SLIT2 regulates the skeletal stem cell niche through sympathetic innervation
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ABSTRACT:
PROVIDER: PRJNA1200752 | ENA |
REPOSITORIES: ENA
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Project description:Sympathetic tone has long been known as a central signaling axis inhibiting osteogenesis. However, the mechanism of this nerve to bone influence remains elusive, especially regarding the specific cellular targets of sympathetic activity. Recently, a bona fide tissue-resident stem cell giving rise to skeletal cell types, skeletal stem cells (SSCs), have been identified. To explore if and how nerves impact SSCs, we utilized mice with conditional deletion of SLIT2, a classic axonal repellent, finding that neural (Slit2syn1 mice) and sympathetic (Slit2th mice) but not bone stem/progenitor (Slit2prx1 mice) or sensory (Slit2adv mice) deletion of Slit2, led to osteopenia due to impaired bone formation associated with an increase in sympathetic innervation and a decrease in the numbers of SSCs. Consistent with this, pharmacological or surgical sympathectomy caused expansion of the SSC pool. More directly, wild type (WT) SSCs transplanted orthotopically into the bones of Slit2th mice with increased sympathetic innervation displayed impaired osteogenic capability, demonstrating that sympathetic nerves functionally contribute to the SSC niche. In line with these findings, the increased sympathetic innervation in Slit2th mice disrupted bone regeneration and bone fracture healing by reducing SSC expansion. Transcriptomic profiling in sympathetic neurons identified Follistatin-like 1 (FSTL1) as a SLIT2-regulated soluble factor that suppressed SSC self-renewal and osteogenic capacity. Accordingly, ablation of Fstl1 in sympathetic neurons enhanced SSC-driven osteogenesis and attenuated the bone loss seen in Slit2th mice in vivo. Altogether, our study both newly establishes SLIT2 as a regulator of skeletal sympathetic innervation and establishes sympathetic nerves as a key component of the SSC niche, providing new therapeutic opportunities to augment SSC function to treat skeletal disorders.
2025-07-28 | GSE284991 | GEO
Project description:Low bone mass is strongly associated with multiple neurologic diseases such as Alzheimer’s disease (AD), however it remains unclear if this represents direct specific biologic sequalae of the primary disease process or rather a non-specific finding attributable to alterations in behavior and activity. The recent discovery of skeletal stem cells (SSCs) generating bone forming osteoblasts offers a new opportunity to understand both AD effects on bone and broader neural effects on bone by determining whether there are neural contributions to the SSC niche. Deletion of p75NTR (an essential neurotrophin receptor) was used to probe the contributions of peripheral innervation to the SSC niche. p75NTR deletion either broadly in neurons (p75NTRsyn1 mice) or more specifically in sensory nerves (p75NTRadv mice) but not osteogenic cells (p75NTRocn and p75NTRprx1 mice) or sympathetic nerves (p75NTRth mice), led to decrease in sensory innervation, impaired SSC homeostasis, and bone loss. Consistent with this, pharmacological sensory denervation resulted in a decrease in SSC numbers. More directly, wild-type SSCs transplanted orthotopically into the bones of p75NTRadv host mice with reduced sensory innervation displayed an impaired osteogenic capability, indicating that sensory nerves comprise part of the SSC niche. Decreased sensory innervation in p75NTRadv mice further impaired fracture healing by suppressing SSC expansion. Transcriptomic profiling to identify sensory nerve derived mediators of the SSC niche effect identified that p75NTR regulates expression of Osteopontin (SPP1) in neurons of the dorsal root ganglion (DRG), and SPP1 in turn acts as to promote SSC self-renewal and osteogenic capacity. Lastly, this p75NTR-SPP1 axis is impaired in AD mice, providing a new, direct mechanism for osteopenia in AD both impacting basal bone turnover and fracture repair. Altogether, our findings newly establish sensory nerves as a key component of SSC niche that is disrupted in AD, providing new therapeutic opportunities to augment SSC function to treat bone disorders such as Alzheimer’s associated osteopenia.
2025-08-27 | GSE263602 | GEO
Project description:Regulation of membrane receptors involves management of endocytosis. At the neuromuscular junction, the synapse between skeletal muscle and motoneuron, proper density of the major receptor, the acetylcholine receptor, is of utmost importance for sustaining life in context of mobility. Recent work has revealed innervation of NMJs by sympathetic neurons and destruction of them had morphological and functional consequences, suggesting influence on endocytosis. To investigate the pathways and proteins that are relevant for acetylcholine receptor turnover and affected by sympathetic signaling, proteomes of mouse hindlimb muscles from sympathectomized and saline-treated control muscles were compared. Using proteomic, Western blot, and immunofluorescence analysis in chemically sympathectomized mouse hindlimb muscles, the cause of these consequences were aimed to analyzed. This revealed extensive regulation of the proteome by the sympathetic nervous system and a possible regulatory function of the endo/lysosomal and autophagic pathway by sympathetic neuronal input. This finding might provide a new explanation to the observed benefit of sympathicomimetic treatment in several congenital myasthenic syndromes.
