Stem Cell Therapy for Myocardial Infarction 2001–2013 Revisited

Edlinger, Christoph; Schreiber, C; Wernly, Bernhard; Anker, Alexandra; Ruzicka, Katja; Jung, Christian; Hoppe, Uta C.; Lichtenauer, Michael

doi:10.1007/s12015-015-9602-z

Cited by 10 publications

(8 citation statements)

References 43 publications

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“…Over the past few decades, stem cell-based therapy has emerged as a promising therapeutic approach for ischemic cardiac repair and regeneration. 19 Endothelial progenitor cells derived from bone marrow or peripheral blood have been tested in clinical studies. However, myocardial infarction, the leading cause of death in U.S. patients, triggers an intense immune response and greatly decreases the therapeutic effects of EPC transplantation.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-10 Deficiency Impairs Reparative Properties of Bone Marrow-Derived Endothelial Progenitor Cell Exosomes

Yue

Garikipati

Verma

et al. 2017

Tissue Engineering Part A

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Endothelial progenitor cell (EPC)-based therapy has immense potential to promote cardiac neovascularization and attenuate ischemic injury. Functional benefits of EPCs and other adult stem cell therapies largely involve paracrine mechanisms and exosomes secreted by stem cells are emerging as pivotal paracrine entity of stem/progenitor cells. However, modest outcomes after EPC-/stem cell-based clinical trials suggest that stem cell/exosome function might be modulated by stimuli they encounter in ischemic tissues, including systemic inflammation. We hypothesized that EPCs under inflammatory stress might produce exosomes of altered and dysfunctional content, which may compromise EPC repair in ischemic heart disease. We have previously shown that EPCs obtained from interleukin-10 knockout (IL-10KO) mice (model mimicking systemic inflammation) display impaired angiogenic functions. Whether IL-10KO-EPC-derived exosomes inherit their parental dysfunctional phenotype and whether inflammatory environment alters the cargo of their secreted exosomes are not known. After cell expansion from IL-10KO and wild-type (WT) mice, we isolated exosomes and compared their functions in terms of effect on cell survival, proliferation, migration, and angiogenic capacity in vitro. WT-EPC-Exo treatment enhanced endothelial cell proliferation and tube formation, and inhibited apoptosis, whereas IL-10KO-Exo exhibited impaired or even detrimental effects, suggesting that the reparative capacity of WT-EPC-Exo is lost in exosomes derived from IL-10-KO-EPCs. Deep RNA sequencing and proteomic analyses to compare WT and IL-10KO-Exo revealed drastically altered exosome cargo. Importantly, IL-10KO-EPC-Exo were highly enriched in microRNAs and proteins that promote inflammation and apoptosis and inhibit angiogenesis. Through modulation of a specific enriched miRNA (miR-375), we partially rescued IL-10KO-EPC-Exo dysfunction. Thus, our study revealed that EPC exosomes display impaired function under inflammatory stimulus through changed exosome contents, and the dysfunction can be rescued by modulation of a specific target packed in exosomes.

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Section: Discussionmentioning

confidence: 99%

Interleukin-10 Deficiency Impairs Reparative Properties of Bone Marrow-Derived Endothelial Progenitor Cell Exosomes

Yue

Garikipati

Verma

et al. 2017

Tissue Engineering Part A

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“…Of importance, Gnecchi et al reported that conditioned medium of mesenchymal stem cells alone markedly reduced cell death in rat cardiomyoctes exposed to hypoxia . Therefore, in the following years focus has shifted from stem‐cell therapy to paracrine mechanisms via cytokines, chemokines, and growth factors . In several studies cell‐free approaches by administration of supernatants of cells alone, could be shown to have beneficial effects on cytoprotection and inhibition on tissue remodeling after AMI .…”

Section: Introductionmentioning

confidence: 99%

Differences in Stem Cell Processing Lead to Distinct Secretomes Secretion—Implications for Differential Results of Previous Clinical Trials of Stem Cell Therapy for Myocardial Infarction

