Pim1 Kinase Overexpression Enhances ckit+ Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine

Shathiyah Kulandavelu, Vasileios Karantalis, Julia Fritsch, Konstantinos E. Hatzistergos, Viky Y. Loescher, Frederic McCall, Bo Wang, Luiza Bagno, Samuel Golpanian, Ariel Wolf, Justin Grenet, Adam Williams, Aaron Kupin, Aaron Rosenfeld, Sadia Mohsin, Mark A. Sussman, Azorides R Morales, Wayne E Balkan, Joshua Hare

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Background Pim1 kinase plays an important role in cell division, survival, and commitment of precursor cells towards a myocardial lineage, and overexpression of Pim1 in ckit+ cardiac stem cells (CSCs) enhances their cardioreparative properties. Objectives The authors sought to validate the effect of Pim1-modified CSCs in a translationally relevant large animal preclinical model of myocardial infarction (MI). Methods Human cardiac stem cells (hCSCs, n = 10), hckit+ CSCs overexpressing Pim1 (Pim1+; n = 9), or placebo (n = 10) were delivered by intramyocardial injection to immunosuppressed Yorkshire swine (n = 29) 2 weeks after MI. Cardiac magnetic resonance and pressure volume loops were obtained before and after cell administration. Results Whereas both hCSCs reduced MI size compared to placebo, Pim1+ cells produced a ∼3-fold greater decrease in scar mass at 8 weeks post-injection compared to hCSCs (−29.2 ± 2.7% vs. −8.4 ± 0.7%; p < 0.003). Pim1+ hCSCs also produced a 2-fold increase of viable mass compared to hCSCs at 8 weeks (113.7 ± 7.2% vs. 65.6 ± 6.8%; p <0.003), and a greater increase in regional contractility in both infarct and border zones (both p < 0.05). Both CSC types significantly increased ejection fraction at 4 weeks but this was only sustained in the Pim1+ group at 8 weeks compared to placebo. Both hCSC and Pim1+ hCSC treatment reduced afterload (p = 0.02 and p = 0.004, respectively). Mechanoenergetic recoupling was significantly greater in the Pim1+ hCSC group (p = 0.005). Conclusions Pim1 overexpression enhanced the effect of intramyocardial delivery of CSCs to infarcted porcine hearts. These findings provide a rationale for genetic modification of stem cells and consequent translation to clinical trials.

Original languageEnglish (US)
Pages (from-to)2454-2464
Number of pages11
JournalJournal of the American College of Cardiology
Volume68
Issue number22
DOIs
StatePublished - Dec 6 2016

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Phosphotransferases
Swine
Stem Cells
Myocardial Infarction
Placebos
Injections
Cell Division
Cicatrix
Cell Survival
Magnetic Resonance Spectroscopy
Animal Models
Clinical Trials
Pressure

Keywords

  • heart failure
  • human cardiac progenitor cells
  • injection
  • pressure volume

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Pim1 Kinase Overexpression Enhances ckit+ Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine. / Kulandavelu, Shathiyah; Karantalis, Vasileios; Fritsch, Julia; Hatzistergos, Konstantinos E.; Loescher, Viky Y.; McCall, Frederic; Wang, Bo; Bagno, Luiza; Golpanian, Samuel; Wolf, Ariel; Grenet, Justin; Williams, Adam; Kupin, Aaron; Rosenfeld, Aaron; Mohsin, Sadia; Sussman, Mark A.; Morales, Azorides R; Balkan, Wayne E; Hare, Joshua.

In: Journal of the American College of Cardiology, Vol. 68, No. 22, 06.12.2016, p. 2454-2464.

