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  1. Article ; Online: State-of-play for cellular therapies in cardiac repair and regeneration.

    Vaka, Ramana / Davis, Darryl R

    Stem cells (Dayton, Ohio)

    2021  Volume 39, Issue 12, Page(s) 1579–1588

    Abstract: Cardiovascular disease is the primary cause of death around the world. For almost two decades, cell therapy has been proposed as a solution for heart disease. In this article, we report on the "state-of-play" of cellular therapies for cardiac repair and ... ...

    Abstract Cardiovascular disease is the primary cause of death around the world. For almost two decades, cell therapy has been proposed as a solution for heart disease. In this article, we report on the "state-of-play" of cellular therapies for cardiac repair and regeneration. We outline the progression of new ideas from the preclinical literature to ongoing clinical trials. Recent data supporting the mechanics and mechanisms of myogenic and paracrine therapies are evaluated in the context of long-term cardiac engraftment. This discussion informs on promising new approaches to indicate future avenues for the field.
    MeSH term(s) Cell- and Tissue-Based Therapy ; Heart ; Heart Diseases ; Humans ; Myocytes, Cardiac ; Stem Cell Transplantation
    Language English
    Publishing date 2021-08-27
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1143556-2
    ISSN 1549-4918 ; 1066-5099
    ISSN (online) 1549-4918
    ISSN 1066-5099
    DOI 10.1002/stem.3446
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Is Mitochondrial Oxidative Stress a Viable Therapeutic Target in Preeclampsia?

    Vaka, Ramana / Deer, Evangeline / LaMarca, Babbette

    Antioxidants. 2022 Jan. 22, v. 11, no. 2

    2022  

    Abstract: Despite considerable research efforts over the past few decades, the pathology of preeclampsia (PE) remains poorly understood with no new FDA-approved treatments. There is a substantial amount of work being conducted by investigators around the world to ... ...

    Abstract Despite considerable research efforts over the past few decades, the pathology of preeclampsia (PE) remains poorly understood with no new FDA-approved treatments. There is a substantial amount of work being conducted by investigators around the world to identify targets to develop therapies for PE. Oxidative stress has been identified as one of the crucial players in pathogenesis of PE and has garnered a great deal of attention by several research groups including ours. While antioxidants have shown therapeutic benefit in preclinical models of PE, the clinical trials evaluating antioxidants (vitamin E and vitamin C) were found to be disappointing. Although the idea behind contribution of mitochondrial oxidative stress in PE is not new, recent years have seen an enormous interest in exploring mitochondrial oxidative stress as an important pathological mediator in PE. We and others using animals, cell models, and preeclamptic patient samples have shown the evidence for placental, renal, and endothelial cell mitochondrial oxidative stress, and its significance in PE. These studies offer promising results; however, the important and relevant question is can we translate these results into clinical efficacy in treating PE. Hence, the purpose of this review is to review the existing literature and offer our insights on the potential of mitochondrial antioxidants in treating PE.
    Keywords ascorbic acid ; endothelial cells ; mitochondria ; oxidative stress ; pathogenesis ; patients ; pre-eclampsia ; therapeutics ; vitamin E
    Language English
    Dates of publication 2022-0122
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article
    ZDB-ID 2704216-9
    ISSN 2076-3921
    ISSN 2076-3921
    DOI 10.3390/antiox11020210
    Database NAL-Catalogue (AGRICOLA)

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  3. Article: Is Mitochondrial Oxidative Stress a Viable Therapeutic Target in Preeclampsia?

    Vaka, Ramana / Deer, Evangeline / LaMarca, Babbette

    Antioxidants (Basel, Switzerland)

    2022  Volume 11, Issue 2

    Abstract: Despite considerable research efforts over the past few decades, the pathology of preeclampsia (PE) remains poorly understood with no new FDA-approved treatments. There is a substantial amount of work being conducted by investigators around the world to ... ...

    Abstract Despite considerable research efforts over the past few decades, the pathology of preeclampsia (PE) remains poorly understood with no new FDA-approved treatments. There is a substantial amount of work being conducted by investigators around the world to identify targets to develop therapies for PE. Oxidative stress has been identified as one of the crucial players in pathogenesis of PE and has garnered a great deal of attention by several research groups including ours. While antioxidants have shown therapeutic benefit in preclinical models of PE, the clinical trials evaluating antioxidants (vitamin E and vitamin C) were found to be disappointing. Although the idea behind contribution of mitochondrial oxidative stress in PE is not new, recent years have seen an enormous interest in exploring mitochondrial oxidative stress as an important pathological mediator in PE. We and others using animals, cell models, and preeclamptic patient samples have shown the evidence for placental, renal, and endothelial cell mitochondrial oxidative stress, and its significance in PE. These studies offer promising results; however, the important and relevant question is can we translate these results into clinical efficacy in treating PE. Hence, the purpose of this review is to review the existing literature and offer our insights on the potential of mitochondrial antioxidants in treating PE.
    Language English
    Publishing date 2022-01-22
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2704216-9
    ISSN 2076-3921
    ISSN 2076-3921
    DOI 10.3390/antiox11020210
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Atrial Fibrosis and Inflammation in Postoperative Atrial Fibrillation: Comparative Effects of Amiodarone, Colchicine, or Exosomes.

