Neurogenesis in the subventricular zone and hippocampus following cell therapy in a non-human primate model of cortical damage

Approximately 795,000 Americans experience a new or recurrent stroke each year (American Heart Association 2016; Mozaffarian et al. 2016). However, the only experimental therapeutic to have gained FDA approval for treatment of stroke in humans is the thrombolytic agent tPA that can dissolve clots and restore blood flow, if given within a narrow therapeutic window of a few hours following stroke onset (AHA 2016, Li et al. 2016). Nevertheless, in many cases with or without tPA there is significant residual impairment, and there are currently no FDA approved therapeutic agents that facilitate functional recovery following stroke (Zhang L et al. 2012). Recent studies have suggested that neural plasticity and neurogenesis following stroke may play a role in recovery of function, and promising findings have been demonstrated with cell therapies for enhancing recovery after stroke (Kokaia and Darasalia, 2015; Kozorovitskiy et al, 2013; Zhao et al, 2012). Our recent study (Moore et al. 2013) showed significant recovery of function following a reproducible ischemic lesion limited to the hand representation of the motor cortex in non-human primates (NHPs) treated with the investigational cell drug product CNTO 0007, that contains human umbilical tissue-derived cells (hUTC). While the treatment group in this study demonstrated significantly better recovery of motor function, the mechanism of recovery remains unclear. Previous studies conducted with brain tissue from these monkeys have suggested that functional recovery may be related to cortical reorganization induced by the hUTC treatment. To explore the possibility that neurogenesis may have also played a role in the enhanced recovery, these same monkeys received an injection of the thymidine analog Bromodeoxyuridine (BrdU), which was visualized in the brain tissue to investigate cell proliferation in the subventricular zone and hippocampus. Results show that there is no significant difference in the number of BrdU positive cells in the hUTC treated vs. untreated monkeys, however there is a trend towards significant increase in BrdU labeling in the granule cell layer of the hippocampus of the hUTC treated animals. Clusters of proliferating cells were also found in the GCL of treated monkeys, but not in the untreated monkeys. These findings support the hypothesis that enhanced recovery of function may be related to a combination of reorganization of undamaged cortical motor regions and generation of new cells in the brain