Macrophage-Induced Blood Vessels Guide Schwann Cell-Mediated Regeneration of Peripheral Nerves

Cattin, Anne-Laure; Burden, Jemima J.; Emmenis, Lucie Van; Mackenzie, Francesca E.; Hoving, Julian J.A.; Calavia, Noelia Garcia; Guo, Yao; McLaughlin, Maeve; Rosenberg, Laura H.; Quereda, Víctor; Jamecna, Denisa; Napoli, Ilaria; Parrinello, Simona; Enver, Tariq; Ruhrberg, Christiana; Lloyd, Alison C.

doi:10.1016/j.cell.2015.07.021

Cited by 713 publications

(746 citation statements)

References 43 publications

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Section: Schwann Cells and Their Interactionsmentioning

confidence: 99%

“…For example, hypoxia upregulates VEGF production after nerve injury, initiating migration of Schwann cells 18 . VEGF also stimulates formation of endoneurial blood vessels into hypoxic areas, directing Schwann cells to bridge the gap between the proximal and distal nerve stumps 18 . However, studies have shown that diabetes reduces expression of the Schwann-cell-derived neurotrophic factors ciliary neuronotrophic factor (CNTF) 19 and sonic hedgehog 20 , which act on neurons and endothelial cells, respectively.…”

Section: Schwann Cells and Their Interactionsmentioning

confidence: 99%

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Schwann cell interactions with axons and microvessels in diabetic neuropathy

et al. 2017

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The incidence of diabetes mellitus has increased dramatically over the past two to three decades. According to the International Diabetes Federation Diabetes Atlas, 415 million people worldwide had diabetes in 2015, and this number is expected to grow by 5% annually, predominantly as a result of increasing prevalence of type 2 diabetes. Furthermore, an estimated 100 million Europeans and 80 million Americans have impaired glucose tolerance or prediabetes. Few people die from acute diabetes in countries with comprehensive health care systems, but the disease is inflicting a huge medical, social and economic burden on society owing to the need for lifelong treatment of its systemic consequences and the insidious development of multi-organ damage.Peripheral neuropathy (BOXES 1,2) is a common but often neglected complication of long-term diabetes, and the lack of treatment options reflects an incomplete understanding of the pathogenic mechanisms. Hyperglycaemia is generally accepted as the primary pathogenic insult in type 1 and type 2 diabetic neuropathy, although roles are emerging for other factors, such as impaired insulin signalling, hypertension and dyslipidaemia (particularly for type 2 diabetes), which might precede overt hyperglycaemia 1 . Many preclinical studies, and occasional clinical studies, have indicated that diabetic neuropathy -like diabetic nephropathy and retinopathy -results from microvascular disease, with a focus on axonal degeneration as a consequence of ischaemia and/or hypoxia. This mechanism, however, is likely to be only one aspect of a more complex pathogenesis.The earliest descriptions of pathology in diabetic neuropathy indicated that Schwannopathy accompanied axonal degeneration. The majority of clinical and basic research in diabetic neuropathy since then has focused on the effects on neurons. However, accumulating data from research into the development and regeneration of the PNS has identified Schwann cells as equally indispensable components that maintain neuronal structure and function, nourish axons, and promote survival and growth upon injury. The early reports from 1979 that demonstrated morphological changes in Schwann cells in human diabetic neuropathy 2 are now supported by an increased awareness of molecular alterations in Schwann cells during diabetes 3 . Schwann cells express a wide range of receptors and, when they sense insults or danger signals, they upregulate synthesis and secretion of factors that stimulate neuroprotection, regrowth and remyelination, or factors that aggravate disease phenotypes 4 . The most recent studies have demonstrated that Schwann cells regulate many aspects of axonal function, so that disruption of their metabolism by diabetes results in the accumulation of neurotoxic intermediates and compromises production of neuronal support factors, contributing to axonal degeneration, endothelial dysfunction and diabetic neuropathy. Abstract | The prevalence of diabetes worldwide is at pandemic levels, with the number of patients increasing by 5% annu...

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Section: Schwann Cells and Their Interactionsmentioning

confidence: 99%

Section: Schwann Cells and Their Interactionsmentioning

confidence: 99%

Schwann cell interactions with axons and microvessels in diabetic neuropathy

et al. 2017

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“…Hallmarks of Wallerian degeneration are as follows: (a) detachment of resident Schwann cells from associated axons, (b) transition of these Schwann cells into a “repair Schwann cell” phenotype, (c) breakdown of the blood–nerve barrier, and (d) influx of macrophages into the tissue that, (e) in concert with “repair Schwann cells,” phagocytize axonal and myelin‐derived debris (Chen, Yu, & Strickland, 2007; Jessen, Mirsky, & Lloyd, 2015). During the regeneration phase, macrophages support “repair Schwann cells” in mediating axonal regrowth to re‐innervate the target tissue (Cattin et al, 2015; Mietto, Mostacada, & Martinez, 2015; Mokarram, Merchant, Mukhatyar, Patel, & Bellamkonda, 2012). Regeneration is completed when inflammatory processes resolve and “repair Schwann cells” redifferentiate.…”

Section: Introductionmentioning

confidence: 99%

Inflammaging impairs peripheral nerve maintenance and regeneration

et al. 2018

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The regenerative capacity of peripheral nerves declines during aging, contributing to the development of neuropathies, limiting organism function. Changes in Schwann cells prompt failures in instructing maintenance and regeneration of aging nerves; molecular mechanisms of which have yet to be delineated. Here, we identified an altered inflammatory environment leading to a defective Schwann cell response, as an underlying mechanism of impaired nerve regeneration during aging. Chronic inflammation was detected in intact uninjured old nerves, characterized by increased macrophage infiltration and raised levels of monocyte chemoattractant protein 1 (MCP1) and CC chemokine ligand 11 (CCL11). Schwann cells in the old nerves appeared partially dedifferentiated, accompanied by an activated repair program independent of injury. Upon sciatic nerve injury, an initial delayed immune response was followed by a persistent hyperinflammatory state accompanied by a diminished repair process. As a contributing factor to nerve aging, we showed that CCL11 interfered with Schwann cell differentiation in vitro and in vivo. Our results indicate that increased infiltration of macrophages and inflammatory signals diminish regenerative capacity of aging nerves by altering Schwann cell behavior. The study identifies CCL11 as a promising target for anti‐inflammatory therapies aiming to improve nerve regeneration in old age.

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“…It is known that such space is quickly filled with plasma exudate composed mostly of a fibrin network and platelets. It has been recently shown that blood vessel formation and polarized growth precedes Schwann cell migration, which in turn produce the so-called Bands of Büngner (Cattin et al, 2015). Such cell cords guide the growing axons toward the distal stump of the nerve.…”

Section: Ratio Of the Massesmentioning

confidence: 99%