    Parent, Sandrine / Amant, Jennifer St / Remortel, Sophie Van / Kahn, Saad / Vaka, Ramana / Courtman, David / Stewart, Duncan John / Davis, Darryl Raymond

    JACC. Clinical electrophysiology

    2024  

    Abstract: Background: Extracellular vesicles (EVs) isolated from human heart-derived cells have shown promise in suppressing inflammation and fibroblast proliferation. However, their precise benefits in atrial fibrillation (AF) prevention and the role of their ... ...

    Abstract Background: Extracellular vesicles (EVs) isolated from human heart-derived cells have shown promise in suppressing inflammation and fibroblast proliferation. However, their precise benefits in atrial fibrillation (AF) prevention and the role of their antifibrotic/anti-inflammatory properties remain unclear.
    Objectives: The purpose of this study was to conduct a head-to-head comparison of antiarrhythmic strategies to prevent postoperative AF using a rat model of sterile pericarditis. Specifically, we aimed to assess the efficacy of amiodarone (a classic antiarrhythmic drug), colchicine (an anti-inflammatory agent), and EVs derived from human heart-derived cells, which possess anti-inflammatory and antifibrotic properties, on AF induction, inflammation, and fibrosis progression.
    Methods: Heart-derived cells were cultured from human atrial appendages under serum-free xenogen-free conditions. Middle-aged Sprague Dawley rats were randomized into different groups, including sham operation, sterile pericarditis with amiodarone treatment, sterile pericarditis with colchicine treatment (2 dose levels), and sterile pericarditis with intra-atrial injection of EVs or vehicle. Invasive electrophysiological testing was performed 3 days after surgery before sacrifice.
    Results: Sterile pericarditis increased the likelihood of inducing AF. Colchicine and EVs exhibited anti-inflammatory effects, but only EV treatment significantly reduced AF probability, whereas colchicine showed a positive trend without statistical significance. EVs and high-dose colchicine reduced atrial fibrosis by 46 ± 2% and 26 ± 2%, respectively. Amiodarone prevented AF induction but had no effect on inflammation or fibrosis.
    Conclusions: In this study, both amiodarone and EVs prevented AF, whereas treatment with colchicine was ineffective. The additional anti-inflammatory and antifibrotic effects of EVs suggest their potential as a comprehensive therapeutic approach for AF prevention, surpassing the effects of amiodarone or colchicine.
    Language English
    Publishing date 2024-04-03
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2846739-5
    ISSN 2405-5018 ; 2405-500X ; 2405-500X
    ISSN (online) 2405-5018 ; 2405-500X
    ISSN 2405-500X
    DOI 10.1016/j.jacep.2024.02.019
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Extracellular vesicle microRNA and protein cargo profiling in three clinical-grade stem cell products reveals key functional pathways.

    Vaka, Ramana / Parent, Sandrine / Risha, Yousef / Khan, Saad / Courtman, David / Stewart, Duncan J / Davis, Darryl R

    Molecular therapy. Nucleic acids

    2023  Volume 32, Page(s) 80–93

    Abstract: The cell origin-specific payloads within extracellular vesicles (EVs) mediate therapeutic bioactivity for a wide variety of stem cell types. In this study, we profiled the microRNA (miRNA) and protein cargos found within EVs produced by three clinical- ... ...

    Abstract The cell origin-specific payloads within extracellular vesicles (EVs) mediate therapeutic bioactivity for a wide variety of stem cell types. In this study, we profiled the microRNA (miRNA) and protein cargos found within EVs produced by three clinical-grade stem cell products of different ontogenies being considered for clinical application, namely bone marrow-derived mesenchymal stromal cells (BM-MSCs), heart-derived cells (HDCs), and umbilical cord-derived MSCs (UC-MSCs). Although several miRNAs (757) and proteins (420) were found in common, each producer cell type expressed unique miRNA profiles when the most highly expressed transcripts were compared. Differential expression analysis revealed that BM-MSCs and HDCs were quite similar, while UC-MSCs had the greatest number of unique miRNAs and proteins. Despite these differences, all three EVs promoted cell adhesion/migration, immune response, platelet aggregation, protein translation/stabilization, and RNA processing. EVs from BM-MSCs were implicated in apoptosis, cell-cycle progression, collagen formation, heme pigment synthesis, and smooth muscle differentiation, while HDC and UC-MSC EVs were found to regulate complement activation, endopeptidase activity, and matrix metallopeptidases. Overall, miRNA and protein profiling reveal functional differences between three leading stem cell products. These findings provide a framework for mechanistic exploration of candidate therapeutic molecules driving the salutary effects of EVs.
    Language English
    Publishing date 2023-03-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2662631-7
    ISSN 2162-2531
    ISSN 2162-2531
    DOI 10.1016/j.omtn.2023.03.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Inactivation of the NLRP3 inflammasome mediates exosome-based prevention of atrial fibrillation.

