G-CSF Promotes Bone Marrow Cells to Migrate into Infarcted Mice Heart, and Differentiate into Cardiomyocytes

Abstract

A recent study showed that granulocyte-colony stimulating factor (G-CSF) treatment improved the infarcted cardiac function. Although mobilized stem cells may affect it, the mechanism is unclear. In this study, we investigated the origins of stem cells and phenotypic changes of the migrated cells, and evaluated the efficacy of G-CSF. Eighteen C57BL/6 mice were irradiated (900 cGy) and GFP mouse-derived bone marrow cells (GFP-BMC: 10(6) cells) were injected via a tail vein followed by splenectomy 4 weeks later. Ligation of the left descending coronary artery was performed 2 weeks later. Recombinant human G-CSF (200 microg/kg/day) was injected for 3 days before and 5 days after ligation (group 1, n = 10). Saline was injected in group 2 (n = 8). Four weeks after infarction, hearts and other organs were fixed for histology. The survival rate after postoperative day 3 in group 1 was 100%, while that in group 2 was 50% (p = 0.03). Bone marrow-derived GFP cells (BMD-GFP) in group 1 (103.3+/-71.9/mm2) were located at the infarcted border area significantly more than those in group 2 (43.6+/-23.7/mm2) (p < 0.0001). BMD-GFP cells were positive for troponin I (16.6%), myosin heavy chain-slow (16.7%), and nestin (8.8%) in group 1. Ki-67-positive BMD-GFP in group 1 (10.0+/-7.0/mm2) were significantly more than those in group 2 (4.8+/-6.1/mm2) (p = 0.01). G-CSF increased the survival rate after infarction. G-CSF promoted BMC to migrate into the infarcted border area. Bone marrow was one of the origins of regenerated cardiomyocytes.

Cardiac Stem Cells and Mechanisms of Myocardial Regeneration

“…For example, lineage-negative c-kit-positive cells (228,258,356), lineage-negative c-kit-positive Sca-1-positive cells, c-kit-positive-Thy1.1-low-lineage-negative Sca-1-positive, long-term reconstituting HSCs (45), CD34-positive cells (545), mesenchymal-like progenitor cells (424,434), EPCs (281,282), mononuclear BMCs, and clonally expanded human multipotent stem cells (539) have been tested. Moreover, BMCs with the potential of restoring the dead myocardium have been mobilized from the bone marrow into the systemic circulation utilizing several cytokines; SCF, G-CSF, and SDF-1␣ have been administered alone or in combination in various animal species (1,38,162,188,334,357,462). The effects of these various modalities of therapy ranged from improvement in regional cardiac function together with the restoration of the dead myocardium to a modest recovery of ventricular performance in the absence of tissue regeneration.…”

Aging Impairs the Beneficial Effect of Granulocyte Colony-Stimulating Factor and Stem Cell Factor on Post-Myocardial Infarction Remodeling

“…9,10 However, a recent randomized controlled trial in patients with a mean age of 60 years of age failed to demonstrate benefit from G-CSF administration following MI, despite ample CD34 ϩ cell mobilization. 11 One of the main mechanisms by which G-CSF and SCF exert favorable effects on cardiac remodeling is enhancement of endogenous cardiac repair mechanisms that include both bone marrow stem cell mobilization, engraftment, and differentiation [12][13][14][15] as well as proliferation of cardiomyocytes. 16 In addition, G-CSF inhibits cardiomyocyte apoptosis 17 and accelerates healing by stimulating absorption of necrotic tissue and reducing granulation and scar tissue via expression of matrix metalloproteinases.…”

Current address: Shinji Tomita, MD, Cardiothoracic Surgical Unit, Level 4, Auckland City Hospital, Auckland, New Zealand

“…28 We previously reported that bone marrow was one of the origins of regenerated myocardium in a self-renewal system. 29 The present findings raise a new hypothesis that exogenous BMC implantation would trigger endogenous stem cells to regenerate myocardium. When we detected the expression of the nestin-positive cells in the infarcted area, not in normal myocardium, we assumed there was a correlation between the nestinpositive cells and ischemia, although the reason for the nestin positive cells in the PGAC remains unknown.…”