Single‐cell <scp>RNA</scp>‐seq uncovers novel metabolic functions of Schwann cells beyond myelination

Eid, Stéphanie; Noureldein, Mohamed; Kim, Bhumsoo; Hinder, Lucy M.; Mendelson, Faye E.; Hayes, John M.; Hur, Junguk; Feldman, Eva L.

doi:10.1111/jnc.15877

Cited by 10 publications

(6 citation statements)

References 135 publications

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“…We find that macrophages are recruited into peripheral nerves but not the skin of diabetic mice. Mice on a HFD develop an upregulation of Lgals3 in the sciatic nerve 22 , which is one of the most highly expressed genes in the recMacs that we find infiltrate into the nerves of HFHFD diabetic mice (Fig. 4f).…”

Section: Discussionmentioning

confidence: 83%

“…Macrophages may be recruited into peripheral nerves early in diabetes in response to changes in the nerve microenvironment. Non-neuronal cell types, such as Schwann cells could be modified by the HFHFD as they are responsive to changes in glucose or insulin 22 and may release mediators that alter the nerve resident macrophages to trigger recruitment of circulating myeloid cells. Metabolomic studies show that a HFD alone and when supplemented with low dose streptozotocin modifies the fatty acid composition of the nerve 40 .…”

Section: Discussionmentioning

confidence: 99%

“…The sciatic nerve immune dataset enabled an in-depth analysis of changes in the nerve immune landscape in diabetic neuropathy, which has not been examined before. Recently, another group performed a study in high-fat diet-fed mice 22 , but did not enrich for immune cells, and in consequence did not capture the depth and heterogeneity of our dataset. We identified 13 clusters of immune cells in the sciatic nerve, including five distinct sets of macrophages defined by expression of Csf1r, including 2 sciatic nerve resident macrophages (resMacs) which were Ccr2of which one was Retnla+Clec10a+ and the other Retnla-Clec10a-and are likely the epineural and endoneurial populations previously described 4 .…”

Section: Macrophages Are Recruited Into Nerves Of Diabetic Micementioning

confidence: 99%

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Macrophages protect against sensory axon degeneration in diabetic neuropathy

Woolf,

Hakim,

Jain

et al. 2024

Preprint

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Diabetic peripheral neuropathy (DPN) is a common complication of diabetes, causing sensory loss and debilitating neuropathic pain1,2. Although the onset and progression of DPN have been linked with dyslipidemia and hyperglycemia3, the contribution of inflammation in the pathogenesis of DPN has not been investigated. Here, we use a High Fat High Fructose Diet (HFHFD) to model DPN and its metabolic syndrome in mice. Diabetic mice develop persistent heat hypoalgesia after three months, but a reduction in epidermal skin innervation only manifests at 6 months. Using single-cell sequencing, we find that CCR2+ macrophages infiltrate the sciatic nerves of diabetic mice well before axonal degeneration is detectable. We show that these infiltrating macrophages share gene expression similarities with nerve crush-induced macrophages4 and express neurodegeneration-associated microglia marker genes5 although there is no axon loss or demyelination yet. Inhibiting this macrophage recruitment in diabetic mice by genetically or pharmacologically blocking CCR2 signaling results in a more severe heat hypoalgesia and accelerated skin denervation. These findings reveal a novel neuroprotective recruitment of macrophages into peripheral nerves of diabetic mice that delays the onset of terminal axonal degeneration, thereby reducing sensory loss. Potentiating and sustaining this early neuroprotective immune response in patients represents, therefore, a potential means to reduce or prevent DPN.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Macrophages Are Recruited Into Nerves Of Diabetic Micementioning

confidence: 99%

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Macrophages protect against sensory axon degeneration in diabetic neuropathy