    Parent, Sandrine / Vaka, Ramana / St Amant, Jennifer / Kahn, Saad / Van Remortel, Sophie / Bi, Christina / Courtman, David / Stewart, Duncan John / Davis, Darryl Raymond

    Theranostics

    2024  Volume 14, Issue 2, Page(s) 608–621

    Abstract: Rationale: ...

    Abstract Rationale:
    MeSH term(s) Male ; Rats ; Humans ; Animals ; Atrial Fibrillation/prevention & control ; Atrial Fibrillation/drug therapy ; Inflammasomes ; NLR Family, Pyrin Domain-Containing 3 Protein ; Exosomes ; Rats, Sprague-Dawley ; Pericarditis ; Fibrosis
    Chemical Substances Inflammasomes ; NLR Family, Pyrin Domain-Containing 3 Protein
    Language English
    Publishing date 2024-01-01
    Publishing country Australia
    Document type Journal Article
    ZDB-ID 2592097-2
    ISSN 1838-7640 ; 1838-7640
    ISSN (online) 1838-7640
    ISSN 1838-7640
    DOI 10.7150/thno.89520
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Direct comparison of different therapeutic cell types susceptibility to inflammatory cytokines associated with COVID-19 acute lung injury.

    Vaka, Ramana / Khan, Saad / Ye, Bin / Risha, Yousef / Parent, Sandrine / Courtman, David / Stewart, Duncan J / Davis, Darryl R

    Stem cell research & therapy

    2022  Volume 13, Issue 1, Page(s) 20

    Abstract: Background: Although 90% of infections with the novel coronavirus 2 (COVID-19) are mild, many patients progress to acute respiratory distress syndrome (ARDS) which carries a high risk of mortality. Given that this dysregulated immune response plays a ... ...

    Abstract Background: Although 90% of infections with the novel coronavirus 2 (COVID-19) are mild, many patients progress to acute respiratory distress syndrome (ARDS) which carries a high risk of mortality. Given that this dysregulated immune response plays a key role in the pathology of COVID-19, several clinical trials are underway to evaluate the effect of immunomodulatory cell therapy on disease progression. However, little is known about the effect of ARDS associated pro-inflammatory mediators on transplanted stem cell function and survival, and any deleterious effects could undermine therapeutic efficacy. As such, we assessed the impact of inflammatory cytokines on the viability, and paracrine profile (extracellular vesicles) of bone marrow-derived mesenchymal stromal cells, heart-derived cells, and umbilical cord-derived mesenchymal stromal cells.
    Methods: All cell products were manufactured and characterized to established clinical release standards by an accredited clinical cell manufacturing facility. Cytokines and Extracellular vesicles in the cell conditioned media were profiled using proteomic array and nanoparticle tracking analysis. Using a survey of the clinical literature, 6 cytotoxic cytokines implicated in the progression of COVID-19 ARDS. Flow cytometry was employed to determine receptor expression of these 6 cytokines in three cell products. Based on clinical survey and flow cytometry data, a cytokine cocktail that mimics cytokine storm seen in COVID-19 ARDS patients was designed and the impact on cytokine cocktail on viability and paracrine secretory ability of cell products were assessed using cell viability and nanoparticle tracking analysis.
    Results: Flow cytometry revealed the presence of receptors for all cytokines but IL-6, which was subsequently excluded from further experimentation. Despite this widespread expression, exposure of each cell type to individual cytokines at doses tenfold greater than observed clinically or in combination at doses associated with severe ARDS did not alter cell viability or extracellular vesicle character/production in any of the 3 cell products.
    Conclusions: The paracrine production and viability of the three leading cell products under clinical evaluation for the treatment of severe COVID-19 ARDS are not altered by inflammatory mediators implicated in disease progression.
    MeSH term(s) Acute Lung Injury/therapy ; COVID-19 ; Cytokines ; Humans ; Mesenchymal Stem Cell Transplantation ; Proteomics ; SARS-CoV-2
    Chemical Substances Cytokines
    Language English
    Publishing date 2022-01-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2548671-8
    ISSN 1757-6512 ; 1757-6512
    ISSN (online) 1757-6512
    ISSN 1757-6512
    DOI 10.1186/s13287-021-02699-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Prevention of atrial fibrillation after open-chest surgery with extracellular vesicle therapy.

