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 language | English (US) |
|---|---|
| Pages (from-to) | 2454-2464 |
| Number of pages | 11 |
| Journal | Journal of the American College of Cardiology |
| Volume | 68 |
| Issue number | 22 |
| DOIs | |
| State | Published - Dec 6 2016 |
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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 journal › Article
}
TY - JOUR
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
UR - http://www.scopus.com/inward/record.url?scp=84999635843&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84999635843&partnerID=8YFLogxK
U2 - 10.1016/j.jacc.2016.09.925
DO - 10.1016/j.jacc.2016.09.925
M3 - Article
C2 - 27908351
AN - SCOPUS:84999635843
VL - 68
SP - 2454
EP - 2464
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
SN - 0735-1097
IS - 22
ER -