In Situ Maturated Early-Stage Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Improve Cardiac Function by Enhancing Segmental Contraction in Infarcted Rats
Abstract
:1. Introduction
2. Results
2.1. Descriptive Analysis of Mortality and Echocardiography-Based Randomization
2.2. Early-Stage Human iPSC-CMs Are Predominantly MLC2a Positive (Atrial-Like Cardiomyocytes) at the Time of Injection
2.3. Early-Stage Human iPSC-CM Therapy Significantly Improves the Overall Cardiac Function of Immunosuppressed Infarcted Rats
2.4. The Human Grafts Are Composed of Cardiomyocytes That Preserve Certain Levels of Cell Cycling Activity
2.5. The Human Cardiac Grafts Maturate In Situ after Injection
2.6. Immunosuppression Confidently Preserves Human Cardiac Grafts from Rejection or Ectopic Cellular Formations
3. Discussion
4. Material and Methods
4.1. Immunosuppression Confidently Preserves Human Cardiac Grafts from Rejection or Ectopic Cellular Formations
4.2. hiPSC-CM Differentiation
4.3. hiPSC-CM Characterization: Flow Cytometry and Immunofluorescence
4.4. Myocardial Infarction Induction
4.5. Immunosuppression
4.6. Early-Stage hiPSC-CM Priming and Intramyocardial Injection
4.7. Echocardiography, Randomization, and Exclusion Criteria
4.8. Euthanasia and Tissues Sampling
4.9. Histology, Immunohistochemistry (IHC), and Immunofluorescent (IF) Assays
4.10. Biodistribution
4.11. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Status | Phase | N#/ Phase | % (From Total) | Cause | Group | N#/ Group | % (From Total) |
---|---|---|---|---|---|---|---|
Dead | MI induction | 1 | 2.4% | Irreversible fibrillation | MI | 1 | 2.4% |
1–6 days after MI induction (pre-echocardiography) | 2 | 4.8% | Anesthetic overload | MI | 1 | 2.4% | |
Sudden death * | MI | 1 | 2.4% | ||||
Baseline echocardiogram (day 6) | 2 | 4.8% | Anesthetic overload | MI | 2 | 4.8% | |
Injections procedure | 6 | 14.3% | Cardiorespiratory arrest | PSC | 3 | 7.1% | |
CELL | 3 | 7.1% | |||||
1–30 days after injection (pre-final echocardiography) | 6 | 14.3% | Sudden death * | SHAM | 1 | 2.4% | |
PSC | 3 | 7.1% | |||||
CELL | 2 | 4.8% | |||||
Final echocardiogram (day 37) | 0 | 0.0% | - | 0 | 0.0% | ||
Live | LVEF cutoff (based on CTRLs) | 4 ** | 9.5% | 20% impairment vs. CTRL animals at baseline | PSC | 2 | 4.8% |
CELL | 2 | 4.8% | |||||
Completed follow-up and used for further analysis | 21 | 50.0% | - | CTRL | 4 | 9.5% | |
- | SHAM | 4 | 9.5% | ||||
- | PSC | 6 | 14.2% | ||||
- | CELL | 7 | 16.7% | ||||
Total | 42 | 100% | 42 | 100% |
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Biagi, D.; Fantozzi, E.T.; Campos-Oliveira, J.C.; Naghetini, M.V.; Ribeiro, A.F., Jr.; Rodrigues, S.; Ogusuku, I.; Vanderlinde, R.; Christie, M.L.A.; Mello, D.B.; et al. In Situ Maturated Early-Stage Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Improve Cardiac Function by Enhancing Segmental Contraction in Infarcted Rats. J. Pers. Med. 2021, 11, 374. https://doi.org/10.3390/jpm11050374
Biagi D, Fantozzi ET, Campos-Oliveira JC, Naghetini MV, Ribeiro AF Jr., Rodrigues S, Ogusuku I, Vanderlinde R, Christie MLA, Mello DB, et al. In Situ Maturated Early-Stage Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Improve Cardiac Function by Enhancing Segmental Contraction in Infarcted Rats. Journal of Personalized Medicine. 2021; 11(5):374. https://doi.org/10.3390/jpm11050374
Chicago/Turabian StyleBiagi, Diogo, Evelyn Thais Fantozzi, Julliana Carvalho Campos-Oliveira, Marcus Vinicius Naghetini, Antonio Fernando Ribeiro, Jr., Sirlene Rodrigues, Isabella Ogusuku, Rubia Vanderlinde, Michelle Lopes Araújo Christie, Debora Bastos Mello, and et al. 2021. "In Situ Maturated Early-Stage Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Improve Cardiac Function by Enhancing Segmental Contraction in Infarcted Rats" Journal of Personalized Medicine 11, no. 5: 374. https://doi.org/10.3390/jpm11050374
APA StyleBiagi, D., Fantozzi, E. T., Campos-Oliveira, J. C., Naghetini, M. V., Ribeiro, A. F., Jr., Rodrigues, S., Ogusuku, I., Vanderlinde, R., Christie, M. L. A., Mello, D. B., de Carvalho, A. C. C., Valadares, M., Cruvinel, E., & Dariolli, R. (2021). In Situ Maturated Early-Stage Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Improve Cardiac Function by Enhancing Segmental Contraction in Infarcted Rats. Journal of Personalized Medicine, 11(5), 374. https://doi.org/10.3390/jpm11050374