M2 muscarinic receptor activation regulates schwann cell differentiation and myelin organization

Uggenti, Carolina; Stefano, Maria Egle De; Costantino, Michele; Loreti, Simona; Pisano, Annalinda; Avallone, Bice; Talora, Claudio; Magnaghi, Valerio; Tata, Ada Maria

doi:10.1002/dneu.22161

Cited by 31 publications

(58 citation statements)

References 50 publications

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“…Moreover, it is known that NGF, acting through neuronal TrkA, strongly regulates myelination of DRG axons by both SCs and oligodendrocytes 60 . In accordance with our previous work on SCs 23 and dASCs 33 , NGF release could act in an autocrine way, via trkA and p75NTR receptors, improving SCs activity during nerve regeneration. This article postulates the first evidence of the involvement of muscarinic receptors, and in particular M2 receptor, in the regulation of nerve growth factor expression and release in the PNS.…”

Section: Discussionsupporting

confidence: 92%

Muscarinic receptors modulate Nerve Growth Factor production in rat Schwann-like adipose-derived stem cells and in Schwann cells

Piovesana

Faroni

Taggi

et al. 2020

Sci Rep

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Regenerative capability of the peripheral nervous system after injury is enhanced by Schwann cells (Scs)producing several growth factors. the clinical use of Scs in nerve regeneration strategies is hindered by the necessity of removing a healthy nerve to obtain the therapeutic cells. Adipose-derived stem cells (ASCs) can be chemically differentiated towards a SC-like phenotype (dASCs), and represent a promising alternative to Scs. their physiology can be further modulated pharmacologically by targeting receptors for neurotransmitters such as acetylcholine (ACh). In this study, we compare the ability of rat dASCs and native SCs to produce NGF in vitro. We also evaluate the ability of muscarinic receptors, in particular the M2 subtype, to modulate NGF production and maturation from the precursor (proNGF) to the mature (mNGF) form. For the first time, we demonstrate that dASCs produce higher basal levels of proNGF and mature NGF compared to SCs. Moreover, muscarinic receptor activation, and in particular M2 subtype stimulation, modulates NGF production and maturation in both SCs and dASCs. Indeed, both cell types express both proNGF A and B isoforms, as well as mNGF. After M2 receptor stimulation, proNGF-B (25 kDa), which is involved in apoptotic processes, is strongly reduced at transcript and protein level. Thus, we demonstrate that dASCs possess a stronger neurotrophic potential compared to SCs. ACh, via M2 muscarinic receptors, contributes to the modulation and maturation of NGF, improving the regenerative properties of dASCs.Neurotrophins are a group of proteins that specifically stimulate neuronal activity during development, adult life and injury, supporting neuron survival, neurite outgrowth and controlling neuron and glial cell differentiation 1 .Nerve growth factor (NGF) has particular relevance for the survival and functional activity of sensory and sympathetic neurons 2,3 . NGF is synthesised as a precursor (proNGF) which is proteolytically cleaved to produce mature NGF (mNGF) 3,4 . In particular, two different isoforms of proNGF are described: proNGF-A (32 kDa) and proNGF-B (25 kDa) 5 . There are consistent clues that proNGF-A isoform may act as a modulator of cell survival 6 , whereas proNGF-B isoform acts as an apoptotic signal 7 . proNGF undergoes post-translational intracellular and extracellular processing at both amino-and carboxyl-terminal ends, thanks to the action of plasmin cleavage, to produce the mNGF form of 13.2kDa 4 . Both proNGF and mNGF can be secreted and have active functional roles 5,7,8 . In healthy peripheral nerves, NGF is produced by the target organs and retrogradely transported to the neuronal soma 1 binding two distinct receptors: the high-affinity Tropomyosin receptor kinase A (TrkA) and the low-affinity p75NTR 9,10 . After nerve injury, axons are dissociated from the source of neurotrophic support, and the Schwann cells (SCs) lose their contact with the axons before acquiring the repair phenotype. At this stage, open Scientific RepoRtS | (2020) 10:7159 | https://doi.org/10.1...