Wernly

Gonçalves

Kiss

et al. 2017

Biotechnology Journal

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Stem cell therapy for acute myocardial infarction (AMI) seemed to be a promising therapy, however, large clinical trials brought differential outcome. It has been shown that paracrine effects of secretomes of stem cells rather than cell therapy might play a fundamental role. The present study seeks to compare cell processing protocols of clinical trials and investigate effects of differential cell culture conditions on chemokine secretion and functional effects. Different secretomes are compared regarding IL-8, VEGF, MCP-1, and TNF-alpha secretion. Secretome mediated effects are evaluated on endothelial cell (HUVEC) tube formation and migration. Cardioprotective signaling kinases in human cardiomyocytes are determined by Western immunoblotting. Cells processed according to the REPAIR-AMI protocol secrete significantly higher amounts of IL-8 (487.3 ± 1231.1 vs 9.1 ± 8.2 pg mL ; p < 0.05). REAPIR-AMI supernatants lead to significantly pronounced tube formation and migration on HUVEC and enhance the phosphorylation of Akt, ERK, and CREB. Cell processing conditions have a major impact on the composition of the secretome. The REPAIR-AMI secretome significantly enhances proangiogenic chemokine secretion, angiogenesis, cell migration, and cardioprotective signaling pathways. These results might explain differential outcomes between clinical trials. Optimizing cell processing protocols with special regards to paracrine factors, might open a new therapeutic concept for improving patient outcome.

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“…The initial hope that stem cell therapy has a benefit was disappointed by several large clinical trials. [2][3][4][5]. Consequently, the so-called "paracrine paradigm" was formulated stating not the stem cells themselves but their secretomes are responsible for some of the promising results in clinical trials investigating "stem cell" therapy [10,11].…”

Section: Discussionmentioning

confidence: 99%

Anti-CD3 Antibody Treatment Reduces Scar Formation in a Rat Model of Myocardial Infarction

Wernly

Paar

Aigner

et al. 2020

Cells

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Introduction: Antibody treatment with anti-thymocyte globulin (ATG) has been shown to be cardioprotective. We aimed to evaluate which single anti-T-cell epitope antibody alters chemokine expression at a level similar to ATG and identified CD3, which is a T-cell co-receptor mediating T-cell activation. Based on these results, the effects of anti-CD3 antibody treatment on angiogenesis and cardioprotection were tested in vitro and in vivo. Methods: Concentrations of IL-8 and MCP-1 in supernatants of human peripheral blood mononuclear cell (PBMC) cultures following distinct antibody treatments were evaluated by Enzyme-linked Immunosorbent Assay (ELISA). In vivo, anti-CD3 antibodies or vehicle were injected intravenously in rats subjected to acute myocardial infarction (AMI). Chemotaxis and angiogenesis were evaluated using tube and migration assays. Intracellular pathways were assessed using Western blot. Extracellular vesicles (EVs) were quantitatively evaluated using fluorescence-activated cell scanning, exoELISA, and nanoparticle tracking analysis. Also, microRNA profiles were determined by next-generation sequencing. Results: Only PBMC stimulation with anti-CD3 antibody led to IL-8 and MCP-1 changes in secretion, similar to ATG. In a rat model of AMI, systemic treatment with an anti-CD3 antibody markedly reduced infarct scar size (27.8% (Inter-quartile range; IQR 16.2-34.9) vs. 12.6% (IQR 8.3-27.2); p < 0.01). The secretomes of anti-CD3 treated PBMC neither induced cardioprotective pathways in cardiomyocytes nor pro-angiogenic mechanisms in human umbilical vein endothelial cell (HUVECs) in vitro. While EVs quantities remained unchanged, PBMC incubation with an anti-CD3 antibody led to alterations in EVs miRNA expression. Conclusion: Treatment with an anti-CD3 antibody led to decreased scar Cells 2020, 9, 295 2 of 19 size in a rat model of AMI. Whereas cardioprotective and pro-angiogenetic pathways were unaltered by anti-CD3 treatment, qualitative changes in the EVs miRNA expression could be observed, which might be causal for the observed cardioprotective phenotype. We provide evidence that EVs are a potential cardioprotective treatment target. Our findings will also provide the basis for a more detailed analysis of putatively relevant miRNA candidates.

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Stem Cell Therapy for Myocardial Infarction 2001–2013 Revisited

Cited by 10 publications

References 43 publications

Interleukin-10 Deficiency Impairs Reparative Properties of Bone Marrow-Derived Endothelial Progenitor Cell Exosomes

Interleukin-10 Deficiency Impairs Reparative Properties of Bone Marrow-Derived Endothelial Progenitor Cell Exosomes

Differences in Stem Cell Processing Lead to Distinct Secretomes Secretion—Implications for Differential Results of Previous Clinical Trials of Stem Cell Therapy for Myocardial Infarction

Anti-CD3 Antibody Treatment Reduces Scar Formation in a Rat Model of Myocardial Infarction

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