BMP-2 and FGF-2 Synergistically Facilitate Adoption of a Cardiac Phenotype in Somatic Bone Marrow c-kit+/Sca-1+Stem Cells

被引：15

作者：

DeGeorge, Brent R., Jr. ^{[2
]}

Rosenberg, Marc ^{[3
]}

Eckstein, Volker ^{[4
]}

Gao, Erhe ^{[1
]}

Herzog, Nicole ^{[3
]}

Katus, Hugo A. ^{[3
]}

Koch, Walter J. ^{[2
]}

Frey, Norbert ^{[3
]}

Most, Patrick ^{[1
]}

机构：

[1] Thomas Jefferson Univ, Dept Med, Lab Cardiac Stem Cell & Gene Therapy, Ctr Translat Med, Philadelphia, PA 19107 USA

[2] Thomas Jefferson Univ, Dept Med, George Zallie & Family Lab Cardiovasc Gene Therap, Ctr Translat Med, Philadelphia, PA 19107 USA

[3] Heidelberg Univ, Dept Internal Med 3, Otto Meyerhof Zentrum, Heidelberg, Germany

[4] Heidelberg Univ, Dept Internal Med 5, Otto Meyerhof Zentrum, Heidelberg, Germany

来源：

CTS-CLINICAL AND TRANSLATIONAL SCIENCE | 2008年 / 1卷 / 02期

关键词：

mBMSCs; BMP-2; FGF-2; paracrine signaling;

D O I：

10.1111/j.1752-8062.2008.00034.x

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

The aim of this study was to explore the effect of bone morphogenetic protein-2 (BMP-2) and fibroblast growth factor-2 (FGF-2)-paracrine factors implicated in both cardiac embryogenesis and cardiac repair following myocardial infarction (MI)-on murine bone marrow stem cell (mBMSC) differentiation in an ex vivo cardiac microenvironment. For this purpose, green fluorescent protein (GFP) expressing hematopoietic lineage negative (lin-) c-kit ligand (c-kit) and stem cell antigen-1 (Sca-1) positive (GFP-lin-/c-kit+/sca+) mBMSC were co-cultured with neonatal rat ventricular cardiomyocytes (NVCMs). GFP+ mBMSC significantly induced the expression of BMP-2 and FGF-2 in NVCMs, and approximately 4% GFP+ mBMSCs could be recovered from the co-culture at day 10. The addition of BMP-2 in concert with FGF-2 significantly enhanced the amount of integrated GFP+ mBMSCs by 5-fold (similar to 20%), whereas the addition of anti-BMP-2 and/or anti-FGF-2 antibodies completely abolished this effect. An analysis of calcium cycling revealed robust calcium transients in GFP+ mBMSCs treated with BMP-2/FGF-2 compared to untreated co-cultures. BMP-2 and FGF-2 addition led to a significant induction of early (NK2 transcription factor related, locus 5; Nkx2.5, GATA binding protein 4; GATA-4) and late (myosin light chain kinase [MLC-2v], connexin 43 [Cx43]) cardiac marker mRNA expression in mBMSCs following co-culture. In addition, re-cultured fluorescence-activated cell sorting (FACS)-purified BMP-2/FGF-2-treated mBMSCs revealed robust calcium transients in response to electrical field stimulation which were inhibited by the L-type calcium channel (LTCC) inhibitor, nifedipine, and displayed caffeine-sensitive intracellular calcium stores. In summary, our results show that mBMSCs can adopt a functional cardiac phenotype through treatment with factors essential to embryonic cardiogenesis that are induced after cardiac ischemia. This study provides the first evidence that mBMSCs with long-term self-renewal potential possess the capability to serve as a functional cardiomyocyte precursor through the appropriate paracrine input and cross-talk within an appropriate cardiac microenvironment.

引用

页码：116 / 125

页数：10

共 44 条

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