Fibroblastic reticular cells drive sympathetic nerve reinnervation to adapt to lymph node expansion induced by tumor cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE280461 | GEO | 2026/05/01
REPOSITORIES: GEO
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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.
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2016-07-11 | GSE73728 | GEO
Project description:Immune responses within barrier tissues are regulated, in part, by nociceptors, specialized peripheral sensory neurons that detect noxious stimuli. Previous work has shown that nociceptor ablation not only alters local responses at peripheral sites of immune challenge, but also within draining lymph nodes (LNs). The mechanism and significance of nociceptor-dependent modulation of LN homeostasis are unknown. Indeed, although sympathetic innervation of LNs is well documented, it has been unclear whether the LN parenchyma itself is innervated by sensory neurons. Here, using a combination of high-resolution imaging, retrograde viral tracing, optogenetics, and single-cell transcriptomics (scRNA-seq), we describe a sensory neuro-immune circuit that is preferentially located in the outermost cortex of skin-draining LNs. Transcriptomic profiling revealed that sensory neurons that innervate LNs are composed of at least four discrete subsets with a predominance of peptidergic nociceptors, an innervation pattern that is distinct from that in the surrounding skin. To identify potential LN-resident communication partners for LN-innervating sensory neurons, we employed scRNA-seq to generate an atlas of all murine LN cells and, based on receptor-ligand expression patterns, nominated candidate target populations among stromal and immune cells. We experimentally validated these inferred connections by comparing scRNA-seq signatures before and after selective optogenetic stimulation of LN-innervating axons. Acute neuronal activation triggered rapid transcriptional changes preferentially in endothelium and other nodal stroma cells, as well as in several innate leukocyte populations. Thus, LNs are monitored by a unique population of sensory neurons that possess profound immunomodulatory potential.
2019-11-01 | GSE139658 | GEO
Project description:Immune responses within barrier tissues are regulated, in part, by nociceptors, specialized peripheral sensory neurons that detect noxious stimuli. Previous work has shown that nociceptor ablation not only alters local responses at peripheral sites of immune challenge, but also within draining lymph nodes (LNs). The mechanism and significance of nociceptor-dependent modulation of LN homeostasis are unknown. Indeed, although sympathetic innervation of LNs is well documented, it has been unclear whether the LN parenchyma itself is innervated by sensory neurons. Here, using a combination of high-resolution imaging, retrograde viral tracing, optogenetics, and single-cell transcriptomics (scRNA-seq), we describe a sensory neuro-immune circuit that is preferentially located in the outermost cortex of skin-draining LNs. Transcriptomic profiling revealed that sensory neurons that innervate LNs are composed of at least four discrete subsets with a predominance of peptidergic nociceptors, an innervation pattern that is distinct from that in the surrounding skin. To identify potential LN-resident communication partners for LN-innervating sensory neurons, we employed scRNA-seq to generate an atlas of all murine LN cells and, based on receptor-ligand expression patterns, nominated candidate target populations among stromal and immune cells. We experimentally validated these inferred connections by comparing scRNA-seq signatures before and after selective optogenetic stimulation of LN-innervating axons. Acute neuronal activation triggered rapid transcriptional changes preferentially in endothelium and other nodal stroma cells, as well as in several innate leukocyte populations. Thus, LNs are monitored by a unique population of sensory neurons that possess profound immunomodulatory potential.
2019-10-31 | GSE139600 | GEO
Project description:The lymph node is home to resident macrophage populations that are essential for healthy immune function and homeostasis. They are involved in multiple processes including the initiation of the local response to pathogens, halting viral and bacterial spread, and clearance of apoptotic cells, but the macrophage niche and factors that create it are largely undefined. Here we analyse fibroblastic reticular cells (FRCs) as an essential component of the lymph node macrophage niche using single-cell RNA-sequencing. Our analysis revealed that most reticular cell subsets within lymph nodes expressed master macrophage regulator CSF1. We further show that signalling through CSF1R was sufficient to support macrophage development, while in the presence of LPS, FRCs underwent a mechanistic switch and maintained support through CSF1R-independent mechanisms. Our data reveal a critically important role for FRCs in the creation of the parenchymal macrophage niche within LNs.
2023-05-01 | E-MTAB-10908 | biostudies-arrayexpress
Project description:Peripheral nerve injuries due to physical insults or chronic diseases are quite common, yet no pharmacological therapies are available for the effective repair of injured nerves. The slow growth rate of adult nerves and insufficient access to growth factors pose major hurdles in timely reinnervating target tissues and restoring functions after nerve injuries. A better understanding of the molecular changes that occur during the immediate regenerative reprogramming of neurons, stated here as in vivo priming, following nerve injury may reveal ideal candidates for future therapies. Hence, molecular profiling of neuronal soma within the first week of nerve injury has been the gold standard for revealing molecular candidates critical for nerve regeneration. A complementary in vitro regenerative priming approach was recently shown to induce enhanced outgrowth in adult sensory neurons. In this work, we exploited the in vitro priming model to reveal novel candidates for adult nerve regeneration. We performed the whole tissue proteomics analysis of in vitro primed DRGs and compared their molecular profile with that of the in vivo primed, and control DRGs. Through this approach, we identified several commonly and uniquely altered molecules in the in vitro and in vivo primed DRGs that have the potential to modulate adult nerve regrowth. We further validated the growth inducing potential of mesencephalic astrocyte-derived neurotrophic factor (MANF), one of the hits identified in our proteomics analysis, in primary adult sensory neurons. Overall, this study showed that in vitro priming partially reproduces the molecular features in in vivo primed adult sensory neurons. The shortlisted candidates presented here from the two priming approaches may serve as potential therapeutic targets for adult nerve regeneration.
