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. 2011 Aug;15(8):1726-36.
doi: 10.1111/j.1582-4934.2010.01195.x.

Circulating stem cell vary with NYHA stage in heart failure patients

Cinzia Fortini  1 , Barbara Toffoletto, Alessandro Fucili, Elisa Puppato, Adriana Olivares, Antonio Paolo Beltrami, Valeria Fiorelli, Natascha Bergamin, Daniela Cesselli, Cristina Morelli, Gloria Francolini, Roberto Ferrari, Carlo Alberto Beltrami
Affiliations

Circulating stem cell vary with NYHA stage in heart failure patients

Cinzia Fortini et al. J Cell Mol Med. 2011 Aug.

Abstract

We have investigated the blood levels of sub-classes of stem cells (SCs) [mesenchymal stem cells (MSCs), haematopoietic stem cells (HSCs), endothelial progenitor cells/circulating endothelial cells (EPCs/CECs) and tissue-committed stem cells (TCSCs)] in heart failure (HF) patients at different stage of pathology and correlated it with plasmatic levels of proangiogenic cytokines. Peripheral blood level of SCs were analysed in 97 HF patients (24 in NYHA class I, 41 in class II, 17 in class III and 15 in class IV) and in 23 healthy controls. Plasmatic levels of PDGF-BB, bFGF, HGF, vascular endothelial growth factor (VEGF), SDF-1α, TNF-α and NTproBNP were also measured. Compared with healthy individuals, MSC, and in particular the sub-classes CD45(-) CD34(-) CD90(+) , CD45(-) CD34(-) CD105(+) and CD45(-) CD34(-) CXCR4(+) were significantly enhanced in NYHA class IV patients (16.8-, 6.4- and 2.7-fold, respectively). Level of CD45(-) CD34(-) CD90(+) CXCR4(+) cells progressively increased from class II to class IV (fold increases compared with controls: 8.5, 12 and 21.5, respectively). A significant involvement of CXCR4(+) subpopulation of HSC (CD45(+) CD34(+) CD90(+) CXCR4(+) , 1.4 versus 13.3 cells/μl in controls and NYHA class III patients, respectively) and TCSC (CD45(-) CD34(+) CXCR4(+) , 1.5 cells/ μl in controls versus 12.4 and 28.6 cells/μl in NYHA classes II and IV, respectively) were also observed. All tested cytokines were enhanced in HF patients. In particular, for PDGF-BB and SDF-1α we studied specific ligand/receptors pairs. Interestingly, the first one positively correlated with TCSCs expressing PDGFR (r = 0.52, P = 0.001), whereas the second one correlated with TCSCs (r = 0.34, P = 0.005) and with MSCs CD90(+) expressing CXCR4 (r = 0.39, P = 0.001). HF is characterized by the increase in the circulating levels of different MSC, HSC, EPC and TCSC subsets. Both the entity and kinetic of this process varied in distinct cell subsets. Specifically, differently from HSCs and EPCs/CECs, MSCs and TCSCs significantly increased with the progression of the disease, suggesting a possible distinct role of these cells in the pathophysiology of HF.

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Figures

Fig 1
Fig 1
Gating strategy. Orange box: MSC and HSPC enumeration. Pulse width versus FSC (A), FSC versus SSC (B), and CD45/CD34 (C) dot plots were utilized to exclude cell doublets, platelets, erythrocytes, dead cells, debris and neutrophilis, restricting the analysis to the lympho-monocyte fraction. On the basis of the level of expression of CD45 and CD34, we recognized, within the gated blood cells, a CD45+CD34+ population and a CD45−CD34− population (D). HSC were recognized within the CD45+CD34+ fraction, FL2-CD133+, FL2-CD90+ or FL2-CD105+ cells (HSC gate, D). MSC were studied within the CD45/CD34low/neg cells, as either FL2-CD90+ or FL2-CD105+ (MSC gate, D). Blue box: CD34lowSSC and EPC/EC enumeration. To count CD34+SSClow cells and EPC/EC, cells were first gated on pulse width versus FSC (E) and FSC versus SSC (F) dot plots. CD34 versus SSC dot plots were exploited to establish the gate identifying the CD34+ fraction characterized by low SSC (G). CD34 versus FL2-CD144 dot plots were utilized to recognize circulating CD144+ EPC/EC and to distinguish, within this class, the subpopulation of cells co-expressing CD144 and CD34 (H). White box: CXCR4+ cell enumeration and characterization. Regarding CXCR4+SCs, we first gated cells on the basis of pulse width versus FSC (I) and FSC versus SSC (J) dot plots. Samples stained with CD45 and isotype-matched antibodies were then plotted on CD45 versus CXCR4 charts to establish the gates identifying both the CXCR4+CD45+ and the CXCR4+CD45− populations (K). These two latter populations (L) were then analysed separately plotting CXCR4 versus either FL2-CD105, FL2-CD90 (M and N).
Fig 2
Fig 2
Circulating mesenchymal stem cells in HF patients. Peripheral blood level of CD45−CD34−CD90+ cells (A) are significantly increased in HF patients, and in particular in NYHA class IV patients compared with healthy donors (Ctrl). CD45−CD34−CD105+ cells (B) are significantly higher in NYHA class IV patients compared with controls. The CXCR4+ subpopulation of CD45−CD34− cells is also highly recruited (C) and, in particular, the subset CD45−CD34−CD90+CXCR4+ shows a significative increment in worsening of pathology (D). No differences between controls and patients are present regarding CD45−CD34−CD105+CXCR4+ subset (E). Also the level of PDGFR-positive MSCs and the CXCR4-positive component are higher in patients than in controls (F and G, respectively). Significative differences are reported as P value. Data are expressed as mean ± S.D.
Fig 3
Fig 3
Circulating haematopoietic stem cells in HF patients. Level of CD90+ and CD105+ HSC (A and B, respectively) are analysed in peripheral blood of controls and patient. No significative difference are observed between healthy donors and patients considered for New York Association class. In the CXCR4+ subtype, only the subset CD45+CD34+ CD90+CXCR4+ differs significatively between controls and patients in NYHA class III (C). No differences are reported in CD45+CD34+CD105+CXCR4+ cells (D). Regarding PDGFR-positive cells, statistically significative increase is observed in CD45+CD34+ class (E), but not in CXCR4+ component (F). Significative difference between controls and patients are reported as P value. Data are expressed as mean ± S.D.
Fig 4
Fig 4
Circulating endothelial precursors/cells in HF patients. Differences in EPCs/ECs level between all patients and control is significative. Number of cells, compared with controls, is higher in I–III NYHA classes and decreases in IV NYHA class, even if differences are not significative in any tested point. (A) Endothelial precursors cells; (B) differentiating endothelial cells; (C) mature endothelial cells. Data are expressed as mean ± S.D.
Fig 5
Fig 5
Circulating tissue committed stem cells in HF patients. Specific subset (CD45− and CD45+ and CD45−PDGFR+) of CD34+CXCR4+ SCs are analysed. Significative difference are found between all patients and controls in all populations. Differences in specific NYHA classes was found in CD45−CD34+CXCR4+ (B), but not in CD45−CD34+CXCR4+ (A) and in PDGFR-positive (C) cells. Significative difference between controls and patients are reported as P value. Data are expressed as mean ± S.D.
Fig 6
Fig 6
Cytokines plasmatic level in HF patients. Histograms represent plasma concentration of PDGF-BB (A), HGF (B), bFGF (C), VEGF (D), TNF-α (E) and SDF-1α (F) in healthy individuals and HF patients. Significative difference between controls and patients are reported as P value. Data are expressed as mean ± S.D.
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