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Myocardial interstitial fluid inhibits proliferation and cardiomyocyte differentiation in pluripotent embryonic stem cells. Am J Physiol Heart Circ Physiol 2009 Oct;297(4):H1369-76



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Scopus ID

2-s2.0-70349610458   1 Citation


Several recent studies have demonstrated that the transplantation of pluripotent murine embryonic stem cells (mESCs) can improve or restore the function of infarcted myocardium. Although the extent of remuscularization and its contribution to the restoration of function are unclear, these outcomes are likely strongly influenced by factors in the infarcted and/or ischemic environment. As an initial step toward understanding how the ischemic environment of host myocardium affects transplanted pluripotent cells, we have taken a reductionist approach wherein mESCs are cultured in medium containing ischemic myocardial interstitial fluid (iMIF). iMIF is generated in canine myocardium during eight hourly episodes of transient ischemia and collected on a daily basis, over a 24-day collection period. iMIF strongly reduced the numbers of pluripotent mESCs after 11 days in culture. This inhibitory effect, which was most pronounced for iMIF pools from early time points of the 24-day collection period, resulted from an inhibition of cell proliferation. iMIF also inhibited the differentiation of pluripotent mESCs into cardiomyocytes. By contrast, the expression of vascular smooth muscle and endothelial cell markers was relatively unaffected, consistent with previous findings that iMIF promotes angiogenesis. Taken together, these results suggest that whereas the ischemic/infarcted environment is favorable to stem cell-mediated angiogenesis, it is hostile to cardiac myogenesis. These findings also imply that observations of mESC-mediated improvement of cardiac function after transplantation of pluripotent cells do not reflect remuscularization.

Author List

Van Orman JR, Weihrauch D, Warltier DC, Lough J


John W. Lough PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Dorothee Weihrauch DVM, PhD Professor in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cell Differentiation
Cell Line
Cell Proliferation
Disease Models, Animal
Embryonic Stem Cells
Endothelial Cells
Extracellular Fluid
Muscle, Smooth, Vascular
Myocardial Ischemia
Myocytes, Cardiac
Pluripotent Stem Cells
Time Factors
jenkins-FCD Prod-411 e00897e83867fcfa48419861683711f8d99adb75