doi: 10.1161/CIRCULATIONAHA.104.531137
(Circulation. 2005;111:e307-e308.)
© 2005 American Heart Association, Inc.
Correspondence |
Laboratory of Angiogenesis and Tumor Biology, Department of Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria, eberhard.gunsilius{at}uibk.ac.at
Wojakowski et al1 reported the mobilization of "tissue-committed stem cells" into peripheral blood (PB) in patients with acute myocardial infarction (AMI). We have serious concerns about the reliability of their findings. They found up to 1018 CD34+ cells/µL of PB in patients with AMI, as compared with 380 CD34+ cells in healthy controls. This would imply that in healthy individuals up to 10% of white blood cells express the hematopoietic progenitor cell–associated CD34 antigen. In fact, CD34+ cell counts in healthy individuals are at least a hundred times lower, and, even if donors of hematopoietic stem cell transplants are stimulated with recombinant granulocyte colony–stimulating factor for the mobilization of hematopoietic progenitor cells, the amount of CD34+ cells in PB is 
130 cells/µL.2 In addition, the plasma levels of vascular endothelial growth factor in their control patients are 6-fold higher than reported previously.3 Performing quantitative reverse transcriptase–polymerase chain reaction for cardiac-, muscle-, and endothelial cell–associated genes with mRNA isolated from crude PB mononuclear cells is not a sufficient characterization of "tissue-committed stem cells." This should be done after fluorescence-activated cell sorting and in vitro characterization with well-chosen antigens, thus possibly supporting the disputed hypothesis that myocardial damage mobilizes progenitor cells into the circulation, perhaps from the bone marrow.
 |
References |
|---|
 Top References References |
|---|
1. Wojakowski W, Tendera M, Micha
owska A, Majka M, Kucia M, Ma
lankiewicz K, Wyderka R, Ochaa 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: 3213–3220.2. Carlo-Stella C, Cesana C, Regazzi E, Falzetti F, Aversa F, Rizzoli V, Martelli M, Tabilio A. Peripheral blood progenitor cell mobilization in healthy donors receiving recombinant human granulocyte colony–stimulating factor. Exp Hematol. 2000; 28: 216–224.[CrossRef][Medline] [Order article via Infotrieve]
3. Lee KW, Lip GY, Blann AD. Plasma angiopoietin-1, angiopoietin-2, angiopoietin receptor tie-2, and vascular endothelial growth factor levels in acute coronary syndromes. Circulation. 2004; 110: 2355–2360.
Response
Tendera, MD, FESClankiewicz, MD Wyderka, MDa, MDThird Division of Cardiology, Silesian School of Medicine, Katowice, Poland
owska, MD
Department of Transplantology, Polish-American Children’s Hospital, Medical College, Jagiellonian University, Kraków, Poland
Stem Cell Biology Program, James Graham Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, Ky
Dr Muller-Ehmsen and colleagues express concerns as to the validity of real-time reverse transcriptase–polymerase chain reaction results.1 The mRNA increase was shown in the whole population of peripheral blood mononuclear cells (PBMNCs), not in the cardiomyogenic subpopulation; therefore, the 2-fold increase in GATA-4 expression corresponds to a 2-fold increase in mRNA copies detected in cell lysates from acute myocardial infarction (AMI) subjects. Dr Gunsilius and associates correctly suggest that the expression of tissue-specific markers in PBMNCs does not prove that these cells will actually transform into the cardiac lineage and that mRNA expression for these markers should be assayed in a subpopulation of flow cytometer–sorted cells in patients with AMI. This concern, however, was addressed in our article.1 Moreover, in another study, we observed a 20-fold increase in the expression of mRNA for Nkx2.5/Csx and GATA-4 in CXCR4+ stem cells isolated from the bone marrow–derived MNCs by a chemotactic isolation to stromal cell–derived factor-1 gradient, which coexisted with the immunocytochemically detectable presence of Nkx2.5/Csx and GATA-4 proteins in these cells.2
We also demonstrated that a mobile pool of CXCR4+ nonhematopoietic cells is found in both mouse and human bone marrow, which show expression of markers specific for different tissues and may be mobilized into PB in AMI.2,3 We believe that it is the same population of cells that is subsequently found in PB in patients with AMI. Again, we acknowledge that our findings were somewhat hypothetical when the manuscript was submitted, but they are consistent with our recent observations in murine models of AMI,2 and with regard to the number of mobilized cells, similar to those recently published by Massa et al4 (absolute CD34+ counts range up to 700/µL, CD34+CD33+ up to 1000/µL). We agree, however, that if we had used immunomagnetic purification and International Society of Hematotherapy and Graft Engineering guidelines, the number of CD34+ cells would have been lower in both control and AMI patient groups and that it should become a "gold standard" that potential discrepancies in total cell numbers between the studies be avoided.4
|
References |
|---|
|
TopReferencesReferences |
|---|
1. Wojakowski W, Tendera M, Micha
owska A, Majka M, Kucia M, Malankiewicz K, Wyderka R, Ochaa 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.
2. Kucia M, Dawn B, Hunt G, Guo Y, Wysoczynski M, Majka M, Ratajczak J, Rezzoug F, Ildstad ST, Bolli R, Ratajczak MZ. Cells expressing early cardiac markers reside in the bone marrow and are mobilized into the peripheral blood after myocardial infarction. Circ Res. 2004; 95: 1191–1199.
3. Ratajczak MZ, Kucia M, Reca R, Majka M, Janowska-Wieczorek A, Ratajczak J. Stem cell plasticity revisited: CXCR4-positive cells expressing mRNA for early muscle, liver and neural cells "hide out" in the bone marrow. Leukemia. 2004; 18: 29–40.[CrossRef][Medline] [Order article via Infotrieve]
4. Massa M, Rosti V, Ferrario M, Campanelli R, Ramajoli I, Rosso R, De Ferrari GM, Ferlini M, Goffredo L, Bertoletti A, Klersy C, Pecci A, Moratti R, Tavazzi L. Increased circulating hematopoietic and endothelial progenitor cells in the early phase of acute myocardial infarction. Blood. 2005; 105: 199–206.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||