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TGFβ links EBV to multisystem inflammatory syndrome in children
(Springer Science and Business Media LLC, 2025-03-12)
Carl Christoph Goetzke
;
Mona Massoud
;
Stefan Frischbutter
;
Gabriela Maria Guerra
;
Marta Ferreira-Gomes
<jats:title>Abstract</jats:title> <jats:p>In a subset of children and adolescents, SARS-CoV-2 infection induces a severe acute hyperinflammatory shock<jats:sup>1</jats:sup> termed multisystem inflammatory syndrome in children (MIS-C) at four to eight weeks after infection. MIS-C is characterized by a specific T cell expansion<jats:sup>2</jats:sup> and systemic hyperinflammation<jats:sup>3</jats:sup>. The pathogenesis of MIS-C remains largely unknown. Here we show that acute MIS-C is characterized by impaired reactivation of virus-reactive memory T cells, which depends on increased serum levels of the cytokine TGFβ resembling those that occur during severe COVID-19 (refs. <jats:sup>4,5</jats:sup>). This functional impairment in T cell reactivity is accompanied by the presence of TGFβ-response signatures in T cells, B cells and monocytes along with reduced antigen-presentation capabilities of monocytes, and can be reversed by blocking TGFβ. Furthermore, T cell receptor repertoires of patients with MIS-C exhibit expansion of T cells expressing TCRVβ21.3, resembling Epstein–Barr virus (EBV)-reactive T cell clones capable of eliminating EBV-infected B cells. Additionally, serum TGFβ in patients with MIS-C can trigger EBV reactivation, which is reversible with TGFβ blockade. Clinically, the TGFβ-induced defect in T cell reactivity correlates with a higher EBV seroprevalence in patients with MIS-C compared with age-matched controls, along with the occurrence of EBV reactivation. Our findings establish a connection between SARS-CoV-2 infection and COVID-19 sequelae in children, in which impaired T cell cytotoxicity triggered by TGFβ overproduction leads to EBV reactivation and subsequent hyperinflammation.</jats:p>
Scopus© Citations 4 2
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Amelioration of morphine withdrawal syndrome by systemic and intranasal administration of mesenchymal stem cell‐derived secretome in preclinical models of morphine dependence
(2023)
Mauricio Quezada
;
Carolina Ponce
;
Pablo Berríos‐Cárcamo
;
Daniela Santapau
;
Javiera Gallardo
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Morphine is an opiate commonly used in the treatment of moderate to severe pain. However, prolonged administration can lead to physical dependence and strong withdrawal symptoms upon cessation of morphine use. These symptoms can include anxiety, irritability, increased heart rate, and muscle cramps, which strongly promote morphine use relapse. The morphine‐induced increases in neuroinflammation, brain oxidative stress, and alteration of glutamate levels in the hippocampus and nucleus accumbens have been associated with morphine dependence and a higher severity of withdrawal symptoms. Due to its rich content in potent anti‐inflammatory and antioxidant factors, secretome derived from human mesenchymal stem cells (hMSCs) is proposed as a preclinical therapeutic tool for the treatment of this complex neurological condition associated with neuroinflammation and brain oxidative stress.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Two animal models of morphine dependence were used to evaluate the therapeutic efficacy of hMSC‐derived secretome in reducing morphine withdrawal signs. In the first model, rats were implanted subcutaneously with mini‐pumps which released morphine at a concentration of 10 mg/kg/day for seven days. Three days after pump implantation, animals were treated with a simultaneous intravenous and intranasal administration of hMSC‐derived secretome or vehicle, and withdrawal signs were precipitated on day seven by i.p. naloxone administration. In this model, brain alterations associated with withdrawal were also analyzed before withdrawal precipitation. In the second animal model, rats voluntarily consuming morphine for three weeks were intravenously and intranasally treated with hMSC‐derived secretome or vehicle, and withdrawal signs were induced by morphine deprivation.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In both animal models secretome administration induced a significant reduction of withdrawal signs, as shown by a reduction in a combined withdrawal score. Secretome administration also promoted a reduction in morphine‐induced neuroinflammation in the hippocampus and nucleus accumbens, while no changes were observed in extracellular glutamate levels in the nucleus accumbens.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Data presented from two animal models of morphine dependence suggest that administration of secretome derived from hMSCs reduces the development of opioid withdrawal signs, which correlates with a reduction in neuroinflammation in the hippocampus and nucleus accumbens.</jats:p></jats:sec>
