Secondary sphere formation enhances the functionality of cardiac progenitor cells

Hyun Jai Cho, Ho Jae Lee, Seock Won Youn, Seok Jin Koh, Joo Yun Won, Yeon Ju Chung, Hyun Ju Cho, Chang Hwan Yoon, Sae Won Lee, Eun Ju Lee, Yoo Wook Kwon, Hae Young Lee, Sang Hun Lee, Won Kyung Ho, Young Bae Park, Hyo Soo Kim

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Loss of cardiomyocytes impairs cardiac function after myocardial infarction (MI). Recent studies suggest that cardiac stem/progenitor cells could repair the damaged heart. However, cardiac progenitor cells are difficult to maintain in terms of purity and multipotency when propagated in two-dimensional culture systems. Here, we investigated a new strategy that enhances potency and enriches progenitor cells. We applied the repeated sphere formation strategy (cardiac explant → primary cardiosphere (CS) formation → sphere-derived cells (SDCs) in adherent culture condition → secondary CS formation by three-dimensional culture). Cells in secondary CS showed higher differentiation potentials than SDCs. When transplanted into the infarcted myocardium, secondary CSs engrafted robustly, improved left ventricular (LV) dysfunction, and reduced infarct sizes more than SDCs did. In addition to the cardiovascular differentiation of transplanted secondary CSs, robust vascular endothelial growth factor (VEGF) synthesis and secretion enhanced neovascularization in the infarcted myocardium. Microarray pathway analysis and blocking experiments using E-selectin knock-out hearts, specific chemicals, and small interfering RNAs (siRNAs) for each pathway revealed that E-selectin was indispensable to sphere initiation and ERK/Sp1/VEGF autoparacrine loop was responsible for sphere maturation. These results provide a simple strategy for enhancing cellular potency for cardiac repair. Furthermore, this strategy may be implemented to other types of stem/progenitor cell-based therapy.

Original languageEnglish (US)
Pages (from-to)1750-1766
Number of pages17
JournalMolecular Therapy
Volume20
Issue number9
DOIs
StatePublished - Sep 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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