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 language | English (US) |
|---|---|
| Pages (from-to) | 2397-2406 |
| Number of pages | 10 |
| Journal | Stem Cells |
| Volume | 32 |
| Issue number | 9 |
| DOIs | |
| State | Published - 2014 |
| Externally published | Yes |
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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
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 journal › Article
}
TY - JOUR
T1 - Importance of cell-cell contact in the therapeutic benefits of cardiosphere-derived cells
AU - Xie, Yucai
AU - Ibrahim, Ahmed
AU - Cheng, Ke
AU - Wu, Zhijun
AU - Liang, Wenbin
AU - Malliaras, Konstantinos
AU - Sun, Baiming
AU - Liu, Weixin
AU - Shen, Deliang
AU - Cheol Cho, Hee
AU - Li, Taosheng
AU - Lu, Lin
AU - Lu, Guoping
AU - Marbán, E.
PY - 2014
Y1 - 2014
N2 - 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
AB - 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
KW - Cardiomyocyte
KW - Cardiosphere-derived cells
KW - Cell-cell communication
KW - Paracrine factors
KW - Proliferation
KW - β1 integrin
UR - http://www.scopus.com/inward/record.url?scp=84906278987&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84906278987&partnerID=8YFLogxK
U2 - 10.1002/stem.1736
DO - 10.1002/stem.1736
M3 - Article
VL - 32
SP - 2397
EP - 2406
JO - Stem Cells
JF - Stem Cells
SN - 1066-5099
IS - 9
ER -