c-kitpos GATA-4 high rat cardiac stem cells foster adult cardiomyocyte survival through IGF-1 paracrine signalling

Nanako Kawaguchi, Andrew J Smith, Cheryl D Waring, Md Kamrul Hasan, Shinka Miyamoto, Rumiko Matsuoka, Georgina M Ellison

Research output: Contribution to journalArticlepeer-review

75 Citations (Scopus)

Abstract

Background

Resident c-kit positive (c-kitpos) cardiac stem cells (CSCs) could be considered the most appropriate cell type for myocardial regeneration therapies. However, much is still unknown regarding their biological properties and potential.

Methodology/Principal Findings

We produced clones of high and low expressing GATA-4 CSCs from long-term bulk-cultured c-kitpos CSCs isolated from adult rat hearts. When c-kitpos GATA-4 high expressing clonal CSCs (cCSCs) were co-cultured with adult rat ventricular cardiomyocytes, we observed increased survival and contractility of the cardiomyocytes, compared to cardiomyocytes cultured alone, co-cultured with fibroblasts or c-kitpos GATA-4 low expressing cCSCs. When analysed by ELISA, the concentration of IGF-1 was significantly increased in the c-kitpos GATA-4 high cCSC/cardiomyocyte co-cultures and there was a significant correlation between IGF-1 concentration and cardiomyocyte survival. We showed the activation of the IGF-1 receptor and its downstream molecular targets in cardiomyocytes co-cultured with c-kitpos GATA-4 high cCSCs but not in cardiomyocytes that were cultured alone, co-cultured with fibroblasts or c-kitpos GATA-4 low cCSCs. Addition of a blocking antibody specific to the IGF-1 receptor inhibited the survival of cardiomyocytes and prevented the activation of its signalling in cardiomyocytes in the c-kitpos GATA-4 high cCSC/cardiomyocyte co-culture system. IGF-1 supplementation or IGF-1 high conditioned medium taken from the co-culture of c-kitpos GATA-4 high cCSCs plus cardiomyocytes did extend the survival and contractility of cardiomyocytes cultured alone and cardiomyocytes co-cultured with c-kitpos GATA-4 low cCSCs.

Conclusion/Significance

c-kitpos GATA-4 high cCSCs exert a paracrine survival effect on cardiomyocytes through induction of the IGF-1R and signalling pathway.
Original languageEnglish
Article numbere14297
JournalPLoS ONE
Volume5
Issue number12
DOIs
Publication statusPublished - 2010

Keywords

  • Heart
  • Animals
  • GATA4 Transcription Factor
  • Proto-Oncogene Proteins c-kit
  • Cell Culture Techniques
  • Insulin-Like Growth Factor I
  • Cell Survival
  • Rats
  • Tissue Therapy
  • Paracrine Communication
  • Regeneration
  • Stem Cells
  • Myocytes, Cardiac
  • Signal Transduction
  • Myocardium

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