UC Irvine

Spinal Cord Injury (SCI) is a devastating condition that results in a serious burden on the health care system. Currently, no therapeutics for the disease exist, and thus research into generating effective therapies for SCI is a paramount concern. One exciting avenue for treatment is neural stem cell (NSC) transplantation. This method has shown efficacy in rodent models, but the therapeutic outcome is highly dependent upon the timing of the transplantation relative to injury. Acutely transplanted cells will migrate primarily towards the injury epicenter, exhibiting pronounced astrogliosis, and not improving animal recovery vs. vehicle control. NSC transplanted with a delay of 9 or more days relative to injury will instead migrate more distally from the epicenter, exhibit a more neuronal and oligodendrocytic phenotype, and will improve animal locomotor recovery vs. vehicle control. This dramatic shift in outcome is due to parallel shifts in the post-SCI microenvironment, including an increase in immune components such as C1q, the recognition molecule of the complement cascade. Here, I first highlight recently published data from my lab showing that C1q signals to NSC through several receptors, including CD44, a receptor known to regulate a wide variety of cellular behaviors. We have shown that C1q signals to NSC through CD44, serving as a chemotactic cue. CD44 knockout (KO) NSC, when transplanted into an acute SCI niche, exhibited significantly reduced astrogliosis and migration to the epicenter compared to wild-type (WT) NSC. Additionally, CD44 KO NSC were able to restore locomotor function beyond vehicle control, whereas the WT NSC remained unable to. Next, I then show data from three distinct projects. First, I examine the effect of CD44 KO on human NSC transplanted into the chronic phase of SCI, where I observe that CD44 is necessary for transplant engraftment. Then, I test the effect of CD44 KO on the endogenous response to SCI, discovering that CD44 KO animals have dramatically altered cellular responses to SCI, including acutely activated immune cell recruitment to the injury cite, scar formation, and, strikingly, improved locomotor outcomes vs. WT animals. Finally, I show the development of a new strategy to facilitate the analysis of animal behavioral data obtained from SCI studies, utilizing methods from computational biology. I demonstrate the power of this approach via a pair of use cases, and detail plans to make these methods widely and easily implemented by the field at large by releasing it as a publicly available R package.