Exosomal Preconditioning of Human iPSC-Derived Cardiomyocytes Beneficially Alters Cardiac Electrophysiology and Micro RNA Expression
<p>Exosomes (EXOs) were isolated with a Total Exosome Isolation kit and analyzed using a Nanosight NS300. Nanoparticle tracing analysis (NTA) analysis showed particle size and concentration distribution for EXOs secreted during hypoxia. Particle sizes were captured five times for 60 s for every sample. The mean diameter of EXOs secreted under hypoxic conditions was measured to be 167.4 nm (±25.6 nm). The mean concentration of secreted EXOs was measured to be 9.2 × 10<sup>7</sup> EXO/mL (±2.0 × 10<sup>7</sup> EXO/mL). Data were analyzed using the NanoSight Software NTA 3.2 Dev Build 3.2.16. Black line shows particle concentration while red error bars indicate ± SEM.</p> "> Figure 2
<p>hIPSC-CM electrophysiological activity was recorded in vitro on an MEA system. (<b>A</b>) Experimental setup of the MEA recordings, EXO preconditioning, and hypoxic stimulation. A representative image of the recorded MEA activity map shows hIPSC-CM beat rate at baseline (<b>B</b>) and after 16 h of hypoxia (<b>C</b>). Saturation was set to 80 bpm. (<b>D</b>) hIPSC-CMs displayed a significant increase in beat period after 16 h of hypoxia. Furthermore, cells preconditioned with EXOs exhibited increased beat period compared with non-treated cells. (<b>E</b>) The 16 h of hypoxia significantly increased excitation–contraction (EC)-coupling for the control group. Interestingly, preconditioning with hypoxic EXOs resulted in faster EC-coupling compared with non-treated CMs after 16 h of hypoxia. (<b>F</b>) Field potential duration (FPD)for both preconditioned and non-treated hIPSC was significantly increased after 16 h of hypoxia. There were no significant changes in FPD between the two experimental groups. (<b>G</b>) EXO preconditioning did not affect the beat amplitude of contraction after 16 h of hypoxia. The were no significant changes in (<b>H</b>) FPD spike slope or (<b>I</b>) FPD spike amplitude between the control and preconditioned groups after hypoxia. (<b>J</b>) Visual representation of MEA recordings of hIPSC-CM beat period for the control group (blue) and EXO-treated group (yellow) at baseline and after 16 h of hypoxia for the control group (green) and the EXO-treated group (red). (<b>K</b>) Representative visualizations of cardiomyocyte contractions from the electrophysiological MEA recordings show hIPSC-CM contractions at baseline and after 16 h of hypoxia for both preconditioned and non-preconditioned hIPSC-CMs. Data were analyzed using one-way ANOVA multiple comparison analysis or <span class="html-italic">t</span>-test. Data from the MEA analysis are expressed as mean of raw values or %-change from baseline ± SEM (n = 20). Raw values were calculated from the mean recordings from 3 of the 8 electrodes at the time of baseline and post-hypoxic stimulus. * <span class="html-italic">p</span> ≤ 0.05; ** <span class="html-italic">p</span> ≤ 0.01; *** <span class="html-italic">p</span> ≤ 0.001; **** <span class="html-italic">p</span> ≤ 0.0001; ns: not significant (<span class="html-italic">p</span> > 0.05).</p> "> Figure 3
<p>MEA recordings show electrophysiological changes during 16 h of hypoxia for control (blue) and EXO-preconditioned hIPSC-CMs (red). (<b>A</b>) The beat period was increased for both groups of hIPSC-CMs shortly after initiation and throughout the 16 h of hypoxic stress. (<b>B</b>) FPD increased for both control and preconditioned hIPSC-CMs during hypoxia. FPD was significantly increased in cells preconditioned with EXOs at 8 h of hypoxia compared to non-treated cells. Continuous MEA recordings showed no significant differences in the spike slope (<b>C</b>) or spike amplitude (<b>D</b>) of FPD between the control and preconditioned groups throughout the 16 h of hypoxia. Data were analyzed using mixed-effects analysis and Šídák’s multiple comparisons test. Data from the MEA analysis are expressed as mean of raw values or %-change from baseline ± SEM (n = 20). Raw values were calculated from the mean recordings from 3 of the 8 electrodes once every hour during the 16 h of hypoxic stimulus.</p> "> Figure 4
