Regulation of p38 mitogen‐activated kinase‐mediated fetal membrane senescence by statins

Ayad, Martina; Taylor, Brandie D.; Menon, Ramkumar

doi:10.1111/aji.12999

Cited by 19 publications

(15 citation statements)

References 54 publications

(132 reference statements)

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“…After isolating 2 distinct cell populations, we further tested responsiveness of these cells to stimulants. We have been using a water-soluble CSE extract that is found to be consistent in producing ROS-associated with OS as is often seen in the intrauterine environment prior to term and preterm labor [41][42][43][44][45][46][47][48]. We have been using CSE as a laboratory reagent to induce OS, and it has been much more effective and reproducible than reagents traditionally used, such as hydrogen peroxide or tumor necrosis factor alpha [45].…”

Section: Chorion Cell Stimulation With Cigarette Smoke Extract (Cse)mentioning

confidence: 99%

Isolation and characterization human chorion membrane trophoblast and mesenchymal cells

et al. 2020

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“…Placental and FM (i.e., amniochorion) tissues from term, not in labor, cesarean deliveries (TNIL) (n 5) were used for this project and prepared as previously described by our laboratory (n 6 tissues for western blotting and n 5 tissues for explant culture) (Ayad et al, 2018;Sheller-Miller et al, 2020). Briefly, the FM was dissected from the placenta, washed three times in normal saline, cleaned with sterile saline-moistened gauze to clear any adherent blood clots and all the decidua, and washed in Hank's balanced solution (HBSS) with penicillin 100 U/mL and streptomycin 100 µg/ml.…”

Section: Placental and Fm Explant Culturementioning

confidence: 99%

Organic Anion Transporting Polypeptide 2B1 in Human Fetal Membranes: A Novel Gatekeeper for Drug Transport During Pregnancy?

Ganguly¹,

Kammala²,

Benson³

et al. 2021

Front. Pharmacol.

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Current intervention strategies have not been successful in reducing the risks of adverse pregnancy complications nor maternal and fetal morbidities associated with pregnancy complications. Improving pregnancy and neonatal outcomes requires a better understanding of drug transport mechanisms at the feto-maternal interfaces, specifically the placenta and fetal membrane (FM). The role of several solute carrier uptake transporter proteins (TPs), such as the organic anion transporting polypeptide 2B1 (OATP2B1) in transporting drug across the placenta, is well-established. However, the mechanistic role of FMs in this drug transport has not yet been elucidated. We hypothesize that human FMs express OATP2B1 and functions as an alternate gatekeeper for drug transport at the feto-maternal interface. We determined the expression of OATP2B1 in term, not-in-labor, FM tissues and human FM cells [amnion epithelial cell (AEC), chorion trophoblast cell (CTC), and mesenchymal cells] using western blot analyses and their localization using immunohistochemistry. Changes in OATP2B1 expression was determined for up to 48 h after stimulation with cigarette smoke extract (CSE), an inducer of oxidative stress. The functional role of OATP2B1 was determined by flow cytometry using a zombie violet dye substrate assay. After OATP2B1 gene silencing, its functional relevance in drug transport through the feto-maternal interface was tested using a recently developed feto-maternal interface organ-on-a-chip (OOC) system that contained both FM and maternal decidual cells. Propagation of a drug (Rosuvastatin, that can be transported by OATP2B1) within the feto-maternal interface OOC system was determined by mass spectrometry. FMs express OATP2B1 in the CTC and AEC layers. In FM explants, OATP2B1 expression was not impacted by oxidative stress. Uptake of the zombie violet dye within AECs and CTCs showed OATP2B1 is functionally active. Silencing OATP2B1 in CTCs reduced Rosuvastatin propagation from the decidua to the fetal AEC layer within the feto-maternal interface-OOC model. Our data suggest that TPs in FMs may function as a drug transport system at the feto-maternal interface, a function that was previously thought to be performed exclusively by the placenta. This new knowledge will help improve drug delivery testing during pregnancy and contribute to designing drug delivery strategies to treat adverse pregnancy outcomes.

