Carbachol, along with calcium, indicates new strategy in neural differentiation of human adipose tissue-derived mesenchymal stem cells in vitro

Masoumi, Niloofar; Ghollasi, Marzieh; Halabian, Raheleh; Eftekhari, Elahe; Ghiasi, Mohsen

doi:10.1016/j.reth.2023.04.001

Cited by 10 publications

(3 citation statements)

References 45 publications

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“…We first manipulated calcium levels by supplementing the acetylcholine agonist, carbachol. Carbachol activates acetylcholine receptors, increasing overall intracellular calcium levels 26 . We measured fmo-4 gene expression upon exposure to carbachol using an fmo-4p::mCherry transcriptional reporter strain.…”

Section: Resultsmentioning

confidence: 99%

fmo-4promotes longevity and stress resistance via ER to mitochondria calcium regulation inC. elegans

Tuckowski,

Beydoun,

Kitto

et al. 2024

Preprint

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Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports that C. elegans fmo-2 promotes longevity, stress resistance, and healthspan by rewiring endogenous metabolism. However, there are five C. elegans FMOs and five mammalian FMOs, and it is not known whether promoting longevity and health benefits is a conserved role of this gene family. Here, we report that expression of C. elegans fmo-4 promotes lifespan extension and paraquat stress resistance downstream of both dietary restriction and inhibition of mTOR. We find that overexpression of fmo-4 in just the hypodermis is sufficient for these benefits, and that this expression significantly modifies the transcriptome. By analyzing changes in gene expression, we find that genes related to calcium signaling are significantly altered downstream of fmo-4 expression. Highlighting the importance of calcium homeostasis in this pathway, fmo-4 overexpressing animals are sensitive to thapsigargin, an ER stressor that inhibits calcium flux from the cytosol to the ER lumen. This calcium/fmo-4 interaction is solidified by data showing that modulating intracellular calcium with either small molecules or genetics can change expression of fmo-4 and/or interact with fmo-4 to affect lifespan and stress resistance. Further analysis supports a pathway where fmo-4 modulates calcium homeostasis downstream of activating transcription factor-6 (atf-6), whose knockdown induces and requires fmo-4 expression. Together, our data identify fmo-4 as a longevity-promoting gene whose actions interact with known longevity pathways and calcium homeostasis.

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Section: Resultsmentioning

confidence: 99%

fmo-4promotes longevity and stress resistance via ER to mitochondria calcium regulation inC. elegans

Tuckowski,

Beydoun,

Kitto

et al. 2024

Preprint

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“…The requirement of spontaneous Ca 2+ oscillations for hMSC commitment to a specific cellular lineage is so tight that the intracellular Ca 2+ activity in BM-hMSCs can be physically manipulated, for instance by electrostimulation [ 95 ], to favour osteogenic [ 91 ] or neuronal [ 96 ] differentiation. Similarly, the addition of inductive soluble factors, such as the InsP 3 -producing autacoid carbachol, has been successfully employed to increase the frequency of InsP 3 Rs-mediated spontaneous Ca 2+ oscillations and thereby promote neuronal differentiation in AD-hMSCs [ 97 ]. As described above, SOCE is crucial to maintaining spontaneous Ca 2+ oscillations in hMSCs; an increase or decrease in the rate of Ca 2+ entry can differentially affect their differentiation outcomes.…”

Section: Intracellular Ca 2+ Oscillations Regulate...mentioning

confidence: 99%

Store-Operated Ca2+ Entry as a Putative Target of Flecainide for the Treatment of Arrhythmogenic Cardiomyopathy

Moccia

Brunetti

Soda

et al. 2023

JCM

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Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder that may lead patients to sudden cell death through the occurrence of ventricular arrhythmias. ACM is characterised by the progressive substitution of cardiomyocytes with fibrofatty scar tissue that predisposes the heart to life-threatening arrhythmic events. Cardiac mesenchymal stromal cells (C-MSCs) contribute to the ACM by differentiating into fibroblasts and adipocytes, thereby supporting aberrant remodelling of the cardiac structure. Flecainide is an Ic antiarrhythmic drug that can be administered in combination with β-adrenergic blockers to treat ACM due to its ability to target both Nav1.5 and type 2 ryanodine receptors (RyR2). However, a recent study showed that flecainide may also prevent fibro-adipogenic differentiation by inhibiting store-operated Ca2+ entry (SOCE) and thereby suppressing spontaneous Ca2+ oscillations in C-MSCs isolated from human ACM patients (ACM C-hMSCs). Herein, we briefly survey ACM pathogenesis and therapies and then recapitulate the main molecular mechanisms targeted by flecainide to mitigate arrhythmic events, including Nav1.5 and RyR2. Subsequently, we describe the role of spontaneous Ca2+ oscillations in determining MSC fate. Next, we discuss recent work showing that spontaneous Ca2+ oscillations in ACM C-hMSCs are accelerated to stimulate their fibro-adipogenic differentiation. Finally, we describe the evidence that flecainide suppresses spontaneous Ca2+ oscillations and fibro-adipogenic differentiation in ACM C-hMSCs by inhibiting constitutive SOCE.

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“…Evidence demonstrates that MSCs, subject to physical, chemical, and biological stimuli, can differentiate into neural cells [73][74][75][76][77]. BMSCs have been shown to differentiate into neurons, astrocytes, and oligodendrocytes, thereby attenuating inflammation and demyelination in EAE mouse models [78,79].…”

Section: Regulation Of Mscs On Microglia and Astrocytementioning

confidence: 99%

Mesenchymal Stem Cells-based Cell-free Therapy Targeting Neuroinflammation

Xu,

Wang,

et al. 2023

Aging and disease

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Emerging from several decades of extensive research, key genetic elements and biochemical mechanisms implicated in neuroinflammation have been delineated, contributing substantially to our understanding of neurodegenerative diseases (NDDs). In this minireview, we discuss data predominantly from the past three years, highlighting the pivotal roles and mechanisms of the two principal cell types implicated in neuroinflammation. The review also underscores the extended process of peripheral inflammation that predates symptomatic onset, the critical influence of neuroinflammation, and their dynamic interplay in the pathogenesis of NDDs. Confronting these complex challenges, we introduce compelling evidence supporting the use of mesenchymal stem cell-based cell-free therapy. This therapeutic strategy includes the regulation of microglia and astrocytes, modulation of peripheral nerve cell inflammation, and targeted anti-inflammatory interventions specifically designed for NDDs, while also discussing engineering and safety considerations. This innovative therapeutic approach intricately modulates the immune system across the peripheral and nervous systems, with an emphasis on achieving superior penetration and targeted delivery. The insights offered by this review have significant implications for the better understanding and management of neuroinflammation.

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Carbachol, along with calcium, indicates new strategy in neural differentiation of human adipose tissue-derived mesenchymal stem cells in vitro

Cited by 10 publications

References 45 publications

fmo-4promotes longevity and stress resistance via ER to mitochondria calcium regulation inC. elegans

fmo-4promotes longevity and stress resistance via ER to mitochondria calcium regulation inC. elegans

Store-Operated Ca2+ Entry as a Putative Target of Flecainide for the Treatment of Arrhythmogenic Cardiomyopathy

Mesenchymal Stem Cells-based Cell-free Therapy Targeting Neuroinflammation

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