<p>Time to membrane re-polarization extracted from local extracellular action potential (LEAP) data before and after 16 h of hypoxia. (<b>A</b>) APD30 is significantly increased after 16 h of hypoxia for both cell groups. However, EXO preconditioning did not significantly alter APD30. (<b>B</b>) The 16 h of hypoxia did significantly increase APD50 for both groups. Preconditioned hIPSC-CMs exhibited no significant change in APD50 compared with non-treated hIPSC-CMs. (<b>C</b>) The 16 h of hypoxia significantly increased APD90 for non-treated hIPSC-CMs but not for EXO-preconditioned cells. Furthermore, EXO preconditioning did not significantly alter ADP90. Representative traces from the MEA recordings show hIPSC-CM LEAP at baseline (<b>D</b>) and after 16 h of hypoxia (<b>E</b>) for both preconditioned and non-preconditioned hIPSC-CMs. Data were analyzed using one-way ANOVA multiple-comparisons analysis. Data from the MEA analysis are expressed as mean of raw values ± SEM (n = 6–8). Raw values were calculated from the mean recordings from 3 of the 8 electrodes at the time of baseline and post-hypoxic stimulus. * <span class="html-italic">p</span> ≤ 0.05; ** <span class="html-italic">p</span> ≤ 0.01; ns: not significant (<span class="html-italic">p</span> > 0.05).</p> "> Figure 5
<p>The Gene Ontology (GO) enrichment dot plot depicts the top 30 enriched GO terms for all significantly expressed miRNAs identified in the results. The <span class="html-italic">Y</span>-axis represents enriched terms categorized as biological process (colored in orange), cellular component (colored in blue), and molecular function (colored in green). Terms are ranked based on <span class="html-italic">p</span>-adjusted value. The <span class="html-italic">X</span>-axis denotes the Rich factor for each term. The Rich factor is defined as the ratio of input genes annotated in a term to all genes annotated in the same term. A higher Rich factor indicates a greater degree of enrichment. The size of the dot indicates the number of genes enriched in each term. The color represents the statistical significance of the enrichment, with a brighter shade of color denoting greater significance.</p> "> Figure 6
<p>The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation plot depicts the terms that are significantly enriched in various cell pathways, as identified in the KEGG database. The enriched terms are displayed along the <span class="html-italic">Y</span>-axis, with the BRITE hierarchy parent term in bold black and subordinate terms in various colors. A bar following each term indicates the number of genes enriched in each KEGG term, with the <span class="html-italic">X</span>-axis indicating the number of genes enriched in each term.</p> "> Figure 7
<p>The Sankey diagram illustrates the differential expression of various miRs, regulating their predicted gene targets and the subsequent possible impact on cells, as interpretated in the experiment setting. The diagram comprises three columns with flow paths connecting various strata of the columns. The first column contains miR names, with tile colors indicating expression levels: red for upregulation and blue for downregulation. The flow ribbon color between the miR and Gene Target columns, as well as the tiles in the Impact column, indicate the inverse effect of miR expression: blue for inhibition (blue flow and tiles) and red for promotion (red flow and tiles) of target genes. Grey tiles in the Gene Target column indicate the unknown effects of inhibition or promotion, as they are predicted to be impacted by miRs with mixed effects. The flow ribbon between the Gene Target and Impact columns, as well as the tiles in the Impact column, are colored based on the effects of gene regulation on the cell. Detrimental effects are indicated in purple, while beneficial effects are shown in green.</p> ">
