Cellular plasticity in the adult central nervous system

Adult neural stem cells (NSCs) and neurogenesis.

New neurons are continuously produced in the dentate gyrus and the lateral ventricle in the adult brain. In the dentate gyrus, NSCs give rise to granule neurons, which mature and functionally integrate into existing hippocampal networks. These new neurons are able to fire action potentials and generate long-term potentiation upon stimulation. Furthermore, increasing evidence indicates that they have essential role in hippocampus-dependent learning and memory formation. NSCs found in the lateral ventricle differentiate into rapidly dividing neuroblasts, which migrate along the rostral migratory stream to the olfactory bulbs and further mature into granule or periglomerular interneurons. These newly generated interneurons contribute significantly to the structural and functional integrity of the olfactory bulbs. Our studies showed that a transcriptional network controls the maintenance, activity, and differentiation potential of NSCs (Figure 1). Continuous efforts are on understanding the genetic and epigenetic pathways controlling NSC behavior and adult neurogenesis under physiological and pathological conditions.

In vivo reprogramming of resident glial cells for regeneration.

Irreversible neuron loss is a major cause of the devastating effects that lead to morbidity and mortality after trauma, stroke, or neurodegenerative conditions. The region-restricted localization of endogenous neurogenic NSCs render them inadequate for repair of the damaged network. In contrast to neuron loss, resident glial cells, which are very abundant and ubiquitously distributed in the nervous system, become reactive and proliferate surrounding the damaged regions. Reprogramming some of these glial cells into local neurons may promote regeneration by creating a beneficial environment and forming new circuits between induced and surviving neurons. Our studies revealed that resident glial cells can be sequentially reprogramed into neural progenitors, neuroblasts, and mature neurons in the adult brain and spinal cord after injury (Figure 2).

This is an expandable process such that multiple neurons can be generated from a single reprogrammed glial cells. Research efforts are focusing on the molecular and cellular mechanisms for the in vivo reprogramming process, neuronal circuits created by these induced neurons, specific neuronal subtypes, small molecule-mediated reprogramming, and the biological function of these neurons after traumatic brain injury (TBI), spinal cord injury (SCI), and neurodegeneration.

Modeling human neurodegenerative diseases

Human patient-specific neurons will be crucial for understanding adult-onset neurodegenerative diseases. Induced pluripotent stem cells (iPSCs) derived from human skin fibroblasts and their differentiation into subtype-specific neurons are emerging as a cellular model for investigating these diseases. However, iPSCs and the differentiated neurons are reset to an embryonic stage during reprogramming. These embryonic or young neurons are inappropriate for modeling adult-onset neurological diseases. We have established a direct reprogramming approach by converting adult human skin fibroblasts to highly pure subtype-specific neurons without passing a stem cell stage. These neurons maintain aging features of their parental fibroblasts and are therefore ideal for modeling adult-onset neurodegeneration. Using this unique cell model, research efforts are on understanding disease mechanism, therapeutic drug identification and validation (Figure 3).