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“…Culturing fetal membrane tissues or biopsy-based explants obtained from discarded human fetal membrane from scheduled cesarean deliveries are commonly utilized for tissue-level culture and studies (Fortunato et al, 1994;Menon et al, 2011;Menon et al, 2014;Richardson et al, 2017a;Ayad et al, 2018). Additionally, live fetal membrane samples can be mounted into imaging chambers allowing for cellular and collagen visualization over time.…”

Section: Ex Vivo Tissue Culture Techniquesmentioning

confidence: 99%

Organ-On-Chip Technology: The Future of Feto-Maternal Interface Research?

et al. 2020

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“…Simvastatin has shown efficacy in delaying brain atrophy and disability progression in MS trials (Chataway et al, 2014). This neuroprotective effect may be mediated via its senomorphic actions, which include downregulation of p38MAPK activation, SASP markers, TNFa, and GM-CSF as shown in other settings (Liu et al, 2015;Ayad et al, 2018). Many promising compounds with senolytic or senomorphic activity, such as metformin or simvastatin used with different indications could be repurposed and used as neuroprotectants combined with currently available immunomodulators.…”

Section: Can Senolysis Be Neuroprotective?mentioning

confidence: 99%

Aging, Cellular Senescence, and Progressive Multiple Sclerosis

Papadopoulos

Magliozzi

Mitsikostas

et al. 2020

Front. Cell. Neurosci.

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Aging is one of the most important risk factors for the development of several neurodegenerative diseases including progressive multiple sclerosis (MS). Cellular senescence (CS) is a key biological process underlying aging. Several stressors associated with aging and MS pathology, such as oxidative stress, mitochondrial dysfunction, cytokines and replicative exhaustion are known triggers of cellular senescence. Senescent cells exhibit stereotypical metabolic and functional changes, which include cell-cycle arrest and acquiring a pro-inflammatory phenotype secreting cytokines, growth factors, metalloproteinases and reactive oxygen species. They accumulate with aging and can convert neighboring cells to senescence in a paracrine manner. In MS, accelerated cellular senescence may drive disease progression by promoting chronic non-remitting inflammation, loss or altered immune, glial and neuronal function, failure of remyelination, impaired blood-brain barrier integrity and ultimately neurodegeneration. Here we discuss the evidence linking cellular senescence to the pathogenesis of MS and the putative role of senolytic and senomorphic agents as neuroprotective therapies in tackling disease progression.

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“…Senescence refers to the cell age-associated telomere shortening responsible for cell cycle arrest, and shortening of fetal membrane cell telomeres was found by Menon et al in [40]. This telomere shortening in the membranes is linked to the p38 mitogen-activated signaling kinase pathway, leading to a "senescence-associated secretory phenotype", which can signal to surrounding tissues via secreted extracellular vesicles [41][42][43]. While many studies suggest that apoptosis in the fetal membranes is a major causal event of weakening [23][24][25]44,45], this can be confused for senescence in the membranes, which is more often accompanied by inflammation [34,38,46].…”

Section: The Fetal Membranes During Labormentioning

confidence: 99%

Leveraging bioengineering to assess cellular functions and communication within human fetal membranes

Eastman

Noble

Aronoff

2020

The Journal of Maternal-Fetal & Neonatal Medicine

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The fetal membranes enclose the growing fetus and amniotic fluid. Preterm prelabor rupture of fetal membranes is a leading cause of preterm birth. Fetal membranes are composed of many different cell types, both structural and immune. These cells must coordinate functions for tensile strength and membrane integrity to contain the growing fetus and amniotic fluid. They must also balance immune responses to pathogens with maintaining maternal-fetal tolerance. Perturbation of this equilibrium can lead to preterm premature rupture of membranes without labor. In this review, we describe the formation of the fetal membranes to orient the reader, discuss some of the common forms of communication between the cell types of the fetal membranes, and delve into the methods used to tease apart this paracrine signaling within the membranes, including emerging technologies such as organ-on-chip models of membrane immunobiology.Leveraging Bioengineering to Assess Cellular Functions and Communication Within Human Fetal Membranes

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Regulation of p38 mitogen‐activated kinase‐mediated fetal membrane senescence by statins

Cited by 19 publications

References 54 publications

Isolation and characterization human chorion membrane trophoblast and mesenchymal cells

Organic Anion Transporting Polypeptide 2B1 in Human Fetal Membranes: A Novel Gatekeeper for Drug Transport During Pregnancy?

Organ-On-Chip Technology: The Future of Feto-Maternal Interface Research?

Aging, Cellular Senescence, and Progressive Multiple Sclerosis

Leveraging bioengineering to assess cellular functions and communication within human fetal membranes

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