Modulation of Human Cardiac Progenitors via Hypoxia-ERK Circuit Improves their Functional Bioactivities.
- Author:
Seok Yun JUNG
1
;
Sung Hyun CHOI
;
So Young YOO
;
Sang Hong BAEK
;
Sang Mo KWON
Author Information
1. Laboratory of Vascular Medicine and Stem Cell Biology, Department of Physiology, School of Medicine, Pusan National University, Yangsan 626-870, Republic of Korea. smkwon323@hotmail.com
- Publication Type:Original Article
- Keywords:
Human cardiac progenitor;
Hypoxia preconditioning;
U0126
- MeSH:
Anoxia;
Cell Lineage;
Cell Proliferation;
Digestion;
Endothelial Cells;
Healthcare Common Procedure Coding System;
Heart;
Humans*;
Myocytes, Cardiac;
Myocytes, Smooth Muscle;
Oxygen;
Phosphorylation;
Regeneration;
Stem Cells
- From:Biomolecules & Therapeutics
2013;21(3):196-203
- CountryRepublic of Korea
- Language:English
-
Abstract:
Recent accumulating studies have reported that hypoxic preconditioning during ex vivo expansion enhanced the self-renewal or differentiation of various stem cells and provide an important strategy for the adequate modulation of oxygen in culture conditions, which might increase the functional bioactivity of these cells for cardiac regeneration. In this study, we proposed a novel priming protocol to increase the functional bioactivity of cardiac progenitor cells (CPCs) for the treatment of cardiac regeneration. Firstly, patient-derived c-kit+ CPCs isolated from the atrium of human hearts by enzymatic digestion and secondly, pivotal target molecules identified their differentiation into specific cell lineages. We observed that hCPCs, in response to hypoxia, strongly activated ERK phosphorylation in ex vivo culture conditioning. Interestingly, pre-treatment with an ERK inhibitor, U0126, significantly enhanced cellular proliferation and tubular formation capacities of CPCs. Furthermore, we observed that hCPCs efficiently maintained the expression of the c-kit, a typical stem cell marker of CPCs, under both hypoxic conditioning and ERK inhibition. We also show that hCPCs, after preconditioning of both hypoxic and ERK inhibition, are capable of differentiating into smooth muscle cells (SMCs) and cardiomyocytes (CMs), but not endothelial cells (ECs), as demonstrated by the strong expression of alpha-SMA, Nkx2.5, and cTnT, respectively. From our results, we conclude that the functional bioactivity of patient-derived hCPCs and their ability to differentiate into SMCs and CMs can be efficiently increased under specifically defined culture conditions such as short-term hypoxic preconditioning and ERK inhibition.
