Importance of cell-cell contact in the therapeutic benefits of cardiosphere-derived cells

Yucai Xie, Ahmed Ibrahim, Ke Cheng, Zhijun Wu, Wenbin Liang, Konstantinos Malliaras, Baiming Sun, Weixin Liu, Deliang Shen, Hee Cheol Cho, Taosheng Li, Lin Lu, Guoping Lu, E. Marbán

Research output: Contribution to journalArticle

Abstract

Cardiosphere-derived cells (CDCs) effect therapeutic regeneration after myocardial infarction (MI) both in animal models and in humans. Here, we test the hypothesis that cell-cell contact plays a role in mediating the observed therapeutic benefits of CDCs, above and beyond conventional paracrine effects. Human CDCs or vehicle were injected into immunodeficient (SCID) mouse hearts during acute MI. CDC transplantation augmented the proportion of cycling (Ki67+) cardiomyocytes and improved ventricular function. CDC-conditioned media only modestly augmented the percentage of Ki67+ cardiomyocytes (>control but + or BrdU+ nuclei) increased relative to solitary NRVM culture. To further dissect the relative contributions of soluble factors versus contact-dependent mechanisms, we compared CDCs grown with NRVMs in a transwell contact-free system versus admixed coculture. The percentage of cycling NRVMs was higher in admixed coculture than in the contact-free system. Pretreatment with inhibitors of MEK and PI3K, or with β1 integrin neutralizing antibody, blocked the ability of CDCs to promote myocyte cycling. While conditioned media are not inert, direct apposition of CDCs to cardiomyocytes produces greater enhancement of cardiomyocyte proliferation in vitro and in vivo, and improves function post-MI. Intact cardiomyocyte β1 integrin signaling is necessary for the contact-dependent cardioproliferative effects of CDCs. Stem Cells 2014;32:2397-2406

Original languageEnglish (US)
Pages (from-to)2397-2406
Number of pages10
JournalStem Cells
Volume32
Issue number9
DOIs
StatePublished - 2014
Externally publishedYes

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Cardiac Myocytes
Therapeutics
Myocardial Infarction
Conditioned Culture Medium
Coculture Techniques
Integrins
SCID Mice
Ventricular Function
Cell Transplantation
Mitogen-Activated Protein Kinase Kinases
Therapeutic Uses
Bromodeoxyuridine
Neutralizing Antibodies
Phosphatidylinositol 3-Kinases
Muscle Cells
Regeneration
Stem Cells
Animal Models

Keywords

  • Cardiomyocyte
  • Cardiosphere-derived cells
  • Cell-cell communication
  • Paracrine factors
  • Proliferation
  • β1 integrin

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

Cite this

Xie, Y., Ibrahim, A., Cheng, K., Wu, Z., Liang, W., Malliaras, K., ... Marbán, E. (2014). Importance of cell-cell contact in the therapeutic benefits of cardiosphere-derived cells. Stem Cells, 32(9), 2397-2406. https://doi.org/10.1002/stem.1736

Importance of cell-cell contact in the therapeutic benefits of cardiosphere-derived cells. / Xie, Yucai; Ibrahim, Ahmed; Cheng, Ke; Wu, Zhijun; Liang, Wenbin; Malliaras, Konstantinos; Sun, Baiming; Liu, Weixin; Shen, Deliang; Cheol Cho, Hee; Li, Taosheng; Lu, Lin; Lu, Guoping; Marbán, E.

In: Stem Cells, Vol. 32, No. 9, 2014, p. 2397-2406.

Research output: Contribution to journalArticle

Xie, Y, Ibrahim, A, Cheng, K, Wu, Z, Liang, W, Malliaras, K, Sun, B, Liu, W, Shen, D, Cheol Cho, H, Li, T, Lu, L, Lu, G & Marbán, E 2014, 'Importance of cell-cell contact in the therapeutic benefits of cardiosphere-derived cells', Stem Cells, vol. 32, no. 9, pp. 2397-2406. https://doi.org/10.1002/stem.1736
Xie, Yucai ; Ibrahim, Ahmed ; Cheng, Ke ; Wu, Zhijun ; Liang, Wenbin ; Malliaras, Konstantinos ; Sun, Baiming ; Liu, Weixin ; Shen, Deliang ; Cheol Cho, Hee ; Li, Taosheng ; Lu, Lin ; Lu, Guoping ; Marbán, E. / Importance of cell-cell contact in the therapeutic benefits of cardiosphere-derived cells. In: Stem Cells. 2014 ; Vol. 32, No. 9. pp. 2397-2406.
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