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Cell-to-Cell Metabolic Cross-Talk in Physiology and Pathology
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Cell-to-Cell Metabolic Cross-Talk in Physiology and Pathology (Closed)

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Cell Microenvironment".

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Editors

Prof. Dr. Ciro Isidoro

E-Mail Website
Guest Editor
Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, Italy
Interests: autophagy and protein metabolism in cancer and in neurodegeneration; epigenetics in cancer; nutraceuticals and probiotics in cancer and infectious diseases
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Danny N. Dhanasekaran

E-Mail Website
Guest Editor
Stephenson Cancer Center, Oklahoma University Health Science Center, Oklahoma, OK 73104, USA
Interests: cancer; cell signaling; non-coding RNA; tumor microenvironment
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Dear Colleagues,

This Special Issue of Cells focuses on the mechanisms and pathophysiological role of the metabolic crosstalk between cells and includes selected papers from invited speakers and registered participants of the 1st electronic Cells 2020 conference on “Cell-to-Cell Metabolic Crosstalk in Physiology and Pathology” (https://sciforum.net/conference/Cells2020).

Submitted papers will be subjected to peer review and are published with the aim of rapid and wide dissemination of research results, developments, and applications.

The conference will be held from 17 December 2020 to 17 January 2021 on sciforum.net, a platform service for hosting international electronic conferences for scientific communities. Lectures will be presented live through a series of webinars.

The topical sessions include: 

  1. Cell Cycle Regulators: The Crosstalk with Metabolism
  2. Exosomes and Extracellular Vesicles in Health and Disease
  3. The Crosstalk between Cell Adhesion and Metabolism
  4. Crosstalk between Cell Death Regulation and Metabolism
  5. Crosstalk between Immune Cells and Tissue Microenvironment
  6. Compartmentalization of Cellular Signaling 

Prof. Dr. Ciro Isidoro
Prof. Dr. Danny D Dhanasekaran
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the collection website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • exosomes
  • cell death
  • cell metabolism
  • diseases
  • autophagy
  • cell adhesion
  • cell migration
  • cell signaling
  • cell proliferation
  • tissue microenvironment

Related Special Issue

Published Papers (8 papers)

