SPEAKERS/JAN-ERIC AHLFORS
Jan-Eric Ahlfors

Jan-Eric Ahlfors

New World Laboratories, Laval, QC, Canada

Jan-Eric's lectures

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CAN-ACN 2021

Suppressing CSPGs receptors enhances spinal specific neuronal replacement by human directly reprogrammed neural precursor cells and improves functional recovery after spinal cord injury

Spinal cord injury (SCI) results in neurodegeneration and damage to the spinal neural circuitry. To date, effective neuronal replacement and functional restoration of spinal circuit remain challenging. Transplantation of neural precursor cells (NPCs) offers a promising approach for neuronal replacement in SCI. However, our studies indicate limited neurogenesis by transplanted NPCs in the hostile milieu of SCI. We identified that injury-induced upregulation of chondroitin sulfate proteoglycans (CSPGs) hinders survival and integration of engrafted NPCs after SCI by signaling through two main receptors, LAR and PTP-σ. Here, we have evaluated the therapeutic potential of co-blocking LAR and PTP-σ by ILP and ISP peptides, respectively, in conjunction with transplantation of human directly reprogrammed NPCs (drNPCs) with the capacity to generate spinal neurons. Our in vitro studies confirmed ILP/ISP co-treatment restores the inhibitory effects of CSPGs on drNPCs and promotes their neuronal differentiation, maturation, and synaptogenesis. In rat SCI, systemic delivery of ILP/ISP significantly promoted long-term survival and biodistribution of human drNPCs, enhanced their neuronal differentiation and complexity, and functional recovery after SCI. Our transcriptomic analysis identified that CSPGs impede neuronal differentiation by inactivating the Wnt/β-catenin pathway, which was verified in our in vitro studies. Altogether, we have developed a new targeted, translationally feasible strategy with the potential to optimize neuronal replacement and functional recovery after SCI.

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