    Parent, Sandrine / Vaka, Ramana / Risha, Yousef / Ngo, Clarissa / Kanda, Pushpinder / Nattel, Stanley / Khan, Saad / Courtman, David / Stewart, Duncan J / Davis, Darryl R

    JCI insight

    2023  Volume 8, Issue 15

    Abstract: Almost half of patients recovering from open-chest surgery experience atrial fibrillation (AF) that results principally from inflammation in the pericardial space surrounding the heart. Given that postoperative AF is associated with increased mortality, ... ...

    Abstract Almost half of patients recovering from open-chest surgery experience atrial fibrillation (AF) that results principally from inflammation in the pericardial space surrounding the heart. Given that postoperative AF is associated with increased mortality, effective measures to prevent AF after open-chest surgery are highly desirable. In this study, we tested the concept that extracellular vesicles (EVs) isolated from human atrial explant-derived cells can prevent postoperative AF. Middle-aged female and male rats were randomized to undergo sham operation or induction of sterile pericarditis followed by trans-epicardial injection of human EVs or vehicle into the atrial tissue. Pericarditis increased the probability of inducing AF while EV treatment abrogated this effect in a sex-independent manner. EV treatment reduced infiltration of inflammatory cells and production of pro-inflammatory cytokines. Atrial fibrosis and hypertrophy seen after pericarditis were markedly attenuated by EV pretreatment, an effect attributable to suppression of fibroblast proliferation by EVs. Our study demonstrates that injection of EVs at the time of open-chest surgery shows prominent antiinflammatory effects and prevents AF due to sterile pericarditis. Translation of this finding to patients might provide an effective new strategy to prevent postoperative AF by reducing atrial inflammation and fibrosis.
    MeSH term(s) Middle Aged ; Humans ; Male ; Female ; Rats ; Animals ; Atrial Fibrillation/etiology ; Atrial Fibrillation/prevention & control ; Inflammation/complications ; Pericarditis ; Heart Atria ; Fibrosis ; Extracellular Vesicles
    Language English
    Publishing date 2023-06-29
    Publishing country United States
    Document type Randomized Controlled Trial ; Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.163297
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Characterization of Mitochondrial Bioenergetics in Preeclampsia.

    Vaka, Ramana / Deer, Evangeline / Cunningham, Mark / McMaster, Kristen M / Wallace, Kedra / Cornelius, Denise C / Amaral, Lorena M / LaMarca, Babbette

    Journal of clinical medicine

    2021  Volume 10, Issue 21

    Abstract: Preeclampsia (PE) is characterized by new onset hypertension during pregnancy and is associated with oxidative stress, placental ischemia, and autoantibodies to the angiotensin II type I receptor (AT1-AA). Mitochondrial (mt) dysfunction in PE and various ...

    Abstract Preeclampsia (PE) is characterized by new onset hypertension during pregnancy and is associated with oxidative stress, placental ischemia, and autoantibodies to the angiotensin II type I receptor (AT1-AA). Mitochondrial (mt) dysfunction in PE and various sources of oxidative stress, such as monocytes, neutrophils, and CD4 + T cells, have been identified as important players in the pathophysiology of PE. We have established the significance of AT1-AA, TNF-α, and CD4 + T cells in causing mitochondrial (mt) dysfunction in renal and placental tissues in pregnant rats. Although the role of mt dysfunction from freshly isolated intact placental mitochondria has been compared in human PE and normally pregnant (NP) controls, variations among preterm PE or term PE have not been compared and mechanisms contributing to mt ROS during PE are unclear. Therefore, we hypothesized PE placentas would exhibit impaired placental mt function, which would be worse in preterm PE patients than in those of later gestational ages. Immediately after delivery, PE and NP patient's placentas were collected, mt were isolated and mt respiration and ROS were measured. PE patients at either < or >34 weeks gestational age (GA) exhibited elevated blood pressure and decreased placental mt respiration rates (state 3 and maximal). Patients delivering at >34 weeks exhibited decreased Complex IV activity and expression. Placental mtROS was significantly reduced in both PE groups, compared to NP placental mitochondria. Collectively, the study demonstrates that PE mt dysfunction occurs in the placenta, with mtROS being lower than that seen in NP controls. These data indicate why antioxidants, as a potential target or new therapeutic agent, may not be ideal in treating the oxidative stress associated with PE.
    Language English
    Publishing date 2021-10-29
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662592-1
    ISSN 2077-0383
    ISSN 2077-0383
    DOI 10.3390/jcm10215063
    Database MEDical Literature Analysis and Retrieval System OnLINE

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