Mechanism of improved cardiac function after bone marrow mononuclear cell therapy: Role of cardiovascular lineage commitment

Chang Hwan Yoon, Masamichi Koyanagi, Kazuma Iekushi, Florian Seeger, Carmen Urbich, Andreas M. Zeiher, Stefanie Dimmeler

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Abstract

Background: Cell therapy is a promising option to improve functional recovery after ischemia. Several subsets of bone marrow-derived cells were shown to reduce infarct size and increase ejection fraction in experimental models of ischemia. The mechanisms underlying the functional improvement are diverse and have been shown to include paracrine effects of the injected cells, as well as a variable degree of differentiation to endothelial cells, pericytes, smooth muscle, and cardiac muscle. Methods and Results: To elucidate the true nature of such plasticity and contribution to recovery, we engineered vectors that encoded inducible suicide genes under the control of endothelium (endothelial nitric oxide synthase)-, smooth muscle (SM22α)-, and cardiomyocyte (α-MHC)-specific promoters, thereby allowing selective depletion of the individual cell lineage acquired by the transplanted undifferentiated bone marrow-derived cells. Lentivirally delivered thymidine kinase, which converts the prodrug ganciclovir into a cytotoxic agent, was used to selectively eliminate cells 2 weeks after transplantation of bone marrow mononuclear cells in an acute myocardial infarction model. We demonstrate that elimination of transplanted endothelium-committed or SM22α-expressing cells, but not cardiac-committed cells, induced a significant deterioration of ejection fraction. Moreover, elimination of endothelial nitric oxide synthase-expressing cells 2 weeks after injection reduced capillary and arteriole density. Conclusions: This study demonstrates that elimination of bone marrow mononuclear cells reexpressing endothelial nitric oxide synthase particularly induced a deterioration of cardiac function, which indicates a functional contribution of the vascular cell fate decision of human bone marrow-derived mononuclear cells in vivo.

Original languageEnglish
Pages (from-to)2001-2011
Number of pages11
JournalCirculation
Volume121
Issue number18
DOIs
Publication statusPublished - May 11 2010

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Yoon, C. H., Koyanagi, M., Iekushi, K., Seeger, F., Urbich, C., Zeiher, A. M., & Dimmeler, S. (2010). Mechanism of improved cardiac function after bone marrow mononuclear cell therapy: Role of cardiovascular lineage commitment. Circulation, 121(18), 2001-2011. https://doi.org/10.1161/CIRCULATIONAHA.109.909291