Large Animal Models of Cell-Free Cardiac Regeneration
Abstract
:1. Introduction
2. Cell-Free Cardiac Regeneration Therapies
2.1. Stem Cell Secretomes and Extracellular Vesicles (EVs)
2.1.1. Secretomes
2.1.2. EVs
2.2. RNA-Based Therapies
2.2.1. ncRNAs
2.2.2. Coding RNAs
2.3. Growth Factors and Single Molecules
2.3.1. Growth Factors
2.3.2. Other Molecules
2.4. Physical Stimulation of Regeneration
2.4.1. Shock Wave Therapy (SWT)
2.4.2. Low-Level Laser Therapy (LLLT)
2.4.3. Localized High-Frequency Electrical Stimulation (LHFS)
2.4.4. Bioelectrical Stimulation
2.5. Direct Cardiac Reprogramming
3. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Stem Cell Secretomes and EVs. | ||||
---|---|---|---|---|
Therapy Delivery Method | Animal Model Sample Size Follow-Up | Main Effects | Proposed Mechanism | |
MSC-CM i.v. + i.c. | Pig (AMI) (n = 30) 4 h | ↑ LVEF (+32%) ↓ Infarct size (−60%) | ↓ TGF-β signaling ↓ Apoptosis | [24] |
MSC-CM i.v. | Pig (AMI) (n = 22) 3 w | ↑ LVEF (+37%) ↑ Capillary density (+50%) | [25] | |
EPC-CM i.c. | Pig (AMI) (n = 56) 24 h/8 w | ↑ ± dp/dt ↓ Infarct size (−37%) | ↑ IGF-1 signaling | [26] |
APOSEC m.c. | Pig (AMI) (n = 16) 60 d | ↑ Cardiac index ↓ Infarct size (−42%) | ↑ Angiogenesis ↓ Apoptosis | [27,28] |
CDCexo i.c./m.c. | Pig (AMI) (n = 22) 48 h (n = 13) 60 d | ↑ LVEF (+21.27%) 48 h ↓ Infarct size (−26.9%) 48 h ↑ LVEF (+13.3%) 60 d ↓ ESV (−17.47%) 60 d | ↑ Anti-inflammatory macrophage polarization ↓ Fibrosis ↑ Angiogenesis | [34,35] |
CDCexo m.c. | Pig (AMI) (n = 9) 48 h | ↑ LVEF (+18%) ↓ MVO ↓ CD68+ macrophages | [36] | |
CDCexo intrapericardial | Pig (AMI) (n = 18) 10 w | ↑ M2 macrophages | [22,37] | |
MSCexom.c. | Pig (ameroid constrictor)(n = 23)7 w | ↑ Stroke volume (+33.7%)↑ Capillary density | ↑ Angiogenesis | [38] |
RNA-Based Therapies | ||||
---|---|---|---|---|
Molecule (Delivery Method) | Animal Model Sample Size Follow-Up | Main Effects | Proposed Mechanism | |
miR-199a AAV6 mc. | Pig (AMI) (n = 19) 8 w | ↑ LVEF (+17.1%) ↓ Scar size/mass (−50%) ↓ Fibrosis | CM cell-cycle reentry | [42] |
antimiR-132 i.c./i.v. | Pig (AMI) (n = 156) 56 d | ↑ LVEF ↓ Scar size ↓ Fibrosis ↓ CM size | ↑ Foxo3 (anti-fibrotic)↑ Serca2a | [48] |
antagomiR-92a i.v./i.c. | Pig (AMI) (n = 30) 7 d | ↑ LVEF ↑ Capillary density | ↑ Angiogenesis ↓ Inflammation ↓ CM apoptosis | [50] |
PLGA antagomir-92a i.c. | Pig (AMI) (n = 27) 10 d | ↑ LVEF ↓ Adverse remodeling | [51] |
Growth Factors, Proteins, and Other Molecules | ||||
---|---|---|---|---|
Molecule Delivery Method | Animal Model Sample Size Follow-Up | Main Effects | Proposed Mechanism | |
VEGF + angiopoietin-1 AAV mc. | Pig (AMI) (n = 24) 8 w | ↑ LVEF ↑ Capillary density | ↑ Angiogenesis ↑ CM proliferation ↓ Apoptosis | [58] |
VEGF + PDGF-B AAV i.c. | Pig (reduction stent) (n = 27) 56 d | ↑ LVEF ↑ Collateralization | [59] | |
VEGF-A plasmid + GET mc. | Pig (AMI) (n = 37) 7 w | ↑ Angiogenesis | [60] | |
VEGF-B167 AAV i.c. | Canine (dilated CMP) (n = 53) | ↑ LVEF ↓ LVEDP ↑ dP/dtmax | ↓ Apoptosis | [61] |
FGF-1 + CHIR99021 NPs mc. | Pig (AMI) (n = 12) 28 d | ↑ LVEF ↑ Angiogenesis | CM cell cycle reentry | [62] |