Scopus© Citations 4 1
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Activation of Intra-nodose Ganglion P2X7 Receptors Elicit Increases in Neuronal Activity
(2023)
Julio Alcayaga
;
Jorge Vera
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Mauricio Reyna-Jeldes
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Alejandra A. Covarrubias
;
Claudio Coddou
Scopus© Citations 2 2
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Spheroids derived from the stromal vascular fraction of adipose tissue self-organize in complex adipose organoids and secrete leptin
(2023)
Fermín Robledo
;
Lila González-Hodar
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Pablo Tapia
;
Ana-María Figueroa
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EZQUER, EDUARDO FERNANDO
<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Adipose tissue-derived stromal vascular fraction (SVF) harbors multipotent cells with potential therapeutic relevance. We developed a method to form adipose spheroids (AS) from the SVF with complex organoid structure and enhanced leptin secretion upon insulin stimulation. </jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>SVF was generated from the interscapular brown adipose tissue of newborn mice. Immunophenotype and stemness of cultured SVF were determined by flow cytometry and in vitro differentiation, respectively. Spheroids were generated in hanging drops and non-adherent plates and compared by morphometric methods. The adipogenic potential was compared between preadipocyte monolayers and spheroids. Extracellular leptin was quantified by immunoassay. Lipolysis was stimulated with isoprenaline and quantified by colorimetric methods. AS viability and ultrastructure were determined by confocal and transmission electron microscopy analyses. </jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Cultured SVF contained Sca1 + CD29 + CD44 + CD11b- CD45- CD90- cells with adipogenic and chondrogenic but no osteogenic potential. Culture on non-adherent plates yielded the highest quantity and biggest size of spheroids. Differentiation of AS for 15 days in a culture medium supplemented with insulin and rosiglitazone resulted in greater <jats:italic>Pparg</jats:italic>, <jats:italic>Plin1,</jats:italic> and <jats:italic>Lep</jats:italic> expression compared to differentiated adipocytes monolayers. AS were viable and maintained leptin secretion even in the absence of adipogenic stimulation. Glycerol release after isoprenaline stimulation was higher in AS compared to adipocytes in monolayers. AS were composed of outer layers of unilocular mature adipocytes and an inner structure composed of preadipocytes, immature adipocytes and an abundant loose extracellular matrix.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusion</jats:title> <jats:p>Newborn mice adipose SVF can be efficiently differentiated into leptin-secreting AS. Prolonged stimulation with insulin and rosiglitazone allows the formation of structurally complex adipose organoids able to respond to adrenergic lipolytic stimulation.</jats:p> </jats:sec>
Scopus© Citations 9 1
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Collagen VII maintains proteostasis in dermal fibroblasts by scaffolding TANGO1 cargo
(2022)
Qingqing Cao
;
Grace Tartaglia
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Michael Alexander
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Pyung Hung Park
;
Shiv Poojan
Scopus© Citations 9 7
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Microencapsulation of cellular aggregates composed of differentiated insulin and glucagon-producing cells from human mesenchymal stem cells derived from adipose tissue
(2020)
Claudia Jara
;
Felipe Oyarzun-Ampuero
;
Flavio Carrión
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Esteban González-Echeverría
;
Claudio Cappelli
<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>In type I diabetes mellitus (T1DM) pancreatic β cells are destroyed. Treatment entails exogenous insulin administration and strict diet control, yet optimal glycemic control is hardly attainable. Islet transplant could be an alternative in patients with poor glycemic control, but inefficient islet purification and autoimmune response of patients is still a challenge. For these reasons, it is necessary to explore new cellular sources and immunological isolation methods oriented to develop T1DM cell-based therapies.</jats:p> </jats:sec><jats:sec> <jats:title>Aims</jats:title> <jats:p>We postulate human adipose-derived stem cell (hASC) as an adequate source to generate pancreatic islet cells in vitro, and to produce islet-like structures. Furthermore, we propose microencapsulation of these aggregates as an immunological isolation strategy.