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2021

33 pages, 2738 KiB  
Review
Impact of the Main Cardiovascular Risk Factors on Plasma Extracellular Vesicles and Their Influence on the Heart’s Vulnerability to Ischemia-Reperfusion Injury
by Miłosz Majka, Marcin Kleibert and Małgorzata Wojciechowska
Cells 2021, 10(12), 3331; https://doi.org/10.3390/cells10123331 - 27 Nov 2021
Cited by 6 | Viewed by 4559
Abstract
The majority of cardiovascular deaths are associated with acute coronary syndrome, especially ST-elevation myocardial infarction. Therapeutic reperfusion alone can contribute up to 40 percent of total infarct size following coronary artery occlusion, which is called ischemia-reperfusion injury (IRI). Its size depends on many [...] Read more.
The majority of cardiovascular deaths are associated with acute coronary syndrome, especially ST-elevation myocardial infarction. Therapeutic reperfusion alone can contribute up to 40 percent of total infarct size following coronary artery occlusion, which is called ischemia-reperfusion injury (IRI). Its size depends on many factors, including the main risk factors of cardiovascular mortality, such as age, sex, systolic blood pressure, smoking, and total cholesterol level as well as obesity, diabetes, and physical effort. Extracellular vesicles (EVs) are membrane-coated particles released by every type of cell, which can carry content that affects the functioning of other tissues. Their role is essential in the communication between healthy and dysfunctional cells. In this article, data on the variability of the content of EVs in patients with the most prevalent cardiovascular risk factors is presented, and their influence on IRI is discussed. Full article
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24 pages, 6228 KiB  
Article
Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy
by Alessandra Ferraresi, Andrea Esposito, Carlo Girone, Letizia Vallino, Amreen Salwa, Ian Ghezzi, Suyanee Thongchot, Chiara Vidoni, Danny N. Dhanasekaran and Ciro Isidoro
Cells 2021, 10(11), 3213; https://doi.org/10.3390/cells10113213 - 17 Nov 2021
Cited by 49 | Viewed by 4501
Abstract
Background: Ovarian cancer progression and invasiveness are promoted by a range of soluble factors released by cancer cells and stromal cells within the tumor microenvironment. Our previous studies demonstrated that resveratrol (RV), a nutraceutical and caloric restriction mimetic with tumor-suppressive properties, counteracts [...] Read more.
Background: Ovarian cancer progression and invasiveness are promoted by a range of soluble factors released by cancer cells and stromal cells within the tumor microenvironment. Our previous studies demonstrated that resveratrol (RV), a nutraceutical and caloric restriction mimetic with tumor-suppressive properties, counteracts cancer cell motility induced by stromal IL-6 by upregulating autophagy. Lysophosphatidic acid (LPA), a bioactive phospholipid that shows elevated levels in the tumor microenvironment and the ascites of ovarian cancers, stimulates the growth and tissue invasion of cancer cells. Whether LPA elicits these effects by inhibiting autophagy and through which pathway and whether RV can counteract the same remain obscure. Aims: To investigate the molecular pathways involved in LPA-induced ovarian cancer malignancy, particularly focusing on the role of autophagy, and the ability of RV to counteract LPA activity. Results: LPA stimulated while RV inhibited ovarian cancer cell migration. Transcriptomic and bioinformatic analyses showed an opposite regulation by LPA and RV of genes linked to epithelial-to-mesenchymal transition (EMT) and autophagy with involvement of the PI3K-AKT, JAK-STAT and Hedgehog (Hh) pathways. LPA upregulated the Hh and EMT members GLI1, BMI-1, SNAIL-1 and TWIST1 and inhibited autophagy, while RV did the opposite. Similar to the inhibitors of the Hh pathway, RV inhibited LPA-induced cancer cell migration and 3D growth of ovarian cancer cells. BMI-1 silencing prevented LPA-induced EMT, restored autophagy and hampered cell migration, resembling the effects of RV. TCGA data analyses indicated that patients with low expression of Hh/EMT-related genes together with active autophagy flux tended to have a better prognosis and this correlates with a more effective response to platinum therapy. In in vitro 3D spheroids, LPA upregulated BMI-1, downregulated autophagy and inhibited platinum toxicity while RV and Hh inhibitors restored autophagy and favored BAX-mediated cell death in response to platinum. Conclusions: By inhibiting the Hh pathway and restoration of autophagy, RV counteracts LPA-induced malignancy, supporting its inclusion in the therapy of ovarian cancer for limiting metastasis and chemoresistance. Full article
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17 pages, 1978 KiB  
Review
Iron Metabolism in Pancreatic Beta-Cell Function and Dysfunction
by Algerta Marku, Alessandra Galli, Paola Marciani, Nevia Dule, Carla Perego and Michela Castagna
Cells 2021, 10(11), 2841; https://doi.org/10.3390/cells10112841 - 22 Oct 2021