Abstract
:1. Introduction
2. Results
2.1. EXO Isolation
2.2. Electrophysiological Activity of hIPSC-CMs
2.3. miR Sequencing of Non-Treated and Pre-Conditioned hIPSC-CMs
2.4. miR Target Prediction Analysis
3. Discussion
4. Materials and Methods
4.1. hIPSC-CMs for EXO Production
4.2. EXO Isolation and Resuspension
4.3. EXO Quantification and Characterization
4.4. Culturing and Maintenance of Human IPSC-Derived Cardiomyocytes
4.5. EXO Preconditioning
4.6. Hypoxia
4.7. Analysis of Cardiac Electrophysiology on MEA System
4.8. RNA Isolation
4.9. miR Sequencing
4.10. miR Target Prediction Analysis
4.11. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AKT | AKT serine/threonine kinase |
AMI | acute myocardial infarction |
ANK2 | ankyrin 2 |
ANK3 | ankyrin 3 |
APD | action potential durations |
APLN | apelin |
AXIN1 | axin 1 |
BAK1 | BCL2 antagonist/killer 1 |
BAX | BCL2-associated X |
BBC3 | BCL2 binding component 3 |
BCL2 | B-cell lymphoma 2 |
BCL2L1 | BCL2-like 1 |
BCL2L11 | BCL2-like 11 |
BCL2L2 | BCL2-like 2 |
BRCA1 | BRCA1 DNA repair associated |
CACNA1C | calcium voltage-gated channel subunit alpha1 C |
CACNA1D | calcium voltage-gated channel subunit alpha1 D |
CACNA1H | calcium voltage-gated channel subunit alpha1 H |
CACNG8 | calcium voltage-gated channel auxiliary subunit gamma 8 |
CALM1 | calmodulin 1 |
CASP3 | caspase 3 |
CASP9 | caspase 9 |
DAPK1 | death-associated protein kinase 1 |
DAPK2 | death-associated protein kinase 2 |
EC | excitation–contraction |
EGLN1 | Egl-9 family hypoxia inducible factor 1 |
EV | extracellular vesicles |
EXO | exosome |
FOXO3 | forkhead box O3 |
FPD | field potential duration |
GCF | Genomics Core Facility |
GO | Gene Ontology |
GRK2 | G protein-coupled receptor kinase 2 |
HCM | hypertrophic cardiomyopathy |
Hipsc-CM | human-induced pluripotent stem cell-derived cardiomyocytes |
IHD | ischemic heart disease |
IPSC | induced pluripotent stem cell |
KEGG | Kyoto Encyclopedia of Genes and Genomes |
LEAP | local extracellular action potential |
LTCC | L-type Ca2+ channel |
MCL1 | MCL1 apoptosis regulator |
MEA | multielectrode array |
MI | myocardial infarction |
miR | microRNA |
MITF | microphthalmia-associated transcription factor |
NTA | nanoparticle tracing analysis |
NTNU | Norwegian University of Science and Technology |
PEDOT | poly(3,4-ethylenedioxythiophere) |
PRKCE | protein kinase C epsilon |
ROS | reactive oxygen species |
SHC1 | SHC adaptor protein 1 |
SLC25A6 | solute carrier family 25 member 6 |
SOX4 | SRY-box transcription factor 4 |
SR | sarcoplasmic reticulum |
TGF-β1 | transforming growth factor beta |
WHO | World Health Organization |
XIAP | x-linked inhibitor of apoptosis |
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miR | Adjusted p-Value | Log2FoldChange | Regulation |
---|---|---|---|
miR-1234-3p | 0.0001 | −1.28 | Down |
miR-6088-5p | 0.0072 | −0.38 | Down |
miR-9718-3p | 0.0110 | −0.43 | Down |
miR-762-3p | 0.0110 | −0.34 | Down |
miR-6877-5p | 0.0373 | −0.29 | Down |
miR-1293-5p | 0.0668 | −0.26 | Down |
miR-218-5p | 0.1790 | 0.99 | Up |
miR-4284-3p | 0.1805 | 0.22 | Up |
miR-3176-5p | 0.1805 | 0.22 | Up |
miR-361-3p | 0.1997 | 0.21 | Up |
Target Genes | Associated Function | Level of Expression in Human Cardiomyocytes | Author |
---|---|---|---|
AHNAK nucleoprotein (AHNAK) | Excitation–contraction coupling | Medium | [31] |
AKT serine/threonine kinase 1 (AKT1) | Cell survival | Medium | [32] |
AKT serine/threonine kinase 2 (AKT2) | Cell survival | Medium | [33] |
AKT serine/threonine kinase 3 (AKT3) | Cell survival | Low | [34] |