Research output: Contribution to journalArticle

Kulandavelu, S, Karantalis, V, Fritsch, J, Hatzistergos, KE, Loescher, VY, McCall, F, Wang, B, Bagno, L, Golpanian, S, Wolf, A, Grenet, J, Williams, A, Kupin, A, Rosenfeld, A, Mohsin, S, Sussman, MA, Morales, AR, Balkan, WE & Hare, J 2016, 'Pim1 Kinase Overexpression Enhances ckit+ Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine', Journal of the American College of Cardiology, vol. 68, no. 22, pp. 2454-2464. https://doi.org/10.1016/j.jacc.2016.09.925
Kulandavelu, Shathiyah ; Karantalis, Vasileios ; Fritsch, Julia ; Hatzistergos, Konstantinos E. ; Loescher, Viky Y. ; McCall, Frederic ; Wang, Bo ; Bagno, Luiza ; Golpanian, Samuel ; Wolf, Ariel ; Grenet, Justin ; Williams, Adam ; Kupin, Aaron ; Rosenfeld, Aaron ; Mohsin, Sadia ; Sussman, Mark A. ; Morales, Azorides R ; Balkan, Wayne E ; Hare, Joshua. / Pim1 Kinase Overexpression Enhances ckit+ Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine. In: Journal of the American College of Cardiology. 2016 ; Vol. 68, No. 22. pp. 2454-2464.
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abstract = "Background Pim1 kinase plays an important role in cell division, survival, and commitment of precursor cells towards a myocardial lineage, and overexpression of Pim1 in ckit+ cardiac stem cells (CSCs) enhances their cardioreparative properties. Objectives The authors sought to validate the effect of Pim1-modified CSCs in a translationally relevant large animal preclinical model of myocardial infarction (MI). Methods Human cardiac stem cells (hCSCs, n = 10), hckit+ CSCs overexpressing Pim1 (Pim1+; n = 9), or placebo (n = 10) were delivered by intramyocardial injection to immunosuppressed Yorkshire swine (n = 29) 2 weeks after MI. Cardiac magnetic resonance and pressure volume loops were obtained before and after cell administration. Results Whereas both hCSCs reduced MI size compared to placebo, Pim1+ cells produced a ∼3-fold greater decrease in scar mass at 8 weeks post-injection compared to hCSCs (−29.2 ± 2.7{\%} vs. −8.4 ± 0.7{\%}; p < 0.003). Pim1+ hCSCs also produced a 2-fold increase of viable mass compared to hCSCs at 8 weeks (113.7 ± 7.2{\%} vs. 65.6 ± 6.8{\%}; p <0.003), and a greater increase in regional contractility in both infarct and border zones (both p < 0.05). Both CSC types significantly increased ejection fraction at 4 weeks but this was only sustained in the Pim1+ group at 8 weeks compared to placebo. Both hCSC and Pim1+ hCSC treatment reduced afterload (p = 0.02 and p = 0.004, respectively). Mechanoenergetic recoupling was significantly greater in the Pim1+ hCSC group (p = 0.005). Conclusions Pim1 overexpression enhanced the effect of intramyocardial delivery of CSCs to infarcted porcine hearts. These findings provide a rationale for genetic modification of stem cells and consequent translation to clinical trials.",
keywords = "heart failure, human cardiac progenitor cells, injection, pressure volume",
author = "Shathiyah Kulandavelu and Vasileios Karantalis and Julia Fritsch and Hatzistergos, {Konstantinos E.} and Loescher, {Viky Y.} and Frederic McCall and Bo Wang and Luiza Bagno and Samuel Golpanian and Ariel Wolf and Justin Grenet and Adam Williams and Aaron Kupin and Aaron Rosenfeld and Sadia Mohsin and Sussman, {Mark A.} and Morales, {Azorides R} and Balkan, {Wayne E} and Joshua Hare",
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T1 - Pim1 Kinase Overexpression Enhances ckit+ Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine

AU - Kulandavelu, Shathiyah

AU - Karantalis, Vasileios

AU - Fritsch, Julia

AU - Hatzistergos, Konstantinos E.

AU - Loescher, Viky Y.

AU - McCall, Frederic

AU - Wang, Bo

AU - Bagno, Luiza

AU - Golpanian, Samuel

AU - Wolf, Ariel

AU - Grenet, Justin

AU - Williams, Adam

AU - Kupin, Aaron

AU - Rosenfeld, Aaron

AU - Mohsin, Sadia

AU - Sussman, Mark A.

