Jay Shah, MD

Strecker J-K, Olk J, Hoppen M, Gess B, Diederich K, Schmidt A, et al. Combining Growth Factor and Bone Marrow Cell Therapy Induces Bleeding and Alters Immune Response After Stroke in Mice. Stroke. 2016

Cell-based therapies, such as transplantation of exogenous cells or stimulation of endogenous cells, for stroke are lacking. Bone marrow-derived cells (BMCs) are a viable option as they allow autologous transplantation and can be mobilized by granulocyte colony-stimulating factor (G-CSF). Cytokines released by BMCs contain neuroprotective properties and stimulate endogenous repair thereby potentially improving outcomes following ischemia. In this animal study, the authors’ hypothesis is that the combination of G-CSF and BMC is more effective than either single treatment in mice subjected to focal ischemia. There were 4 randomly assigned groups:  placebo, G-CSF, BMC, and G-CSF and BMC. Ischemia was induced by occlusion of the middle cerebral artery for 30 minutes. Treatment occurred 90 minutes after ischemia induction. Rotarod and cylinder test were used to assess motor performance and forelimb activity, respectively. At 1 or 7 days after ischemia, brains were harvested to assess for ischemic damage by various techniques.

Results revealed that mice treated with G-CSF alone showed increased running time compared to G-CSF and BMC group. Infarct volumes were reduced in G-CSF group compared to placebo. Parenchymal bleeding was only seen in mice treated with BMCs or combination therapy. There was evidence of increased astrogliosis in mice treated with G-CSF and BMC as evident by increased GFAP-signal intensity and increased mean blood vessel diameter.  

An unexpected result of this study was the detrimental effects of combination therapy, namely due to hemorrhagic transformation. Potential mechanisms to account for this complication include altered immune cell polarization, excessive astrogliosis, increased number of dilated blood vessels and blood brain barrier loss. There are several confounding variables. Foremost, time is certainly a crucial element in ischemia. In this study, treatment was conducted at a single time point. Treatment with BMC at a different time, perhaps earlier, may potentially alter results. It’s well established that molecular changes occur within minutes of ischemia and early intervention may be crucial to consistently affect outcome before irreversible molecular changes occur. Secondly, there is an assumption that all mice were clinically equal following ischemia but this may not be accurate. Lastly, additional studies will need to be conducted to further evaluate G-CSF and its impact on blood brain barrier. Cell-based treatment in animal models may not translate into human studies given the complex heterogeneity and multitude of variables that cannot be controlled.