Spinal cord injury (SCI) is a yet untreatable neuropathology that causes severe dysfunction and disability. Cell-based therapies hold neuroregenerative and neuroprotective potential but, although being studied in SCI patients for more than two decades, long-term efficacy and safety remain unproven, and it is still debated which cell types result in higher neurological and functional recovery. In a comprehensive scoping review of 142 reports and registries of SCI cell-based clinical trials, we addressed the current therapeutical trends and critically analyzed the strengths and limitations of the studies. Schwann cells, olfactory ensheathing cells (OECs), macrophages, and various types of stem cells (SCs) have been tested, as well as combinations of these and other cells. A comparative analysis between the reported outcomes of each cell type was performed, according to gold-standard efficacy outcome measures like the ASIA impairment scale (AIS), motor and sensory scores. Most of the trials were in the early phases of clinical development (phase I/II), involved patients with complete chronic injuries of traumatic etiology, and did not display a randomized comparative control arm. Bone marrow SCs and OECs were the mainly used cells, while open surgery and injection were the most common methods, delivering cells into the spinal cord or submeningeal spaces. Transplantation of support cells, such as OECs and Schwann cells, resulted in the highest AIS grade conversion rates (improvements in ∼40% of transplanted patients), which surpasses the spontaneous improvement rate expected for complete chronic SCI patients within one-year post-injury (5-20%). Some stem cells, such as peripheral blood-isolated ones (PB-SCs) and Neural SCs (NSCs) and also present potential for improving patients’ recovery. Complementary treatments, particularly post-transplantation rehabilitation regimes, may highly contribute to neurological and functional recovery. However, unbiased comparisons between the tested therapies are difficult to draw, given the great heterogeneity of the design and outcome measures used in the SCI cell-based clinical trials, and how these are reported. It is therefore crucial to standardize these trials when aiming for clinical evidence-based conclusions of higher value.

Tetraspanins, such as CD81, can form lateral associations with each other and with other transmembrane proteins. These interactions may underlie CD81 functions in multiple cellular processes, such as adhesion, morphology, migration, and differentiation. Since CD81's role in neuronal cells’ migration has not been established, we here evaluated effects of CD81 on the migratory phenotype of SH-SY5Y neuroblastoma cells. CD81 was found enriched at SH-SY5Y cell's membrane, co-localizing with its interactor filamentous-actin (F-actin) in migratory relevant structures of the leading edge (filopodia, stress fibers, and adhesion sites). CD81 overexpression increased the number of cells with a migratory phenotype, in a potentially phosphatidylinositol 3 kinase (PI3K)–Ak strain transforming (AKT) mediated manner. Indeed, CD81 also co-localized with AKT, a CD81-interactor and actin remodeling agent, at the inner leaflet of the plasma membrane. Pharmacologic inhibition of PI3K, the canonical AKT activator, led both to a decrease in the acquisition of a migratory phenotype and to a redistribution of intracellular CD81 and F-actin into cytoplasmic agglomerates. These findings suggest that in neuronal-like cells CD81 bridges active AKT and actin, promoting the actin remodeling that leads to a motile cell morphology. Further studies on this CD81-mediated mechanism will improve our knowledge on important physiological and pathological processes such as cell migration and differentiation, and tumor metastasis.

Contrary to the adult central nervous system (CNS), the peripheral nervous system (PNS) has an intrinsic ability to regenerate that, among others, passes by expressing regeneration-associated genes such as kinesin family members. We here show that Kinesin family motor protein 4a (KIF4A), associated to neurodevelopmental disorders and thought for long to be only embryonically expressed, is highly abundant in axons and Schwann cells of adult rat CNS and rat and human PNS. Moreover, Kif4a is up-regulated in injured PNS neurons, being detected in their nuclei and regrowing axons, consistent with its functions as a chromokinesin and in the axonal transport of e.g. β1-integrin and L1CAM. Interestingly, Kif4a is also highly up-regulated in Schwann cells transdifferentiating into a proliferative repair phenotype at the injured distal nerve stumps. A role for Kif4a in cultured Schwann cells proliferation was confirmed, with Kif4a mRNA expression being ≈6-fold higher in proliferating versus growth-arrested Schwann cells, and Kif4a knockdown impairing Schwann cells proliferation. To our knowledge, this is the first description of KIF4A expression in adult nervous systems, up-regulation in neuroregeneration and pro-neuroregenerative roles, including promoting Schwann cells proliferation. KIF4A dual role in axonal regeneration, through neurons and glia, places as an attractive target for future neuroregeneration therapies.