Lysophosphatidic acid guides the homing of transplanted olfactory ensheathing cells to the lesion site after spinal cord injury in rats.

Olfactory ensheathing cells (OECs) are ideal candidates for cell-based therapies aimed at repairing spinal cord injury (SCI). Accurate targeting of OECs to the lesion site is critical to reconstructing the impaired nervous system. However, the key factors guiding the homing of transplanted OECs to the damaged area after SCI are still unclear. Here, we demonstrate that lysophosphatidic acid (LPA) can significantly facilitate the homing of OECs after SCI in rats. First, we found that OECs exhibited a robust chemotaxis response to LPA in vitro, with LPAR1 being predominant receptor expressed on OECs. We further found that ß-catenin signaling plays an important role in LPA-induced OEC migration. Moreover, silencing LPAR1 not only abolished the migration of OECs but also prevented ERK1/2 phosphorylation and ß-catenin activation, suggesting that LPAR1 ligation serves to activate the ERK1/2 and ß-catenin pathways in LPA-induced OEC chemotactic migration. Finally, cell transplantation experiments confirmed that endogenous LPA, which was observed to be produced at the lesion site after SCI in rat, is a key chemokine that facilitates OEC migration to the injury center. Collectively, our data provide a further description of the homing effects of LPA and a mechanism by which transplanted OECs migrate to the injured area after SCI in rats.

Transplantation of neural scaffolds consisting of dermal fibroblast-reprogrammed neurons and 3D silk fibrous materials promotes the repair of spinal cord injury.

Transplantation of tissue-engineered neural scaffolds bears great potential for reconstructing neural circuits after spinal cord injury (SCI). In this study, a 3D porous silk fibrous scaffold (3D-SF) with biomimetic interconnected micro- to nanofibrous structure and good biocompatibility is fabricated. Then, a small-molecule combination CFLSSVY (CHIR99021, Forskolin, LDN193189, SB431542, SP600125, VPA, and Y27632) that efficiently reprograms rat dermal fibroblasts into neurons is screened, and these chemically induced neurons (CiNs) are shown to readily communicate on the 3D-SF and form neural scaffolds. After transplantation of these silk-based neural scaffolds into the stumps of transected spinal cords in rats, the damaged tissue is repaired significantly, as indicated by the reduced cavity areas, decreased GFAP expression, and improved axonal regeneration and myelination in the injury site. Moreover, the hindlimb movement and motor-nerve conductivity are greatly improved as indicated by the elevated BBB score, the alternate movement of two hindlimbs during the 45° inclined grid test, and the shortened latency and enhanced amplitude in cMEP detection. Together, these results demonstrate that transplantation of neural scaffolds consisting of 3D-SF and dermal fibroblast-reprogrammed neurons leads to significant nerve regeneration and functional recovery, providing a promising therapeutic strategy for SCI.