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Guided cardiogenesis for safe stem cell‐based therapy
Author(s) -
Behfar A.,
PerezTerzic C.,
Hodgson D. M.,
Alekseev A. E.,
Kane G. C.,
Puceat M.,
Terzic A.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.11.015
Subject(s) - mef2c , embryonic stem cell , stem cell , induced pluripotent stem cell , microbiology and biotechnology , cancer research , biology , medicine , transplantation , cell therapy , tumor necrosis factor alpha , immunology , transcription factor , biochemistry , gene
Background/Aims Pluripotent embryonic stem cells are an emerging source for cardiotherapy, but harbor a risk for uncontrolled growth on transplantation to host tissue. This creates a need to identify a stem cell phenotype committed to the cardiac fate to achieve guided cardiogenesis for safe cell‐based cardiac repair. Methods/Results Bolus delivery of uncommitted embryonic stem cells (>1000 cells/mg myocardium) into naïve hearts resulted into a teratogenic side effect. A tumor‐free outcome was achieved with overexpression of the cytokine Tumor Necrosis Factor α (TNFα) which secured guided cardiogenesis of injected stem cells. Protein‐based scans following TNFα stimulation demonstrated an increase in the secreted proteome, which included upregulation of downstream cardiogenic factors, such as Transforming Growth Factor β (TGFβ). With TNFα stimulation, the yield of stem cell‐derived cardiomyocytes doubled, while the TGFβ antagonist, latency associated peptide, abolished the TNFα effect. The TNFα/TGFβ signaling recruited a proliferative cardiac precursor cell phenotype expressing master cardiac transcription factors, Csx/Nkx2.5 and MEF2C. Conclusions This study identifies a novel cell phenotype devoted to the cardiac fate that is recruited and amplified by TNFα initiated TGFβ signaling. With differentiation limited to cardiopotency, such cardiopoetic stem cells loose the teratenogenic capacity thereby enhancing the therapeutic index for cell‐based cardiac repair. Clinical Pharmacology & Therapeutics (2005) 77 , P3–P3; doi: 10.1016/j.clpt.2004.11.015