2021-03-01 | PXD021601 | Pride
Project description:Organ-specific Sympathetic Innervation Defines Visceral Functions
| PRJNA1167307 | ENA
Project description:Piloerection (goosebump) requires concerted actions of the hair follicle, the arrector pili muscle (APM), and the sympathetic nerve, providing a model to study interactions across epithelium, mesenchyme, and nerves. Here, we show that APMs and sympathetic nerves form a dual component niche to modulate hair follicle stem cell (HFSC) activity. Sympathetic nerves form synapse-like structures with HFSCs and regulate HFSCs through norepinephrine, whereas APMs maintain sympathetic innervation to HFSCs. Without norepinephrine signaling, HFSCs enter a deep quiescence state by down-regulating cell cycle machinery and mitochondria metabolism, while up-regulating quiescence regulators Lhx2, Foxp1, and Fgf18. During development, HFSC progeny secrets Sonic Hedgehog (SHH) to direct the formation of this APM-sympathetic nerve niche, which in turn controls hair follicle regeneration in adults. Our results reveal a reciprocal interdependence between a regenerative tissue and its niche at different stages, and illustrate that nerves can modulate stem cell quiescence through synapses and neurotransmitters.
2020-07-15 | GSE130240 | GEO
Project description:Dysregulation of glucagon secretion in type 1 diabetes (T1D) involves hypersecretion during postprandial states, but insufficient secretion during hypoglycemia. The sympathetic nervous system regulates glucagon secretion. To investigate islet sympathetic innervation in T1D, sympathetic tyrosine hydroxylase (TH) axons were analyzed in control non-diabetic organ donors, non-diabetic islet autoantibody-positive individuals (AAb), and age-matched persons with T1D. Islet TH axon numbers and density were significantly decreased in AAb compared to T1D with no significant differences observed in exocrine TH axon volume or lengths between groups. TH axons were in close approximation to islet α-cells in T1D individuals with long-standing diabetes. Islet RNA-sequencing and qRT-PCR analyses identified significant alterations in noradrenalin degradation, α-adrenergic signaling, cardiac b-adrenergic signaling, catecholamine biosynthesis, and additional neuropathology pathways. The close approximation of TH axons at islet α-cells supports a model for sympathetic efferent neurons directly regulating glucagon secretion. Sympathetic islet innervation and intrinsic adrenergic signaling pathways could be novel targets for improving glucagon secretion in T1D.
2021-08-09 | GSE181674 | GEO
Project description:The sympathetic nervous system innervates peripheral organs to regulate their function and maintain homeostasis, whereas target cells also produce neurotrophic factors to promote sympathetic innervation1,2. The molecular basis of this bi-directional communication is unknown. Here we use thermogenic adipose tissue from mice as a model system to show that T cells, specifically T cells, have a crucial role in promoting sympathetic innervation, at least in part by driving the expression of TGF1 in parenchymal cells via the IL-17 receptor complex (IL-17RC). Ablation of IL-17RC specifically in adipose tissue reduces expression of TGF1 in adipocytes, impairs local sympathetic innervation and causes obesity and other metabolic phenotypes that are consistent with defective thermogenesis; innervation can be fully rescued by restoring TGF1 expression. Ablating cells and the IL-17RC signalling pathway also impairs sympathetic innervation in salivary glands and the lungs. These findings demonstrate coordination between T cells and parenchymal cells to regulate sympathetic innervation.
2020-03-02 | PXD017424 | Pride
Project description:The p75 neurotrophin receptor regulates the skeletal stem cell niche through sensory innervation
| PRJNA1098239 | ENA
Project description:The sympathetic nervous system innervates peripheral organs to regulate their function and maintain homeostasis, whereas target cells also produce neurotrophic factors to promote sympathetic innervation. The molecular basis of this bi-directional communication remains to be fully elucidated. We use thermogenic adipose tissue as a model system to show that T cells, specifically gdT cells, play a critical role in promoting sympathetic innervation, at least in part through driving TGFβ1 expression in parenchymal cells via IL-17 Receptor C. Adipose-specific ablation of IL-17 Receptor C reduces TGFβ1 expression in adipocytes, impairs local sympathetic innervation and causes obesity and other metabolic phenotypes consistent with defective thermogenesis; innervation can be fully rescued by restoring TGFβ1 expression. Ablating gdT cells and the IL-17 Receptor C signaling pathway also impairs sympathetic innervation in salivary glands and the lung. These findings demonstrate T cell/parenchymal cell coordination to regulate sympathetic innervation.
2020-02-28 | GSE144255 | GEO
Project description:We performed single-cell RNA-seq (10x Chromium 3' v.3.1) on dissociated single cell suspensions from mouse (C57BL/6) celiac and superior mesenteric sympathetic ganglia to determine transcriptomic cell types. We identified sympathetic neuron types that specifically innervate unique combinations of visceral organs and control physiological functions.
2024-10-02 | GSE278457 | GEO