Cited by 34 | Viewed by 5334
Abstract
Iron is an essential element involved in a variety of physiological functions. In the pancreatic beta-cells, being part of Fe-S cluster proteins, it is necessary for the correct insulin synthesis and processing. In the mitochondria, as a component of the respiratory chain, it [...] Read more.
Iron is an essential element involved in a variety of physiological functions. In the pancreatic beta-cells, being part of Fe-S cluster proteins, it is necessary for the correct insulin synthesis and processing. In the mitochondria, as a component of the respiratory chain, it allows the production of ATP and reactive oxygen species (ROS) that trigger beta-cell depolarization and potentiate the calcium-dependent insulin release. Iron cellular content must be finely tuned to ensure the normal supply but also to prevent overloading. Indeed, due to the high reactivity with oxygen and the formation of free radicals, iron excess may cause oxidative damage of cells that are extremely vulnerable to this condition because the normal elevated ROS production and the paucity in antioxidant enzyme activities. The aim of the present review is to provide insights into the mechanisms responsible for iron homeostasis in beta-cells, describing how alteration of these processes has been related to beta-cell damage and failure. Defects in iron-storing or -chaperoning proteins have been detected in diabetic conditions; therefore, the control of iron metabolism in these cells deserves further investigation as a promising target for the development of new disease treatments. Full article
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30 pages, 10374 KiB  
Article
Extracellular Vesicles Derived from Endothelial Progenitor Cells Protect Human Glomerular Endothelial Cells and Podocytes from Complement- and Cytokine-Mediated Injury
by Davide Medica, Rossana Franzin, Alessandra Stasi, Giuseppe Castellano, Massimiliano Migliori, Vincenzo Panichi, Federico Figliolini, Loreto Gesualdo, Giovanni Camussi and Vincenzo Cantaluppi
Cells 2021, 10(7), 1675; https://doi.org/10.3390/cells10071675 - 2 Jul 2021
Cited by 33 | Viewed by 4836
Abstract
Glomerulonephritis are renal inflammatory processes characterized by increased permeability of the Glomerular Filtration Barrier (GFB) with consequent hematuria and proteinuria. Glomerular endothelial cells (GEC) and podocytes are part of the GFB and contribute to the maintenance of its structural and functional integrity through [...] Read more.
Glomerulonephritis are renal inflammatory processes characterized by increased permeability of the Glomerular Filtration Barrier (GFB) with consequent hematuria and proteinuria. Glomerular endothelial cells (GEC) and podocytes are part of the GFB and contribute to the maintenance of its structural and functional integrity through the release of paracrine mediators. Activation of the complement cascade and pro-inflammatory cytokines (CK) such as Tumor Necrosis Factor α (TNF-α) and Interleukin-6 (IL-6) can alter GFB function, causing acute glomerular injury and progression toward chronic kidney disease. Endothelial Progenitor Cells (EPC) are bone-marrow-derived hematopoietic stem cells circulating in peripheral blood and able to induce angiogenesis and to repair injured endothelium by releasing paracrine mediators including Extracellular Vesicles (EVs), microparticles involved in intercellular communication by transferring proteins, lipids, and genetic material (mRNA, microRNA, lncRNA) to target cells. We have previously demonstrated that EPC-derived EVs activate an angiogenic program in quiescent endothelial cells and renoprotection in different experimental models. The aim of the present study was to evaluate in vitro the protective effect of EPC-derived EVs on GECs and podocytes cultured in detrimental conditions with CKs (TNF-α/IL-6) and the complement protein C5a. EVs were internalized in both GECs and podocytes mainly through a L-selectin-based mechanism. In GECs, EVs enhanced the formation of capillary-like structures and cell migration by modulating gene expression and inducing the release of growth factors such as VEGF-A and HGF. In the presence of CKs, and C5a, EPC-derived EVs protected GECs from apoptosis by decreasing oxidative stress and prevented leukocyte adhesion by inhibiting the expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin). On podocytes, EVs inhibited apoptosis and prevented nephrin shedding induced by CKs and C5a. In a co-culture model of GECs/podocytes that mimicked GFB, EPC-derived EVs protected cell function and permeselectivity from inflammatory-mediated damage. Moreover, RNase pre-treatment of EVs abrogated their protective effects, suggesting the crucial role of RNA transfer from EVs to damaged glomerular cells. In conclusion, EPC-derived EVs preserved GFB integrity from complement- and cytokine-induced damage, suggesting their potential role as therapeutic agents for drug-resistant glomerulonephritis. Full article