2023-01-06 | PXD031927 | Pride
Project description:Pancreatic cancer is a highly innervated gastrointestinal disease in which sympathetic nerves play a critical role in modulating tumor growth and the tumor microenvironment (TME). While recent studies suggest that sympathetic nerves influence various TME components, including lymphoid and myeloid immune cells, their interactions with cancer-associated fibroblasts (CAFs) remain poorly understood. CAFs are a hallmark of pancreatic tumors and are known to upregulate axon guidance and neuroactive cues, suggesting a potential feedback loop with tumor-innervating nerves. Here, we investigated the bidirectional crosstalk between sympathetic nerves and CAFs in human and mouse pancreatic tumors. Using a chemo-genetic ablation model, we selectively eliminated pancreatic sympathetic nerves and found that denervation significantly reduced tumor size in female mice. To further dissect this interaction, we established co-culture systems with immortalized pancreatic fibroblasts and primary sympathetic neuron explants, identifying key transcriptional changes driven by CAF-sympathetic nerve signaling. Our findings demonstrate that sympathetic signaling enhances CAF activation and extracellular matrix remodeling, while activated CAFs, in turn, induce transcriptional programs in sympathetic neurons associated with nerve injury response. These results establish CAFs as central mediators of the tumor-supportive role of sympathetic nerves, offering new insights into the neural regulation of pancreatic cancer progression.
2026-02-12 | GSE318481 | GEO
Project description:Lymph node is a secondary lymphoid organ that has structural organization related to their immune function, which is highly ordered and compartmentalized. Lymph nodes shelter immune cells and also fibroblastic-like cells such as fibroblastic reticular cells (FRCs). FRCs have mesodermal origin and are classically characterized by the expression of podoplanin (PDPN/gp38) and lack of CD31 expression. FRCs are implicated in several immune processes but the pathways subjacent their function are still a matter of research. Another cell population found in LNs, the double negative cells (DNCs), are even less known. They do not express PDPN or CD31 markers and a specific marker is absent, their localization within the LN is undefined and their phenotype or function, remain to be clarified. Although these cells have been studied in murine models, studies on human FRCs and DNCs are limited and therefore our study should contribute to the understanding of biology and function of these cells and should promote knowledge of efficiency and disorders in the lymph node immune response. This study evaluates gene expression and secretion of cytokines and chemokines in human-derived FRCs and DNCs during homeostasis and following inflammatory stimuli. Our results demonstrate that cytokines and chemokines secreted by human FRCs and DNCs partially differ from those identified in murine models. In addition, our study demonstrates that DNCs expressed a more varied of cytokines when compared with FRCs, while FRCs expressed a wider chemokines pattern. Such differences maybe related with specific functional differences between those cell populations within LNs.
2017-06-12 | GSE89612 | GEO
Project description:This study aimed to quantify the regulation of transcripts in the hairy skin of the back of adult rats in the condition of loss of sensory and autonomic (sympathetic) innervation (i.e., denervated). Denervated skin has reduced wound healing capacity, reduced proliferation of epidermal progenitor cells, and also expresses factors that regulate ingrowth of sensory and sympathetic axons from neighboring regions of innervated skin. It was expected that this quantification f transcript regulation would offer insight into the general and specific mechanisms that may contribute to these important biological processes. All animals were adult (200-250g) Sprague-Dawley female rats. Three conditions were examined. Groups were naive (n=6), 7-day denervated skin (n=5), and 14-day (n=5) denervated skin. Denervation preparations: Full-thickness incision along long-axis of the body 1cm to right of midline (to avoid injuring skin to be sampled). Incision was centered rostro-caudally on the T13 (thoracic 13) costo-vertebral angle so as to allow access to the T9-L2 (lumbar 2) cutaneous nerves. Skin was reflected to the left and the left T9, T10, L1, and L2 dorsal and lateral cutaneous nerves were isolated, ligated with 7-0 monofilament suture close to their exit from the body wall, and transected. Approximately 5mm of the distal portion of the nerve was resected. The T11 nerves were left unperturbed and were not isolated from the surrounding fascia. This generated two strips of skin that were devoid of sensory and autonomic innervation (those strips served by the T9 and T10 nerves, and by the L1 and L2 nerves). Between these denervated strips of skin was a strip of skin that retained the sensory and autonomic axons supplied by T11 nerves. The denervated zones were identified by mapping the cutaneous trunk muscle (CTM) reflex (see Petruska-JC et al. (2013) Journal of Comparative Neurology; Diamond-J et al., (1992) J Neuroscience), and the border marked with pen and remarked every few days. The samples were taken from the rostral (T9/10) denervated zone. Samples from naive animals (no denervation) were taken from the same region, using the dorsal cutaneous nerves as registration landmarks. Animals displayed no signs of overgrooming of the denervated skin. Because the CTM inserts onto the dermis of this region of skin, samples necessarily include both skin and underlying CTM (which is innervated from another source so was not denervated in the experiment).
2014-04-08 | E-GEOD-54356 | biostudies-arrayexpress
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