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Published on: March 30, 2022
Granulocyte colony-stimulating factor and stem cell factor improve endogenous repair after myocardial infarction
Peter Kanellakis1, Nicholas J Slater, Xiao-Jun Du
1Cell Biology Laboratory, Baker Heart Research Institute, Melbourne, Australia.
Insights
Granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) improved cardiac function after myocardial infarction (MI). These factors increased blood vessels and cardiomyogenic cells, but not from bone marrow origin.
Area of Science:
- Cardiovascular Research
- Regenerative Medicine
- Hematology
Background:
- Myocardial infarction (MI) leads to significant left ventricular (LV) dysfunction.
- Bone marrow-derived cells are explored for their potential in cardiac repair after MI.
- Granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) are cytokines with known roles in hematopoiesis and tissue repair.
Purpose of the Study:
- To investigate the therapeutic potential of G-CSF and SCF in improving cardiac function post-MI.
- To determine the impact of G-CSF/SCF on cellular repair mechanisms within the infarcted myocardium.
- To elucidate the origin and fate of bone marrow-derived cells homing to the site of cardiac injury.
Main Methods:
- Myocardial infarction was induced in a mouse model via transient coronary artery ligation.
- G-CSF/SCF were administered therapeutically for five days post-MI.
- Cardiac function was assessed using pressure-volume loops, and cellular composition of the infarct zone was analyzed via immunohistochemistry.
- Bone marrow chimeras with DsRed-expressing hematopoietic cells were used to track cell origins.
Main Results:
- G-CSF/SCF treatment significantly improved LV function, including developed pressure and contractility.
- G-CSF alone also demonstrated beneficial effects on cardiac function.
- Treated infarct zones showed a 70% increase in blood vessels and a doubling of cells expressing cardiomyocyte markers (GATA-4, Nkx2.5, alpha-actinin).
- While bone marrow-derived DsRed cells increased 12-fold in the infarct, they predominantly expressed the hematopoietic marker CD45, not cardiomyocyte or endothelial markers.
Conclusions:
- G-CSF/SCF therapy enhances cardiac function following MI.
- The observed improvements are associated with increased vascularity and cardiomyogenic cells within the infarct zone.
- The cellular cardiomyogenic lineage cells are of local myocardial origin, not derived from bone marrow transplantation.
Objective:
The aims of this study were, first, to determine if granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) improved left ventricular function in the setting of a reperfusion model of myocardial infarction (MI) and, second, to evaluate the effects of G-CSF/SCF on cellular repair and, in particular, the fate of bone marrow cells homing to the site of tissue injury.
Methods:
MI was induced in mice by transient ligation of the left descending coronary artery. G-CSF/SCF were administered for 5 days after MI. Cardiac function was assessed 28 days after MI. The effect of G-CSF/SCF on the cellular composition of the infarct region was assessed by immunohistochemistry. MI was performed in mice reconstituted with bone marrow cells expressing DsRed to track the fate of bone marrow-derived cells within the infarct region.
Results:
G-CSF/SCF-treated mice had significantly improved left ventricular (LV) function as determined by LV developed pressure, LV+/-dp/dt(max/min), and LV end-diastolic pressure. G-CSF alone produced similar improvements in cardiac function. These improvements in LV function were associated with 70% more blood vessels and a doubling of cells expressing cardiomyocyte-specific transcription factors GATA-4, Nkx2.5 and alpha-actinin cells within the infarct zone. Cells within the infarct expressing stromal-derived factor also increased by 200%. To elucidate the origin of these cells, bone marrow chimeras, where hematopoietic cells expressed the fluorescent marker DsRed, were treated with G-CSF/SCF after MI. Bone marrow-derived, DsRed-expressing cells in the infarct region of G-CSF/SCF-treated chimeras increased by an average of 12-fold; however, the vast majority of DsRed cells expressed the hematopoietic-specific marker CD45 but not blood vessel or cardiomyocyte markers.
Conclusions:
G-CSF/SCF therapy improved cardiac function when delivered after MI, increasing the number of blood vessels and cells of cardiomyogenic lineage. However, these cells were of myocardial rather than bone marrow origin.
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