Woolf,

Hakim,

Jain

et al. 2024

Preprint

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“…SNs in HFD (60% high fat)-induced diabetic C57BL/6J mice for 17 weeks’ duration were divided into 4 Schwann cell subpopulations (non-myelinating, myelinating, immature, and repair) and a distinct macrophage cluster. Immature Schwann cells in HFD-mice predicted a transition to myelinating Schwann cell cluster and then macrophage cluster associated with changing the expression of genes involved in lipid metabolism and inflammatory response ( 48 ). These findings also imply that lipid metabolism and inflammatory response are deeply involved in the development and progression of DPN.…”

Section: Omics Studies Of Animal Dpn Modelsmentioning

confidence: 99%

Advantages of omics approaches for elucidating metabolic changes in diabetic peripheral neuropathy

Yako,

Niimi,

Takaku

et al. 2023

Front. Endocrinol.

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Various animal and cell culture models of diabetes mellitus (DM) have been established and utilized to study diabetic peripheral neuropathy (DPN). The divergence of metabolic abnormalities among these models makes their etiology complicated despite some similarities regarding the pathological and neurological features of DPN. Thus, this study aimed to review the omics approaches toward DPN, especially on the metabolic states in diabetic rats and mice induced by chemicals (streptozotocin and alloxan) as type 1 DM models and by genetic mutations (MKR, db/db and ob/ob) and high-fat diet as type 2 DM models. Omics approaches revealed that the pathways associated with lipid metabolism and inflammation in dorsal root ganglia and sciatic nerves were enriched and controlled in the levels of gene expression among these animal models. Additionally, these pathways were conserved in human DPN, indicating the pivotal pathogeneses of DPN. Omics approaches are beneficial tools to better understand the association of metabolic changes with morphological and functional abnormalities in DPN.

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“…The non-myelinating Schwann cells line axons with their cytoplasm but do not produce myelin. SCs sustain peripheral nerve longevity under homeostatic conditions, independent of myelination ( Eid et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Schwann cells in the normal and pathological lung microenvironment

Shurin,

Wheeler,

Shurin

et al. 2024

Front. Mol. Biosci.

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The lungs are a key organ in the respiratory system. They are regulated by a complex network of nerves that control their development, structure, function, and response to various pathological stimuli. Accumulating evidence suggests the involvement of a neural mechanism in different pathophysiological conditions in the lungs and the development and progression of common respiratory diseases. Lung diseases are the chief source of death globally. For instance, lung cancer is the second most commonly diagnosed malignancy, after prostate cancer in men and breast cancer in women, and is the most lethal cancer worldwide. However, although airway nerves are accepted as a mechanistically and therapeutically important feature that demands appropriate emphasizing in the context of many respiratory diseases, significantly less is known about the role of the neuroglial cells in lung physiology and pathophysiology, including lung cancer. New data have uncovered some cellular and molecular mechanisms of how Schwann cells, as fundamental components of the peripheral nervous system, may regulate lung cancer cells’ survival, spreading, and invasiveness in vitro and in vivo. Schwann cells control the formation and maintenance of the lung cancer microenvironment and support metastasis formation. It was also reported that the number of lung cancer-associated Schwann cells correlates with patients’ survival. Different factors secreted by Schwann cells, including microRNA, are known to sharpen the lung cancer environment by regulating the tumor-neuro-immune axis. Further clinical and experimental studies are required to elucidate the detailed role of Schwann cells in creating and maintaining pulmonary tumor-neuro-immune axis, which will advance our understanding of the pathogenesis of lung cancer and may inform therapeutic hypotheses aiming neoplasms and metastases in the lung.

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Single‐cell RNA‐seq uncovers novel metabolic functions of Schwann cells beyond myelination

Cited by 10 publications

References 135 publications

Macrophages protect against sensory axon degeneration in diabetic neuropathy

Macrophages protect against sensory axon degeneration in diabetic neuropathy

Advantages of omics approaches for elucidating metabolic changes in diabetic peripheral neuropathy

Schwann cells in the normal and pathological lung microenvironment

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