Background:
Early clinical trials of cell-based therapies in stroke have been very encouraging; however, technical hurdles may prevent widespread adoption. The salutary effects appear to be through release of “trophic” factors and immunomodulators which affect host repair and protection responses. We are developing a novel stroke therapy which is a clinically compliant cell-free, therapeutic factor concentrate (TFC) derived from adipose stem cell conditioned medium (ASC-CM). We will present data from a murine embolic stroke model study to determine the potential for clinical translation of TFC.
Methods:
Embolic stroke was induced in C57/Bl6 male mice (16 - 18 wks old) by delivering 9 - 10 mm clot into the middle cerebral artery (MCA) territory. Mice were randomly picked up for the intravenous treatments (either vehicle or 20/50/100 uL of TFC; N= 10/group) immediately after stroke. Neurological deficits were evaluated at 48 hrs post stroke, and mice were also tested for the somatosensory functions using adhesive tape removal test (ATT) at 72 hrs before the sacrifice for TTC-stained infarct analysis. Statistical significance was determined at P < 0.05.
Results:
Our data demonstrate a clear dose dependent response, with the highest dose tested (100 uL; ~4 mg total protein/kg body weight) being the most effective in the embolic stroke model. While the low-dose (20 uL; 0.8 mg/kg) did not show an effect in any outcomes measured, the middle dose (50 uL, ~2 mg/kg) was effective but less so than the highest dose (100 uL). TFC at 100 uL significantly improved neurological outcomes on Bederson scale, and also somatosensory function as determined by ATT. There was also a trend toward improved survival after stroke in 100 uL TFC treated group. Most importantly, while the 50 uL dose reduced the infarction volume by ~20%, the effect was >50% reduction with 100 uL treatment. TFC at any dose did not show any adverse effects such as the hemorrhagic transformation.
Conclusion:
TFC is a potential therapy to improve post-stroke outcomes. We are repeating these studies with ovariectomized female mice and extending the studies to 1 month. Future studies with this model will test TFC (1) in combination with IV-tPA, (2) with delayed delivery (up to 24 hours post-stroke), (3) and in aged animals.
microRNAs Involved in Regulating Spontaneous Recovery in Embolic Stroke Model