Microencapsulated IGF-1 i.c. | Pig (AMI) (n = 24) 10 w | ↑ LVEF (+18%) ↓ CVF ↓ ESVi | ↑ Angiogenesis ↓ Apoptosis | [64] |
rhPDGF-AB i.v. | Pig (AMI) (n = 36) 28 d | ↑ Survival ↑ LVEF ↑ Scar anisotropy ↓ VT | ↑ Angiogenesis Fibroblast modulation | [65] |
TIMP-3 i.c. | Pig (AMI) (n = 17) 28 d | ↓ Infarct size (−45%) ↓ LV dilation (−40%) | MMP inhibition | [70] |
rhAgrin i.c. | Pig (AMI) (n = 19) 28 d | ↑ LVEF ↓ Scar size ↓ Adverse remodeling | CM cell-cycle reentry ↑ Angiogenesis ↓ Inflammation | [71] |
Fstl-1 Epicardial patch | Pig (AMI) (n = 6) 5 w | ↑ LVEF ↓ Scar size ↑ CM proliferation ↑ Arteriogenesis | ↑ Cardiogenesis ↓ Apoptosis | [73] |
AnxA1 cardiotropic AAV i.v. | Pig (AMI) (n = 7) 7 d | ↑ VEGF-A Macrophage polarization | Macrophage modulation | [75] |
Ccna2 AAV mc. | Pig (AMI) (n = 27) 6 w | ↑ LVEF ↑ CM proliferation | CM cell-cycle reentry | [76] |
SCF mc. | Pig (AMI) (n = 22) 3 m | ↑ LVEF (+12%) ↑ Angiogenesis | ↑ Angiogenesis ↓ Apoptosis | [77] |
Tβ4 + MRTF-A AAV i.v. | Pig (reduction stent) (n = 20) 56 d | ↑ LVEF ↓ LVEDP ↑ Collateralization | ↓ Apoptosis ↑ Collateralization | [78] |
Physical Stimulation | ||||
---|---|---|---|---|
Therapy Delivery Method Target Area | Animal Model Sample Size Follow-Up | Main Effects | Proposed Mechanism | |
SWT Extracorporeal Ischemic myocardium | Pig (Ameroid constrictor) (n = 16) 8 w | ↑ LVEF ↑ WTF ↑ Angiogenesis | ↑ VEGF | [80] |
SWT Invasive Ischemic myocardium | Pig (AMI) (n = 11) 6 w | ↑ LVEF ↑ Angiogenesis | [83] | |
LLLT Invasive Bone marrow | Pig (AMI) (n = 12) 90 d | ↓ Infarct size (−68%) ↑ Angiogenesis | ↑ VEGF ↑ Stem cell proliferation | [84] |
LLLT Invasive Ischemic myocardium | Canine (AMI) (n = 22) 14 d | ↓ Infarct size (−49%) | [85] | |
LLLT Invasive Ischemic myocardium | Canine (AMI) (n = 50) 6 w | ↓ Infarct size (−52%) | [86] | |
LHFS Invasive Ischemic myocardium | Pig (AMI) (n = 11) 28 d | EDV (32% vs. 12%) PCWP (+62% vs. −17%) | ↓ Adverse remodeling | [87] |
SCS Intermittent/continuous T1-T3 | Pig (AMI + Pacing) (n = 30) 10 w | ↑ LVEF ↑ +dP/dt | ↑ Sympathetic nerve sprouting | [89] |
VNS Implanted Electrode Vagus nerve | Canine (Microembolization) (n = 26) 6 m | ↑ LVEF ↓ ESV | ↓ Inflammation Macrophage modulation | [90] |
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Spannbauer, A.; Mester-Tonczar, J.; Traxler, D.; Kastner, N.; Zlabinger, K.; Hašimbegović, E.; Riesenhuber, M.; Pavo, N.; Goliasch, G.; Gyöngyösi, M. Large Animal Models of Cell-Free Cardiac Regeneration. Biomolecules 2020, 10, 1392. https://doi.org/10.3390/biom10101392
Spannbauer A, Mester-Tonczar J, Traxler D, Kastner N, Zlabinger K, Hašimbegović E, Riesenhuber M, Pavo N, Goliasch G, Gyöngyösi M. Large Animal Models of Cell-Free Cardiac Regeneration. Biomolecules. 2020; 10(10):1392. https://doi.org/10.3390/biom10101392
Chicago/Turabian StyleSpannbauer, Andreas, Julia Mester-Tonczar, Denise Traxler, Nina Kastner, Katrin Zlabinger, Ena Hašimbegović, Martin Riesenhuber, Noemi Pavo, Georg Goliasch, and Mariann Gyöngyösi. 2020. "Large Animal Models of Cell-Free Cardiac Regeneration" Biomolecules 10, no. 10: 1392. https://doi.org/10.3390/biom10101392