (Ehninger and Trumpp, 2011Ehninger A. Trumpp A. J. Exp. Med. 2011; 208: 421-428Crossref PubMed Scopus (413) Google Scholar, Katayama et al., 2006Katayama Y. Battista M. Kao W.M. Hidalgo A. Peired A.J. Thomas S.A. Frenette P.S. Cell. 2006; 124: 407-421Abstract Full Text Full Text PDF PubMed Scopus (1021) Google Scholar, Méndez-Ferrer et al., 2008Méndez-Ferrer S. Lucas D. Battista M. Frenette P.S. Nature. 2008; 452: 442-447Crossref PubMed Scopus (944) Google Scholar, Méndez-Ferrer et al., 2010Méndez-Ferrer S. Michurina T.V. Ferraro F. Mazloom A.R. Macarthur B.D. Lira S.A. Scadden D.T. Ma'ayan A. Enikolopov G.N. Frenette P.S. Nature. 2010; 466: 829-834Crossref PubMed Scopus (2468) Google Scholar). Consistent with differences in the proliferation of HSC populations, current models propose an "endosteal niche," which controls HSC quiescence or dormancy, and a "vascular niche" in the center of the bone cavity, which promotes HSC self-renewal (Ehninger and Trumpp, 2011Ehninger A. Trumpp A. J. Exp. Med. 2011; 208: 421-428Crossref PubMed Scopus (413) Google Scholar). The precise cellular interactions and molecular mechanisms controlling the dormancy, or "hibernation," of HSCs remain elusive. In a recent study in Cell, Nakauchi and colleagues make the surprising finding that nonmyelinating Schwann cells, a type of glia wrapping around nerve fibers in the BM, constitute a novel functional component of the hematopoietic niche important for maintaining HSC dormancy (Yamazaki et al., 2011Yamazaki S. Ema H. Karlsson G. Yamaguchi T. Miyoshi H. Shioda S. Taketo M.M. Karlsson S. Iwama A. Nakauchi H. Cell. 2011; 147: 1146-1158Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar). Previously, the Nakauchi group reported that TGF-β signaling induces HSC quiescence by inhibiting raft microdomain clustering and reducing activation of src and signaling pathways that drive HSC proliferation (Yamazaki et al., 2009Yamazaki S. Iwama A. Takayanagi S. Eto K. Ema H. Nakauchi H. Blood. 2009; 113: 1250-1256Crossref PubMed Scopus (233) Google Scholar). Inactive TGF-β, in the form of a Large Latent Complex (LLC), is known to be produced by several cell types in the BM niche, including HSCs. However, which constituent of the hematopoietic niche would activate TGF-β and make it available to HSCs remained unclear (Yamazaki et al., 2009Yamazaki S. Iwama A. Takayanagi S. Eto K. Ema H. Nakauchi H. Blood. 2009; 113: 1250-1256Crossref PubMed Scopus (233) Google Scholar). In their current paper, Nakauchi and colleagues reveal that nonmyelinating Schwann cells of the peripheral nervous system are the major source of active TGF-β in the BM. Schwann cells ensheath peripheral neurons of the autonomic, i.e., the sympathetic and parasympathetic, and the sensory nervous systems, by tightly wrapping around axons. Myelinating Schwann cells insulate larger axons but thin extensions such as the postganglionic sympathetic axons in the BM are ensheathed by nonmyelinating Schwann cells. Activation of TGF-β depends on its release from the LLC. In this complex, TGF-β is kept inactive by Latency Associated Protein (LAP), which derives from the TGF-β precursor and binds to Latent TGF-β Binding Protein 1 (LTBP-1), which tethers the complex to the extracellular matrix. Yamazaki et al. found that integrin β8, which is known to activate TGF-β from the LLC, was specifically expressed by nonmyelinating Schwann cells and colocalized with active TGF-β. Based on this, the authors propose a model in which integrin αvβ8 binds to LAP to enable activation of TGF-β, potentially involving proteolytic cleavage (Figure 1). The authors next took advantage of the fact that glia depend on trophic support from their associated neurons and performed unilateral transection of postganglionic sympathetic nerves in the lumbar trunk to reduce the number of active TGF-β producing Schwann cells in the BM. While the total number of BM cells was not affected by this procedure, relative numbers of HSCs in the BM were reduced and HSCs displayed reduced levels of TGF-β signaling as well as increased proliferation. This phenotype resembled that of HSCs under reduced TGF-β signaling conditions (Tgfbr2+/−) and was reversed by prior infusion of active TGF-β in the denervated mice. BM denervation did not affect the repopulating capacity of the HSCs per se, nor did it trigger measurable egress of HSCs into the peripheral blood or spleen. These observations support the conclusion that active TGF-β produced by Schwann cells controls HSC dormancy in the BM but also raise some interesting questions. Although denervation did not significantly change the number of other niche cells, i.e., MSCs, osteoblasts, or endothelial cells, it seems possible that this procedure could have resulted in functional changes in these or other cell types of the hematopoietic microenvironment. Furthermore, lack of sympathetic innervation in itself, independent from glia or TGF-β signaling, could also have contributed to the observed HSC defects. In this context, it is noteworthy that several recent reports have described a functional role of the peripheral nervous system (PNS) in the hematopoietic niche (Katayama et al., 2006Katayama Y. Battista M. Kao W.M. Hidalgo A. Peired A.J. Thomas S.A. Frenette P.S. Cell. 2006; 124: 407-421Abstract Full Text Full Text PDF PubMed Scopus (1021) Google Scholar, Makhijani et al., 2011Makhijani K. Alexander B. Tanaka T. Rulifson E. Brückner K. Development. 