Converting the glial scar to neurons repairs the injured neural circuits for functional recovery following spinal cord injury

ABSTRACT The cellular basis of the central nervous system (CNS) consists of neurons and glial cells. Although glial cells massively outnumber neurons in the CNS across species, only neurons are specially endowed with the ability to communicate precisely and rapidly with other cells at distant sites in the body. Unfortunately, unlike glial cells, the adult spinal cord is incapable of generating new neurons. In addition, the axons also fail to regenerate after the damage, even their neuron somas are survived. Thus, after the adult spinal cord injury (SCI), the irreversible loss of neurons and disruption of axons lead a permanent functional deficit. The intrinsic reduced regenerative capacity of adult neurons and the extrinsic inhibitory glial scar formation cause the regeneration failure after spinal cord injury. An ideal spinal repair strategy should 1) replenish neurons for circuit reconstruction, 2) modulate the inhibitory glial scar, to allow resident neural regeneration, and 3) establish new functional neural circuits for electrical and chemical signal conduction. Our recent study has confirmed that the spinal cord fails to generate new mature neurons after injury. The critical stem cell factor SOX2 was discovered to be the key modulator of endogenous reprogramming. We demonstrated that our SOX2-mediated reprogramming strategy successfully converted the NG2 glia into a great number of new neurons in the lesioned spinal cord, and simultaneously reduced the astrocytic glial scar. Furthermore, the converted neurons were able to make synaptic connections to the resident neurons in various areas of the CNS, indicating the integration of the converted neurons into the h(1, 2)post neural circuits. Importantly, it also promoted forelimb functional recovery. Surprisingly, our pilot study demonstrated a robust corticospinal axonal regeneration after SCI. Together, we hypothesized that our reprogramming strategy significantly modulates the inhibitory glial scar and activates pro-regenerative factors, allowing for axonal regeneration, which will restore the signal transduction in the injured spinal cord. We aim to characterize the alteration of the glial scar and pyramidal neurons during the reprogramming process and relate it to axonal outgrowth and circuitry establishment. The finding from this proposal is expected to sharpen our understanding of the reprogramming-mediated axonal regeneration and neural circuits reorganization for the development of an optimized reprogramming strategy to treat SCI.