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18 pages, 1038 KiB  
Review
Emerging Role and Clinicopathological Significance of AEG-1 in Different Cancer Types: A Concise Review
by Sushmitha Sriramulu, Xiao-Feng Sun, Sarubala Malayaperumal, Harsha Ganesan, Hong Zhang, Murugesan Ramachandran, Antara Banerjee and Surajit Pathak
Cells 2021, 10(6), 1497; https://doi.org/10.3390/cells10061497 - 15 Jun 2021
Cited by 16 | Viewed by 5566
Abstract
Tumor breakthrough is driven by genetic or epigenetic variations which assist in initiation, migration, invasion and metastasis of tumors. Astrocyte elevated gene-1 (AEG-1) protein has risen recently as the crucial factor in malignancies and plays a potential role in diverse complex oncogenic signaling [...] Read more.
Tumor breakthrough is driven by genetic or epigenetic variations which assist in initiation, migration, invasion and metastasis of tumors. Astrocyte elevated gene-1 (AEG-1) protein has risen recently as the crucial factor in malignancies and plays a potential role in diverse complex oncogenic signaling cascades. AEG-1 has multiple roles in tumor growth and development and is found to be involved in various signaling pathways of: (i) Ha-ras and PI3K/AKT; (ii) the NF-κB; (iii) the ERK or mitogen-activated protein kinase and Wnt or β-catenin and (iv) the Aurora-A kinase. Recent studies have confirmed that in all the hallmarks of cancers, AEG-1 plays a key functionality including progression, transformation, sustained angiogenesis, evading apoptosis, and invasion and metastasis. Clinical studies have supported that AEG-1 is actively intricated in tumor growth and progression which includes esophageal squamous cell, gastric, colorectal, hepatocellular, gallbladder, breast, prostate and non-small cell lung cancers, as well as renal cell carcinomas, melanoma, glioma, neuroblastoma and osteosarcoma. Existing studies have reported that AEG-1 expression has been induced by Ha-ras through intrication of PI3K/AKT signaling. Conversely, AEG-1 also activates PI3K/AKT pathway and modulates the defined subset of downstream target proteins via crosstalk between the PI3K/AKT/mTOR and Hedgehog signaling cascade which further plays a crucial role in metastasis. Thus, AEG-1 may be employed as a biomarker to discern the patients of those who are likely to get aid from AEG-1-targeted medication. AEG-1 may play as an effective target to repress tumor development, occlude metastasis, and magnify the effectiveness of treatments. In this review, we focus on the molecular mechanism of AEG-1 in the process of carcinogenesis and its involvement in regulation of crosstalk between the PI3K/AKT/mTOR and Hedgehog signaling. We also highlight the multifaceted functions, expression, clinicopathological significance and molecular inhibitors of AEG-1 in various cancer types. Full article
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22 pages, 2207 KiB  
Review
Embryonic Origin and Subclonal Evolution of Tumor-Associated Macrophages Imply Preventive Care for Cancer
by Xiao-Mei Zhang, De-Gao Chen, Shengwen Calvin Li, Bo Zhu and Zhong-Jun Li
Cells 2021, 10(4), 903; https://doi.org/10.3390/cells10040903 - 14 Apr 2021
Cited by 17 | Viewed by 5445
Abstract
Macrophages are widely distributed in tissues and function in homeostasis. During cancer development, tumor-associated macrophages (TAMs) dominatingly support disease progression and resistance to therapy by promoting tumor proliferation, angiogenesis, metastasis, and immunosuppression, thereby making TAMs a target for tumor immunotherapy. Here, we started [...] Read more.
Macrophages are widely distributed in tissues and function in homeostasis. During cancer development, tumor-associated macrophages (TAMs) dominatingly support disease progression and resistance to therapy by promoting tumor proliferation, angiogenesis, metastasis, and immunosuppression, thereby making TAMs a target for tumor immunotherapy. Here, we started with evidence that TAMs are highly plastic and heterogeneous in phenotype and function in response to microenvironmental cues. We pointed out that efforts to tear off the heterogeneous “camouflage” in TAMs conduce to target de facto protumoral TAMs efficiently. In particular, several fate-mapping models suggest that most tissue-resident macrophages (TRMs) are generated from embryonic progenitors, and new paradigms uncover the ontogeny of TAMs. First, TAMs from embryonic modeling of TRMs and circulating monocytes have distinct transcriptional profiling and function, suggesting that the ontogeny of TAMs is responsible for the functional heterogeneity of TAMs, in addition to microenvironmental cues. Second, metabolic remodeling helps determine the mechanism of phenotypic and functional characteristics in TAMs, including metabolic bias from macrophages’ ontogeny in macrophages’ functional plasticity under physiological and pathological conditions. Both models aim at dissecting the ontogeny-related metabolic regulation in the phenotypic and functional heterogeneity in TAMs. We argue that gleaning from the single-cell transcriptomics on subclonal TAMs’ origins may help understand the classification of TAMs’ population in subclonal evolution and their distinct roles in tumor development. We envision that TAM-subclone-specific metabolic reprogramming may round-up with future cancer therapies. Full article
