Letters Regarding Article by Wojakowski et al, “Mobilization of CD34/CXCR4+, CD34/CD117+, c-met+ Stem Cells, and Mononuclear Cells Expressing Early Cardiac, Muscle, and Endothelial Markers Into Peripheral Blood in Patients With Acute Myocardial Infarction”
To the Editor:
We read with great interest the article by Wojakowski et al1 on cell mobilization after myocardial infarction (MI) published recently in Circulation. The authors found that immature cells identified by several different surface markers were increased in patients with MI. In parallel, a higher amount of cytokines (such as granulocyte colony–stimulating factor, vascular endothelial growth factor, and others) was found, whereas stromal cell–derived factor-1 was decreased. The mRNA levels of cardiac-specific transcription factors GATA-4, MEF2C, and Nkx2.5/Csx were elevated in mononuclear cells in these patients.
Although we believe that this study adds important information to our knowledge of myocardial regeneration and stem cell mobilization, we would like to discuss a few aspects of it. With regard to the total cell number, which was given in absolute cells per microliter, the authors have found a surprisingly high number of CD34+ cells in peripheral blood (7 days after MI: 882 cells/μL). For example, Shintani et al2 counted ≈250 cells per million white blood cells, equaling 2.5 CD34+ cells/μL, with a white blood cell count of 10 000 cells/μL. In a previous study from our laboratory, we detected similar numbers.3 The usual estimates of cells in peripheral blood assume that ≈0.01% to 0.1% of the cells in peripheral blood are CD34+, and on stimulation with granulocyte colony–stimulating factor, this number can be increased to ≈1% (a similar fraction usually is found in bone marrow). Assuming a white blood cell count of 10 000/μL, the number given by Wojakowski et al equals a CD34+ cell fraction of ≈8.8% at day 7 after MI.
In addition, we would like to discuss the mRNA measurements that were presented. Even in optimistic calculations, it is assumed that at most 0.1% of circulating cells represent a stem cell–like population. Thus, if the increase in GATA-4 expression, which is reported to be ≈2-fold after MI, reflects cardiomyogenic differentiation of circulating stem cells, this increase would be accomplished by only 0.1% of the total cell population. For the total mRNA to increase by 2-fold, the mRNA of the stem cell population therefore must have been increased by 2000-fold. At the very least, this reflects a high induction of gene expression, which deserves a more detailed discussion than that provided by Wojakowski and colleagues.
Wojakowski W, Tendera M, Michałowska A, Majka M, Kucia M, Maślankiewicz K, Wyderka R, Ochała A, Ratajczak MZ. Mobilization of CD34/CXCR4+, CD34/CD117+, c-met+ stem cells, and mononuclear cells expressing early cardiac, muscle, and endothelial markers into peripheral blood in patients with acute myocardial infarction. Circulation. 2004; 110: 3213–3220.
Shintani S, Murohara T, Ikeda H, Ueno T, Honma T, Katoh A, Sasaki K, Shimada T, Oike Y, Imaizumi T. Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation. 2001; 103: 2776–2779.
Müller-Ehmsen J, Scheid C, Grundmann F, Hirsch I, Turan G, Tossios P. Mehlhorn U, Schwinger RHG. The mobilization of CD34 positive mononuclear cells after myocardial infarction is abolished by revascularization of the culprit vessel. Int J Cardiol. In press.