AU - Morales, Azorides R

AU - Balkan, Wayne E

AU - Hare, Joshua

PY - 2016/12/6

Y1 - 2016/12/6

N2 - Background Pim1 kinase plays an important role in cell division, survival, and commitment of precursor cells towards a myocardial lineage, and overexpression of Pim1 in ckit+ cardiac stem cells (CSCs) enhances their cardioreparative properties. Objectives The authors sought to validate the effect of Pim1-modified CSCs in a translationally relevant large animal preclinical model of myocardial infarction (MI). Methods Human cardiac stem cells (hCSCs, n = 10), hckit+ CSCs overexpressing Pim1 (Pim1+; n = 9), or placebo (n = 10) were delivered by intramyocardial injection to immunosuppressed Yorkshire swine (n = 29) 2 weeks after MI. Cardiac magnetic resonance and pressure volume loops were obtained before and after cell administration. Results Whereas both hCSCs reduced MI size compared to placebo, Pim1+ cells produced a ∼3-fold greater decrease in scar mass at 8 weeks post-injection compared to hCSCs (−29.2 ± 2.7% vs. −8.4 ± 0.7%; p < 0.003). Pim1+ hCSCs also produced a 2-fold increase of viable mass compared to hCSCs at 8 weeks (113.7 ± 7.2% vs. 65.6 ± 6.8%; p <0.003), and a greater increase in regional contractility in both infarct and border zones (both p < 0.05). Both CSC types significantly increased ejection fraction at 4 weeks but this was only sustained in the Pim1+ group at 8 weeks compared to placebo. Both hCSC and Pim1+ hCSC treatment reduced afterload (p = 0.02 and p = 0.004, respectively). Mechanoenergetic recoupling was significantly greater in the Pim1+ hCSC group (p = 0.005). Conclusions Pim1 overexpression enhanced the effect of intramyocardial delivery of CSCs to infarcted porcine hearts. These findings provide a rationale for genetic modification of stem cells and consequent translation to clinical trials.

AB - Background Pim1 kinase plays an important role in cell division, survival, and commitment of precursor cells towards a myocardial lineage, and overexpression of Pim1 in ckit+ cardiac stem cells (CSCs) enhances their cardioreparative properties. Objectives The authors sought to validate the effect of Pim1-modified CSCs in a translationally relevant large animal preclinical model of myocardial infarction (MI). Methods Human cardiac stem cells (hCSCs, n = 10), hckit+ CSCs overexpressing Pim1 (Pim1+; n = 9), or placebo (n = 10) were delivered by intramyocardial injection to immunosuppressed Yorkshire swine (n = 29) 2 weeks after MI. Cardiac magnetic resonance and pressure volume loops were obtained before and after cell administration. Results Whereas both hCSCs reduced MI size compared to placebo, Pim1+ cells produced a ∼3-fold greater decrease in scar mass at 8 weeks post-injection compared to hCSCs (−29.2 ± 2.7% vs. −8.4 ± 0.7%; p < 0.003). Pim1+ hCSCs also produced a 2-fold increase of viable mass compared to hCSCs at 8 weeks (113.7 ± 7.2% vs. 65.6 ± 6.8%; p <0.003), and a greater increase in regional contractility in both infarct and border zones (both p < 0.05). Both CSC types significantly increased ejection fraction at 4 weeks but this was only sustained in the Pim1+ group at 8 weeks compared to placebo. Both hCSC and Pim1+ hCSC treatment reduced afterload (p = 0.02 and p = 0.004, respectively). Mechanoenergetic recoupling was significantly greater in the Pim1+ hCSC group (p = 0.005). Conclusions Pim1 overexpression enhanced the effect of intramyocardial delivery of CSCs to infarcted porcine hearts. These findings provide a rationale for genetic modification of stem cells and consequent translation to clinical trials.

KW - heart failure

KW - human cardiac progenitor cells

KW - injection

KW - pressure volume

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