Stem Cell Cytokines Preventing Ischemia Reperfusion

Osaka, Japan -

Granulocyte colony stimulating factor (G-CSF) is one of the largest selling products of the biotechnology industry.  Approved uses of this recombinant cytokine include stimulation of neutrophil production after chemotherapy or bone marrow transplantation.  Another use is in mobilizing the hematopoietic stem cells to leave the bone marrow and enter peripheral circulation.   

Since G-CSF has been in the clinic now for more than 2 decades, many interesting and unexpected activities of G-CSF have been identified.  For example, G-CSF can protect neurons from apoptosis, induce cardiac regeneration, and activates the complement system in the bone marrow through inducing exposure of neo-epitopes that preformed natural antibodies bind to.

One interesting new effect of G-CSF is its ability to induce expression of various genes in target organs that endow protection from ischemia reperfusion injury.  This was studied in a recent paper (Higuchi et al. Granulocyte colony-stimulating factor prevents reperfusion injury after heart preservation. Ann Thorac Surg. 2008 Apr;85(4):1367-73).

The scientists injected rats with increasing doses of G-CSF systemically, as well as with the Jak2 inhibitor AG490.  Injections were given for 3 days, after which animals were sacrificed and hearts were exposed to 4 Celsius for 12 hours and 1 hour at 37 Celsius.  Hearts were reimplanted into syngeneic recipients.  The scientists found:

- Phosphorylated Stat3 was observed with certain concentrations of G-CSF, this was inhibited if the Jak2 inhibitor AG490 was added.

- Improved recovery of left ventricular pressure, maximum positive rate of left ventricular developed pressure (Max dP/dt), and coronary flow (p < 0.05, respectively), as well as lower creatine phosphokinase leakage during reperfusion (p < 0.05) was noted with certain G-CSF concentrations that was abolished by the treatment with AG490.

- Jak2 dependent inhibition of cardiomyocyte apoptosis was seen as detected by decreased TUNEL, decreased Bax, and increased BCL-2XL expression.

These data support the possible use of G-CSF as a cardioprotective agent.  It would be interesting to try combining it with erythropoietin, which also possesses various anti-apoptotic activities.