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Section: Discussionsupporting

confidence: 92%

Muscarinic receptors modulate Nerve Growth Factor production in rat Schwann-like adipose-derived stem cells and in Schwann cells

Piovesana

Faroni

Taggi

et al. 2020

Sci Rep

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“…Cultures of SCs, obtained from sciatic nerve of 2 days post-natal rats express muscarinic receptors (M1–M4) [ 9 ]. In particular, M2 mAChR subtype is the most abundant and persists in mature SCs [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Functional Characterization of Muscarinic Receptors in Human Schwann Cells

Piovesana

Faroni

Tata

et al. 2020

IJMS

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Functional characterization of muscarinic cholinergic receptors in myelinating glial cells has been well described both in central and peripheral nervous system. Rat Schwann cells (SCs) express different muscarinic receptor subtypes with the prevalence of the M2 subtype. The selective stimulation of this receptor subtype inhibits SC proliferation, improving their differentiation towards myelinating phenotype. In this work, we describe for the first time that human SCs are cholinoceptive as they express several muscarinic receptor subtypes and, as for rat SCs, M2 receptor is one of the most abundant. Human SCs, isolated from adult nerves, were cultured in vitro and stimulated with M2 muscarinic agonist arecaidine propargyl ester (APE). Similarly to that observed in rat, M2 receptor activation causes a decreased cell proliferation and promotes SC differentiation as suggested by increased Egr2 expression with an improved spindle-like shape cell morphology. Conversely, the non-selective stimulation of muscarinic receptors appears to promote cell proliferation with a reduction of SC average cell diameter. The data obtained demonstrate that human SCs are cholinoceptive and that human cultured SCs may represent an interesting tool to understand their physiology and increase the knowledge on how the cholinergic stimulation may contribute to address human SC development in normal and pathological conditions.

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“…Additionally, sciatic nerves of M2/M4 knock‐out mice show degenerating axons and alterations in myelin organization (Uggenti et al, ). Activation of M2 receptor arrests cell cycle and promotes Schwann cell differentiation via upregulation of Sox10 and Krox 20 and downregulation of c‐jun , Notch‐1 and Jagged‐1 , and increased expression of myelin proteins (Uggenti et al, ). Moreover, activation of AChR on Schwann cells modifies the viscosity of the myelin membrane (Verdiyan et al, ).…”

Section: Introductionmentioning

confidence: 99%

Cholinergic signaling in myelination

Fields

Dutta

Belgrad

et al. 2017

Glia

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There is a long history of research on acetylcholine (ACh) function in myelinating glia, but a resurgence of interest recently as a result of the therapeutic potential of manipulating ACh signaling to promote remyelination, and the broader interest in neurotransmitter signaling in activity-dependent myelination. Myelinating glia express all the major types of muscarinic and nicotinic ACh receptors at different stages of development, and acetylcholinesterase and butyrylcholinesterase are highly expressed in white matter. This review traces the history of research on ACh signaling in Schwann cells, oligodendrocytes, and in the myelin sheath, and summarizes current knowledge on the intracellular signaling and functional consequences of ACh signaling in myelinating glia. Implications of ACh in diseases, such as Alzheimer's disease, multiple sclerosis, and white matter toxicity caused by pesticides are considered, together with an outline of major questions for future research. GLIA 2017;65:687-698.

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M2 muscarinic receptor activation regulates schwann cell differentiation and myelin organization

Cited by 31 publications

References 50 publications

Muscarinic receptors modulate Nerve Growth Factor production in rat Schwann-like adipose-derived stem cells and in Schwann cells

Muscarinic receptors modulate Nerve Growth Factor production in rat Schwann-like adipose-derived stem cells and in Schwann cells

Functional Characterization of Muscarinic Receptors in Human Schwann Cells

Cholinergic signaling in myelination

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