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11 pages, 1091 KiB  
Article
Genotoxic Bystander Signals from Irradiated Human Mesenchymal Stromal Cells Mainly Localize in the 10–100 kDa Fraction of Conditioned Medium
by Vanessa Kohl, Alice Fabarius, Oliver Drews, Miriam Bierbaum, Ahmed Jawhar, Ali Darwich, Christel Weiss, Johanna Flach, Susanne Brendel, Helga Kleiner, Wolfgang Seifarth, Wolf-Karsten Hofmann and Henning D. Popp
Cells 2021, 10(4), 827; https://doi.org/10.3390/cells10040827 - 7 Apr 2021
Cited by 3 | Viewed by 2349
Abstract
Genotoxic bystander signals released from irradiated human mesenchymal stromal cells (MSC) may induce radiation-induced bystander effects (RIBEs) in human hematopoietic stem and progenitor cells (HSPC), potentially causing leukemic transformation. Although the source of bystander signals is evident, the identification and characterization of these [...] Read more.
Genotoxic bystander signals released from irradiated human mesenchymal stromal cells (MSC) may induce radiation-induced bystander effects (RIBEs) in human hematopoietic stem and progenitor cells (HSPC), potentially causing leukemic transformation. Although the source of bystander signals is evident, the identification and characterization of these signals is challenging. Here, RIBEs were analyzed in human CD34+ cells cultured in distinct molecular size fractions of medium, conditioned by 2 Gy irradiated human MSC. Specifically, γH2AX foci (as a marker of DNA double-strand breaks) and chromosomal instability were evaluated in CD34+ cells grown in approximate (I) < 10 kDa, (II) 10–100 kDa and (III) > 100 kDa fractions of MSC conditioned medium and un-/fractionated control medium, respectively. Hitherto, significantly increased numbers of γH2AX foci (p = 0.0286) and aberrant metaphases (p = 0.0022) were detected in CD34+ cells grown in the (II) 10–100 kDa fraction (0.67 ± 0.10 γH2AX foci per CD34+ cell ∨ 3.8 ± 0.3 aberrant metaphases per CD34+ cell sample; mean ± SEM) when compared to (I) < 10 kDa (0.19 ± 0.01 ∨ 0.3 ± 0.2) or (III) > 100 kDa fractions (0.23 ± 0.04 ∨ 0.4 ± 0.4) or un-/fractionated control medium (0.12 ± 0.01 ∨ 0.1 ± 0.1). Furthermore, RIBEs disappeared after heat inactivation of medium at 75 °C. Taken together, our data suggest that RIBEs are mainly mediated by the heat-sensitive (II) 10–100 kDa fraction of MSC conditioned medium. We postulate proteins as RIBE mediators and in-depth proteome analyses to identify key bystander signals, which define targets for the development of next-generation anti-leukemic drugs. Full article
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21 pages, 6227 KiB  
Article
Extracellular Vesicles from Infected Cells Are Released Prior to Virion Release
by Yuriy Kim, Gifty A. Mensah, Sarah Al Sharif, Daniel O. Pinto, Heather Branscome, Sowmya V. Yelamanchili, Maria Cowen, James Erickson, Pooja Khatkar, Renaud Mahieux and Fatah Kashanchi
Cells 2021, 10(4), 781; https://doi.org/10.3390/cells10040781 - 1 Apr 2021
Cited by 13 | Viewed by 3748
Abstract
Here, we have attempted to address the timing of EV and virion release from virally infected cells. Uninfected (CEM), HIV-1-infected (J1.1), and human T cell leukemia virus-1 (HTLV-1)-infected (HUT102) cells were synchronized in G0. Viral latency was reversed by increasing gene [...] Read more.
Here, we have attempted to address the timing of EV and virion release from virally infected cells. Uninfected (CEM), HIV-1-infected (J1.1), and human T cell leukemia virus-1 (HTLV-1)-infected (HUT102) cells were synchronized in G0. Viral latency was reversed by increasing gene expression with the addition of serum-rich media and inducers. Supernatants and cell pellets were collected post-induction at different timepoints and assayed for extracellular vesicle (EV) and autophagy markers; and for viral proteins and RNAs. Tetraspanins and autophagy-related proteins were found to be differentially secreted in HIV-1- and HTLV-1-infected cells when compared with uninfected controls. HIV-1 proteins were present at 6 h and their production increased up to 24 h. HTLV-1 proteins peaked at 6 h and plateaued. HIV-1 and HTLV-1 RNA production correlated with viral protein expression. Nanoparticle tracking analysis (NTA) showed increase of EV concentration over time in both uninfected and infected samples. Finally, the HIV-1 supernatant from the 6-h samples was found not to be infectious; however, the virus from the 24-h samples was successfully rescued and infectious. Overall, our data indicate that EV release may occur prior to viral release from infected cells, thereby implicating a potentially significant effect of EVs on uninfected recipient cells prior to subsequent viral infection and spread. Full article
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