Ankyrin 2 (ANK2) | Ca2+ signaling, excitation–contraction coupling | Medium | [35] |
Ankyrin 3 (ANK3) | Na+ signaling, excitability | Medium | [36] |
Apelin (APLN) | Ca2+ signaling, contraction | NA | [37] |
ATM serine/threonine kinase (ATM) | Anti-apoptotic, cardiac survival | Medium | [38] |
ATPase Na+/K+ transporting subunit beta 1 (ATP1B1) | Contractility | Medium | [39] |
Axin 1 (AXIN1) | Pro-apoptotic | Medium | [40] |
BCL2 antagonist/killer 1 (BAK1) | Pro-apoptotic | Low | [41] |
BCL2-associated X (BAX) | Pro-apoptotic | Medium | [42] |
BCL2 binding component 3 (BBC3) | Pro-apoptotic | Medium | [43] |
BCL2 apoptosis regulator (BCL2) | Anti-apoptotic | Medium | [44] |
BCL2 Like 1 (BCL2L1) | Pro-apoptotic | NA | [45] |
BCL2 Like 11 (BCL2L11) | Pro-apoptotic | Medium | [46] |
BCL2-like 2 (BCL2L2) | Anti-apoptotic | Medium | [47] |
BRCA1 DNA repair-associated (BRCA1) | anti-apoptotic, cell survival | Low | [48] |
Calcium voltage-gated channel Subunit alpha 1C (CACNA1C) | L-type Ca2+ channel | Medium | [49] |
Calcium voltage-gated channel subunit alpha 1D (CACNA1D) | Ca2+ channel | NA | [49] |
Calcium voltage-gated channel subunit alpha 1H (CACNA1H) | ER stress response | Low | [50] |
Calcium voltage-gated channel auxiliary subunit gamma 8 (CACNG8) | L-type Ca2+ channel | NA | [51] |
Calmodulin 1 (CALM1) | Excitation–contraction coupling | Medium | [52] |
Caspase 3 (CASP3) | Pro-apoptotic | NA | [53] |
Caspase 9 (CASP9) | Pro-apoptotic | NA | [54] |
Death-associated protein kinase 1 (DAPK1) | Pro-inflammatory | Medium | [55] |
Death-associated protein kinase 2 (DAPK2) | Pro-apoptotic | Medium | [56] |
Egl-9 family hypoxia inducible factor 1 (EGLN1) | Contractility | High | [57] |
Forkhead box O3 (FOXO3) | Cell survival, mitochondrial function | NA | [58] |
G protein-coupled receptor kinase 2 (GRK2) | Mitochondrial function | Low | [59] |
Hypoxia inducible factor 1 subunit alpha (HIF1A) | Cell survival | NA | [60] |
Interleukin 15 receptor subunit alpha (IL15RA) | Anti-apoptotic | Medium | [61] |
Potassium calcium-activated channel subfamily M alpha 1 (KCNMA1) | Ca2+ channel, excitation–contraction coupling | NA | [62] |
MCL1 apoptosis regulator (MCL1) | Anti-apoptotic | Medium | [63] |
Mechanistic target of rapamycin kinase (MTOR) | Cell survival | High | [64] |
Phosphodiesterase 3B (PDE3B) | Contractility | NA | [65] |
Pyruvate dehydrogenase kinase 1 (PDK1) | Cardioprotection | Medium | [66] |
Protein phosphatase 1 catalytic subunit alpha (PPP1CA) | Contractility | Medium | [67] |
Protein kinase C Alpha (PRKCA) | Contractility | Medium | [68] |
Protein kinase C Epsilon (PRKCE) | Cardioprotection | NA | [69] |
SHC adaptor protein 1 (SHC1) | Mitochondrial function | NA | [70] |
Solute carrier family 25 member 6 (SLC25A6) | ATP synthesis | High | [71] |
SRY-box transcription factor 4 (SOX4) | Pro-apoptotic | Medium | [72] |
X-linked inhibitor of apoptosis (XIAP) | Anti-apoptotic | High | [73] |
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Røsand, Ø.; Wang, J.; Scrimgeour, N.; Marwarha, G.; Høydal, M.A. Exosomal Preconditioning of Human iPSC-Derived Cardiomyocytes Beneficially Alters Cardiac Electrophysiology and Micro RNA Expression. Int. J. Mol. Sci. 2024, 25, 8460. https://doi.org/10.3390/ijms25158460
Røsand Ø, Wang J, Scrimgeour N, Marwarha G, Høydal MA. Exosomal Preconditioning of Human iPSC-Derived Cardiomyocytes Beneficially Alters Cardiac Electrophysiology and Micro RNA Expression. International Journal of Molecular Sciences. 2024; 25(15):8460. https://doi.org/10.3390/ijms25158460
Chicago/Turabian StyleRøsand, Øystein, Jianxiang Wang, Nathan Scrimgeour, Gurdeep Marwarha, and Morten Andre Høydal. 2024. "Exosomal Preconditioning of Human iPSC-Derived Cardiomyocytes Beneficially Alters Cardiac Electrophysiology and Micro RNA Expression" International Journal of Molecular Sciences 25, no. 15: 8460. https://doi.org/10.3390/ijms25158460