Functionally Competent DNA Damage-Free Induced Pluripotent Stem Cell–Derived Cardiomyocytes for Myocardial Repair

Q: What is the clinical evidence from this study?

Population: Myocardial ischemia / infarction via coronary artery ligation. Intervention: DNA damage-free iPSC-derived cardiomyocytes (DdF-CMs) selected via p53 activation with 4 μM Nutlin-3a vs. Control iPSC-derived cardiomyocytes (Ctrl-CMs). Primary outcome: Cell engraftment rate in the host myocardium at 4 weeks.

Ramaswamy Kannappan; James F. Turner; Jessica M. Miller; Chengming Fan; Amanda G. Rushdi; Namakkal Soorappan Rajasekaran; Jianyi Jay Zhang

doi:10.1161/circulationaha.119.040881

August 5, 2019CirculationOpen Access

Functionally Competent DNA Damage-Free Induced Pluripotent Stem Cell–Derived Cardiomyocytes for Myocardial Repair

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Key result

Nutlin-3a selection of DNA damage-free iPSC-cardiomyocytes increases 4-week cardiac engraftment in ischemic hearts.

Why the study?

Does selecting DNA damage-free iPSCs via Nutlin-3a-mediated p53 activation prior to cardiomyocyte differentiation improve cell engraftment in ischemic mouse hearts compared to unselected control iPSC-derived cardiomyocytes?

Key Points

To determine whether selective elimination of DNA-damaged induced pluripotent stem cells via p53 activation yields cardiomyocytes with improved engraftment capacity for myocardial repair.
Treated iPSCs with 4 μM Nutlin-3a, an MDM2 inhibitor, for 24 hours to selectively trigger apoptosis in DNA-damaged cells, followed by washout and cardiac differentiation.
Injected 9×10^5 control or DNA damage-free iPSC-derived cardiomyocytes into the left ventricular border zone of SCID mice following coronary artery ligation.
Tracked cell engraftment via luciferase bioluminescence imaging at weeks 1 and 4, and quantified hcTnT-positive cardiomyocytes in 10 μm cardiac sections at week 4.
Nutlin-3a treatment significantly reduced the fraction of cells expressing the DNA double-strand break marker γH2A.X in both iPSCs and derived cardiomyocytes.
Bioluminescence imaging showed comparable engraftment at week 1, but revealed significantly greater retention in hearts receiving DNA damage-free cardiomyocytes at week 4.
Transplanted DNA damage-free cardiomyocytes demonstrated a significantly higher engraftment rate per heart and formed mature striated muscle phenotypes.

Structured PICO

Does selecting DNA damage-free iPSCs via Nutlin-3a-mediated p53 activation prior to cardiomyocyte differentiation improve cell engraftment in ischemic mouse hearts compared to unselected control iPSC-derived cardiomyocytes?

P

Population

SCID mice with myocardial ischemia induced by coronary artery ligation, followed for 4 weeks after cell transplantation.

I

Intervention

Transplantation of 9×10^5 DNA damage-free iPSC-derived cardiomyocytes (DdF-CMs), pre-selected by activating p53 in iPSCs using 4 μM Nutlin-3a (an MDM2 inhibitor) for 24 hours, injected into the border zone of the left ventricle.

C

Comparator

Transplantation of 9×10^5 control iPSC-derived cardiomyocytes (Ctrl-CMs) without Nutlin-3a selection injected into the border zone of the left ventricle.

O

Outcome

Cell engraftment efficiency in the mouse heart monitored by luciferase bioluminescence imaging (BLI) at weeks 1 and 4, and quantified by hcTnT immunolabeling in serial cardiac sections at week 4.surrogate

Key expert perspectives

Captured external expert commentary on this paper, strongest first. Original sources are linked where available.

JZ Jianyi ZhangChair of Biomedical Engineering, UAB

“To our knowledge, this is the first study to show that DNA damage-free induced pluripotent stem cells can be selected by p53 activation in induced pluripotent stem cell cultures, and that DNA damage-free cardiomyocytes have enhanced cardiac engraftment potential.”

University of Alabama at BirminghamNews Coverage

RK Ramaswamy KannappanAssistant professor of biomedical engineering, UAB

“As this is a small molecule based approach to select DNA damage-free cells, it can be applied to any type of stem cells, though selection conditions would need to be optimized and evaluated. Other stem cell approaches for diseases such as neurodegenerative diseases, brain and spinal cord injuries, and diabetes might benefit by adopting our method.”

University of Alabama at BirminghamNews Coverage

Implication

Pre-selecting DNA damage-free iPSCs via transient p53 activation with Nutlin-3a eliminates culture-stressed cells and significantly enhances the 4-week myocardial engraftment of derived cardiomyocytes in an ischemic mouse model.

Abstract

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Discussion

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Cite This Study

Kannappan et al. (2019) studied Myocardial ischemia / infarction via coronary artery ligation. DNA damage-free iPSC-derived cardiomyocytes (DdF-CMs) selected via p53 activation with 4 μM Nutlin-3a vs. Control iPSC-derived cardiomyocytes (Ctrl-CMs) was evaluated on Cell engraftment rate in the host myocardium at 4 weeks. Transplanting DNA damage-free iPSC-derived cardiomyocytes selected via Nutlin-3a p53 activation significantly increased the 4-week cardiac engraftment rate in ischemic mouse hearts compared to control cells.

synapsesocial.com/papers/6ad9d446c3759665095848b5 https://doi.org/10.1161/circulationaha.119.040881

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Functionally Competent DNA Damage-Free Induced Pluripotent Stem Cell–Derived Cardiomyocytes for Myocardial Repair

Key Points

Structured PICO

Key expert perspectives

Implication

Abstract

Discussion

Cite This Study

Functionally Competent DNA Damage-Free Induced Pluripotent Stem Cell–Derived Cardiomyocytes for Myocardial Repair

Key Points

Structured PICO

Key expert perspectives

Implication

Abstract

Discussion

Cite This Study

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