2011; 138: 5379-5391Crossref PubMed Scopus (142) Google Scholar, Méndez-Ferrer et al., 2008Méndez-Ferrer S. Lucas D. Battista M. Frenette P.S. Nature. 2008; 452: 442-447Crossref PubMed Scopus (944) Google Scholar, Méndez-Ferrer et al., 2010Méndez-Ferrer S. Michurina T.V. Ferraro F. Mazloom A.R. Macarthur B.D. Lira S.A. Scadden D.T. Ma'ayan A. Enikolopov G.N. Frenette P.S. Nature. 2010; 466: 829-834Crossref PubMed Scopus (2468) Google Scholar, Spiegel et al., 2007Spiegel A. Shivtiel S. Kalinkovich A. Ludin A. Netzer N. Goichberg P. Azaria Y. Resnick I. Hardan I. Ben-Hur H. et al.Nat. Immunol. 2007; 8: 1123-1131Crossref PubMed Scopus (267) Google Scholar). Studies by Frenette and colleagues demonstrated regulation of HSC trafficking and other behaviors by the sympathetic nervous system, both under physiological activation conditions such as circadian inputs from the central nervous system (Méndez-Ferrer et al., 2008Méndez-Ferrer S. Lucas D. Battista M. Frenette P.S. Nature. 2008; 452: 442-447Crossref PubMed Scopus (944) Google Scholar) and under experimental challenges such as G-CSF stimulation (Katayama et al., 2006Katayama Y. Battista M. Kao W.M. Hidalgo A. Peired A.J. Thomas S.A. Frenette P.S. Cell. 2006; 124: 407-421Abstract Full Text Full Text PDF PubMed Scopus (1021) Google Scholar). In both instances, sympathetic adrenergic signals affect the expression of CXCL12 in MSCs or osteoblasts, resulting in reduced signaling through the corresponding receptor CXCR4 on HSCs and HSC egress from the BM (Katayama et al., 2006Katayama Y. Battista M. Kao W.M. Hidalgo A. Peired A.J. Thomas S.A. Frenette P.S. Cell. 2006; 124: 407-421Abstract Full Text Full Text PDF PubMed Scopus (1021) Google Scholar, Méndez-Ferrer et al., 2008Méndez-Ferrer S. Lucas D. Battista M. Frenette P.S. Nature. 2008; 452: 442-447Crossref PubMed Scopus (944) Google Scholar, Méndez-Ferrer et al., 2010Méndez-Ferrer S. Michurina T.V. Ferraro F. Mazloom A.R. Macarthur B.D. Lira S.A. Scadden D.T. Ma'ayan A. Enikolopov G.N. Frenette P.S. Nature. 2010; 466: 829-834Crossref PubMed Scopus (2468) Google Scholar). Sympathetic signals, such as the neurotransmitters dopamine and norepinephrine, can also trigger HSCs directly to regulate HSC proliferation, migration, and mobilization; their cognate receptors are expressed on HSCs, in particular under G-CSF-induced conditions (Spiegel et al., 2007Spiegel A. Shivtiel S. Kalinkovich A. Ludin A. Netzer N. Goichberg P. Azaria Y. Resnick I. Hardan I. Ben-Hur H. et al.Nat. Immunol. 2007; 8: 1123-1131Crossref PubMed Scopus (267) Google Scholar). Roles of the PNS in the hematopoietic niche may be widely conserved across phyla. Recently, genetics and live-imaging studies in the Drosophila larva showed that blood cells colonize hematopoietic "niches," i.e., segmentally repeated epidermal-muscular pockets jointly shared with cells of the PNS, and rely on the PNS for their localization and trophic survival (Makhijani et al., 2011Makhijani K. Alexander B. Tanaka T. Rulifson E. Brückner K. Development. 2011; 138: 5379-5391Crossref PubMed Scopus (142) Google Scholar). In vertebrates, the PNS is also a player in the microenvironments of secondary lymphoid organs and other, nonhematopoietic organ systems. Lymph nodes and spleen are highly innervated by sympathetic nerve fibers, which control the maturation and regulation of T cells and macrophages. This innervation provides a direct anatomical link allowing inputs from the central nervous system to regulate physiological and pathological immune responses (Straub, 2004Straub R.H. Trends Pharmacol. Sci. 2004; 25: 640-646Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). So far, in all these systems, attention has mostly been drawn to neuron-related functions. The findings by Yamazaki et al. challenge this existing view and encourage parallel studies on the role of glia relative to the contribution of neurons in PNS-dependent niches. An outstanding question arising from the work by Nakauchi and colleagues is whether the activity of Schwann cells and the release of active TGF-β are regulated by neural activity of the nerve fibers they are ensheathing. In the PNS, sensory neurons of the dorsal root ganglia directly regulate their associated Schwann cells by ATP-based purinergic signaling and other neurotransmitters. This and similar neuron-glia communications do not require synaptic contacts and can take place at all neuron-glia interfaces, e.g., along nerve fibers or at the somata of neurons (Fields and Burnstock, 2006Fields R.D. Burnstock G. Nat. Rev. Neurosci. 2006; 7: 423-436Crossref PubMed Scopus (663) Google Scholar). By which mechanisms nervous inputs may control glial activity that affects the BM and other hematopoietic or nonhematopoietic niches will be an intriguing topic to explore in the future. Nonmyelinating Schwann Cells Maintain Hematopoietic Stem Cell Hibernation in the Bone Marrow NicheYamazaki et al.CellNovember 23, 2011In BriefGlial cells ensheathing sympathetic nerves in the bone marrow enable the maintenance of hematopoietic stem cells by activating TGF-β signaling Full-Text PDF Open Archive