TNFR1 signaling in sympathetic nerves dampens the inflammatory response in the bone marrow
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PROVIDER: PRJNA1306595 | ENA |
REPOSITORIES: ENA
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Project description:Hematological malignancies and cytotoxic therapy induce sympathetic neuropathy in the bone marrow (BM), leading to niche remodeling, disease progression, and impaired hematopoiesis regeneration after myeloablative therapy. Vincristine induces pro-inflammatory cytokine production in the BM, including tumor necrosis factor a (TNF-a), impairs hematopoietic stem cell function, and harms sympathetic neurons. Deleting TNF receptor R1 (TNFR1) in sympathetic nerves exacerbated hematopoietic stem cell exhaustion. Mechanistically, loss of sympathetic nerve-specific TNFR1 signaling prevented the increase of norepinephrine levels in the BM after vincristine treatment, leading to delayed inflammation resolution due to elevated IL-6 production by BM endothelial cells. Therefore, TNFR1 signaling in sympathetic nerves plays a role in the resolution of the inflammatory state after vincristine treatment. Therapeutic strategies meant to reduce inflammation should be considered to prevent long-term hematopoietic damage in cancer patients.
2025-08-31 | GSE305591 | GEO
Project description:The sympathetic nervous system controls a wide spectrum of bodily functions including operation of vessels, cardiac rhythm, and the “flight or fight response”. Sympathetic neurons, which are neural crest-derived, develop in coordination with presynaptic motor nerves extending from the central nervous system (CNS). By using nerve-selective genetic ablations, we revealed that sympathetic ganglia development depends on CNS-derived motor innervation. In the absence of preganglionic motor nerves, trunk sympathetic chain ganglia were fragmented and smaller in size, while cervical ganglia were severely misshapen. Sympathetic neurons were misplaced along sensory fibers and projected towards abnormal paths, in some cases invading the sensory dorsal root ganglia. The misplaced progenitors of sympathoblasts corresponded to the nerve-associated, neural crest-derived Schwann cell precursors (SCPs). Notably, we found that SCPs activate the autonomic marker PHOX2B while migrating along motor nerves towards the region of the dorsal aorta in wildtype embryos, suggesting that SCP differentiate into sympathetic neurons while still nerve-associated in motor-ablated embryos. Ligand-receptor prediction from single cell transcriptomic data coupled with functional studies identified Semaphorin 3A/3F as candidate motor nerve-derived signals influencing neural crest migration along axons. Thus, motor nerves control the placement of sympathoblasts and their subsequent axonal navigation during critical periods of sympathetic chain development.
2024-07-14 | GSE261748 | GEO
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:Sympathetic nerves regulate intestinal regeneration through IL22 signaling
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Project description:The intestine is a barrier tissue whose epithelium has high intrinsic turnover rate; intestinal stem cells, in response to signals from the niche, self-renew and produce progeny that differentiate to fulfill the continuous demand for new epithelial cells that are continuously shed into the lumen. The intestine is innervated by a dense network of peripheral nerves that controls nutrient absorption, intestinal motility, and visceral pain sensation. However, the roles of neurons in regulating epithelial cell homeostasis or regeneration remain as yet undiscovered. Here we investigate the effects of gut-innervating sympathetic neurons on epithelial cell repair following irradiation (IR)-induced gut injury. We observed that sympathetic innervation density in the gut increases post IR, while chemical sympathetic denervation impairs gut regeneration. Combining single cell RNA-sequencing and in vivo experiments, we discovered that sympathetic neurons regulate gut regeneration through modulation of IL22 production in type 3 innate lymphoid cells (ILC3) downstream of 2-adrenergic receptor signaling. These results define a novel neuroimmune axis important for intestinal regeneration.
2023-08-18 | GSE214821 | GEO
Project description:Hyperactivation of Sympathetic Nerves Drives Melanocyte Stem Cell Depletion
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Project description:Empirical and anecdotal evidence have associated stress with accelerated hair greying (formation of unpigmented hairs), but the scientific evidence linking the two is scant. Here, we report that acute stress leads to hair greying through fast depletion of melanocyte stem cells (MeSCs). Combining adrenalectomy, denervation, chemogenetics, cell ablation, and MeSC-specific adrenergic receptor knockout, we found that stress-induced MeSC loss is independent of immune attack or adrenal stress hormones. Rather, hair greying results from activation of the sympathetic nerves that innervate the MeSC niche. Upon stress, sympathetic nerve activation leads to burst release of the neurotransmitter norepinephrine, which drives quiescent MeSCs into rapid proliferation, followed by differentiation, migration, and permanent depletion from the niche. Transient suppression of MeSC proliferation prevents stress-induced hair greying. Our studies demonstrate that acute stress-induced neuronal activity can drive rapid and permanent loss of somatic stem cells, and illustrate an example in which somatic stem cell maintenance is directly influenced by the overall physiological state of the organism.
2019-11-28 | GSE131566 | GEO
Project description:Motor nerves direct the development of the sympathetic nervous system
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Project description:The β1-adrenergic receptor links sympathetic nerves to T cell exhaustion
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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