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

Publication ,  Journal Article
Kulandavelu, S; Karantalis, V; Fritsch, J; Hatzistergos, KE; Loescher, VY; McCall, F; Wang, B; Bagno, L; Golpanian, S; Wolf, A; Grenet, J ...
Published in: J Am Coll Cardiol
December 6, 2016

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.

Duke Scholars

Published In

J Am Coll Cardiol

DOI

EISSN

1558-3597

Publication Date

December 6, 2016

Volume

68

Issue

22

Start / End Page

2454 / 2464

Location

United States

Related Subject Headings

  • Swine
  • Stem Cell Transplantation
  • Myocytes, Cardiac
  • Myocardial Infarction
  • Mitogen-Activated Protein Kinases
  • Humans
  • Gene Expression Regulation
  • Fungal Proteins
  • Female
  • Disease Models, Animal
 

Citation

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Kulandavelu, S., Karantalis, V., Fritsch, J., Hatzistergos, K. E., Loescher, V. Y., McCall, F., … Hare, J. M. (2016). Pim1 Kinase Overexpression Enhances ckit+ Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine. J Am Coll Cardiol, 68(22), 2454–2464. https://doi.org/10.1016/j.jacc.2016.09.925
Kulandavelu, Shathiyah, Vasileios Karantalis, Julia Fritsch, Konstantinos E. Hatzistergos, Viky Y. Loescher, Frederic McCall, Bo Wang, et al. “Pim1 Kinase Overexpression Enhances ckit+ Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine.J Am Coll Cardiol 68, no. 22 (December 6, 2016): 2454–64. https://doi.org/10.1016/j.jacc.2016.09.925.
Kulandavelu S, Karantalis V, Fritsch J, Hatzistergos KE, Loescher VY, McCall F, et al. Pim1 Kinase Overexpression Enhances ckit+ Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine. J Am Coll Cardiol. 2016 Dec 6;68(22):2454–64.
Kulandavelu, Shathiyah, et al. “Pim1 Kinase Overexpression Enhances ckit+ Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine.J Am Coll Cardiol, vol. 68, no. 22, Dec. 2016, pp. 2454–64. Pubmed, doi:10.1016/j.jacc.2016.09.925.
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 A, Balkan W, Hare JM. Pim1 Kinase Overexpression Enhances ckit+ Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine. J Am Coll Cardiol. 2016 Dec 6;68(22):2454–2464.
Journal cover image

Published In

J Am Coll Cardiol

DOI

EISSN

1558-3597

Publication Date

December 6, 2016

Volume

68

Issue

22

Start / End Page

2454 / 2464

Location

United States

Related Subject Headings

  • Swine
  • Stem Cell Transplantation
  • Myocytes, Cardiac
  • Myocardial Infarction
  • Mitogen-Activated Protein Kinases
  • Humans
  • Gene Expression Regulation
  • Fungal Proteins
  • Female
  • Disease Models, Animal