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>hASC obtained from lipoaspirated fat tissue from human donors were differentiated in vitro to insulin (Ins) and glucagon (Gcg) producing cells. Then, insulin producing cells (IPC) and glucagon producing cells (GPC) were cocultured in low adhesion conditions to form cellular aggregates, and later encapsulated in a sodium alginate polymer. Expression of pancreatic lineage markers and secretion of insulin or glucagon in vitro were analyzed.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>The results show that multipotent hASC efficiently differentiate to IPC and GPC, and express pancreatic markers, including insulin or glucagon hormones which they secrete upon stimulation (fivefold for insulin in IPC, and fourfold for glucagon, compared to undifferentiated cells). In turn, calculation of the Feret diameter and area of cellular aggregates revealed mean diameters of ~ 80 µm, and 65% of the aggregates reached 4000 µm<jats:sup>2</jats:sup> at 72 h of formation. IPC/GPC aggregates were then microencapsulated in sodium-alginate polymer microgels, which were found to be more stable when stabilized with Ba<jats:sup>2+</jats:sup>, yielding average diameters of ~ 300 µm. Interestingly, Ba<jats:sup>2+</jats:sup>-microencapsulated aggregates respond to high external glucose with insulin secretion.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>The IPC/GPC differentiation process from hASC, followed by the generation of cellular aggregates that are later microencapsulated, could represent a possible treatment for T1DM.</jats:p> </jats:sec>
16Scopus© Citations 9
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Comparative study of the neural differentiation capacity of mesenchymal stromal cells from different tissue sources: An approach for their use in neural regeneration therapies
(2019)
Daniela N. Urrutia
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Pablo Caviedes
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Rodrigo Mardones
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José J. Minguell
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ANA MARIA FERNANDA VEGA LETTER
27Scopus© Citations 103
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Specific, Sensitive, and Stable Reporting of Human Mesenchymal Stromal Cell Chondrogenesis
(2019)
Rodolfo E. De la Vega
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ALFREDO MAXIMILIANO SCHEU GONCALVES
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Lennart A. Brown
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Christopher H. Evans
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Elisabeth Ferreira
1Scopus© Citations 7
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Small Extracellular Vesicles Released from Ovarian Cancer Spheroids in Response to Cisplatin Promote the Pro-Tumorigenic Activity of Mesenchymal Stem Cells
(2019)
Nelly Vera
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Stephanie Acuña-Gallardo
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Felipe Grünenwald
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Albano Caceres-Verschae
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Ornella Realini
<jats:p>Despite the different strategies used to treat ovarian cancer, around 70% of women/patients eventually fail to respond to the therapy. Cancer stem cells (CSCs) play a role in the treatment failure due to their chemoresistant properties. This capacity to resist chemotherapy allows CSCs to interact with different components of the tumor microenvironment, such as mesenchymal stem cells (MSCs), and thus contribute to tumorigenic processes. Although the participation of MSCs in tumor progression is well understood, it remains unclear how CSCs induce the pro-tumorigenic activity of MSCs in response to chemotherapy. Small extracellular vesicles, including exosomes, represent one possible way to modulate any type of cell. Therefore, in this study, we evaluate if small extracellular vesicle (sEV) derived from ovarian cancer spheroids (OCS), which are enriched in CSCs, can modify the activity of MSCs to a pro-tumorigenic phenotype. We show that sEV released by OCS in response to cisplatin induce an increase in the migration pattern of bone marrow MSCs (BM-MSCs) and the secretion interleukin-6 (IL-6), interleukin-8 (IL-8), and vascular endothelial growth factor A (VEGFA). Moreover, the factors secreted by BM-MSCs induce angiogenesis in endothelial cells and the migration of low-invasive ovarian cancer cells. These findings suggest that cisplatin could modulate the cargo of sEV released by CSCs, and these exosomes can further induce the pro-tumorigenic activity of MSCs.</jats:p>
3Scopus© Citations 35
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Motor and sensory Schwann cell phenotype commitment is diminished by extracorporeal shockwave treatment in vitro
(2020)
David Hercher
;
Heinz Redl
;
Christina M.a.p. Schuh
11 1Scopus© Citations 5

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