Careful histological analyses can address some of these concerns, with rigorous documentation of lesion extent and serial tracing of axons across different planes of sampling (Figure 5). Functional analyses are compromised unless thorough histological analyses are carried out on every animal to confirm lesion completeness. In all of these partial lesion models, strong, supportive evidence can Selleckchem Talazoparib mitigate concerns about sparing. If the axons take a course that is not seen in uninjured animals,

the claim for regeneration can be persuasive. For example, deletion of the tumor suppressor gene “phosphatase and tensin homolog” (PTEN) in mice after either dorsal hemisection or severe crush lesion results in bilateral extension of CST axons below the lesion that originate from a single hemisphere (Liu et al., 2010). Such bilateral projections are extremely rare in controls, and their

abundance in PTEN-deleted mice is supportive evidence for regeneration. Even when it can be established that axons have regrown past the lesion, it is usually not possible to conclude with certainty whether these axons originate from transected axons or from sprouts of spared CST axons that ordinarily terminate rostral to the injury. This requires complete reconstruction of the origin and course of the axons, which in turn requires sparse labeling. Many studies have assessed whether grafts or transplants can support CST growth. Implanted matrices have included Schwann cells, astrocytes, Dinaciclib neural stem cells, fibroblasts, oligodendrocyte precursor cells, bone marrow stromal cells, or other substances (Blesch and Tuszynski, 2009). While these matrices support the growth of other motor systems, including raphespinal, rubrospinal, and reticulospinal projections after injury, it is noteworthy that none of these matrices support CST axon growth. The only matrix

to date that supports CST growth is the grafting of fetal spinal cord (Coumans et al., 2001), and even then, growth is modest. Also, fetal spinal cord grafts are of limited practical usefulness because the grafted cells exhibit variable survival and rarely fill the lesion site (Coumans et al., 2001). A major unmet challenge in the field of spinal cord injury research remains first the identification of a substrate or matrix that will enable CST axon growth into a cystic lesion site. Although the CST has been relatively refractory to most therapeutic manipulations, other descending systems including raphespinal, cerulospinal, reticulospinal, rubrospinal, and propriospinal axons are somewhat more responsive (Blesch and Tuszynski, 2009). These systems mediate functions (locomotion, posture, balance, autonomic control) that would be important to comprehensively improve functional outcomes in people with SCI (Anderson et al., 2008).