Macrophage Colony-Stimulating Factor Treatment After Myocardial Infarction Attenuates Left Ventricular Dysfunction by Accelerating Infarct Repair
Toshiyuki Yano, MD*,
Tetsuji Miura, MD, PhD, FACC*,*,
Peter Whittaker, PhD ,
Takayuki Miki, MD, PhD*,
Jun Sakamoto, MD, PhD*,
Yuichi Nakamura, MD*,
Yoshihiko Ichikawa, MD, PhD*,
Yoshihiro Ikeda, MD*,
Hironori Kobayashi, MD*,
Katsuhiko Ohori, MD* and
Kazuaki Shimamoto, MD, PhD*
* Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
Departments of Emergency Medicine and Anesthesiology, University of Massachusetts Medical School, Worcester, Massachusetts
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Figure 1 Infarct histology five days after infarction (hematoxylin-eosin staining, x40 magnification). (A) Myocardial infarction (MI); (B) MI + macrophage colony-stimulating factor (M-CSF); (C) MI + granulocyte colony-stimulating factor (G-CSF). G = granulation tissue; N = coagulation necrosis. (D) Numbers of ED1-positive cells in central infarct and non-infarct regions. Inset shows representative staining with anti-ED-1 antibody. *p < 0.05 vs. control MI group.
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Figure 2 Ki-67–positive cells in infarcts and border zones five days after MI. Cells with Ki-67–positive nuclei were mainly observed in granulation tissue and the infarct–non-infarct border zone (A). At higher magnification, Ki-67–positive cells were shown to be mononuclear cells, specifically macrophages (B, thick arrow), spindle-shaped fibroblasts (B, thin arrow) and endothelial cells (C, thin arrow). (D) A cell co-stained with anti-Ki-67 antibody (green fluorescence) and anti– -sarcomeric actin (red fluorescence).
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Figure 3 Effects of M-CSF and G-CSF on TGF-ß-1, collagen I and collagen III mRNA expression in infarct and non-infarct regions. Expression of each gene was normalized by GAPDH mRNA level. *p < 0.05 vs. Sham, #p < 0.05 vs. MI. Abbreviations as in Figure 1.
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Figure 4 Scar collagen deposition 14 days after MI. (A), (D) MI; (B), (E) MI + M-CSF; (C), (F) MI + G-CSF. PSR staining: (A to C) Brightfield illumination and (D to F) polarized light. Abbreviations as in Figure 1.
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Figure 5 Relationship between infarct size and collagen content. In the MI group, infarct collagen content (as percentage of infarct area) correlated inversely with infarct size (as percentage of the left ventricle [LV]): y = –0.65x + 73.26, r = –0.82, p < 0.05 (open circles). M-CSF treatment shifted the regression line upwards: y = 0.17x + 57.24 (closed circles), p < 0.05 vs. the MI group regression line by analysis of co-variance. Other abbreviations as in Figure 1.
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Figure 6 Representative pseudo-color images illustrating intergroup optical retardation differences. Higher retardation is denoted by a progression in pixel color; purple, blue, green, yellow, orange, red. (A) MI, (B) MI + M-CSF, (C) MI + G-CSF. Interstitial space has zero retardation—purple. The M-CSF–treated scar contains more collagen fibers with high retardation values than the MI control or G-CSF cases, consistent with enhanced healing. (Panel width = 260 µm.) Abbreviations as in Figure 1.
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Figure 7 Relationships between left ventricular end-systolic elastance (Ees), collagen content in infarct region, and infarct transmurality. The Ees correlated with infarct collagen content (data pooled for all groups; [A] y = 20.82x + 284.87, r = 0.42, p < 0.05) and negatively correlated with infarct transmurality [B] y = –22.3x + 3,167.5, r = –0.36, p < 0.05). Abbreviations as in Figure 1.
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