In a serendipitous bit of cell reprogramming sleight of hand, scientists have unwittingly managed to convert mature inhibitory neurons in the brains of live adult mice directly into neurons that resemble the dopamine-producing nerve cells that are lost in Parkinson’s disease.
The University of Texas (UT) Southwestern researchers had originally set out to prompt supporting glial cells to develop into dopamine-producing neurons, but their approach instead triggered a type of GABA-producing striatal nerve cells known as medium spiny neurons, to convert directly into dopaminergic (DA) neuron-like cells (iDALs). These neurons displayed markers and electrophysiological properties that mirror those of native mature dopamine-producing nerve cells that are normally found in other areas of the brain.
“Initially, I was a little disappointed that we altered the properties of medium spiny neurons and not the supporting glial cells we were targeting,” admits Chun-Li Zhang, Ph.D., professor of molecular biology at UT Southwestern Medical Center, and a W.W. Caruth, Jr. scholar in biomedical research. “But when we realized the novelty of our results, we were amazed…To find that we could manipulate neurons to change their identity in adulthood was truly unexpected… To our knowledge, changing the identity of resident and mature neurons had never been accomplished.”
The team suggests that as well as providing new insights into neuronal plasticity and the maintenance of cell identity, the demonstration that one type of mature neuron in the adult brain can be converted directly into another—without resorting to stem cells—could lead to new treatment strategies for neurological disorders. Reporting in Stem Cell Reports (“Phenotypic reprogramming of striatal neurons into dopaminergic neuron-like cells in the adult mouse brain,”) they conclude, “Such knowledge may one day be applied to devise therapeutic strategies for treating neurological diseases through reprogramming the phenotype of local neurons.”
Previous work has indicated that while resident glial cells in the mouse brain can be prompted to differentiate into neurons, its always been thought that mature neurons generally can't be reprogrammed. “In contrast to glial cells that can become reactive and proliferate under certain conditions, postmitotic neurons do not normally change their identity for the lifespan of the organism,” the authors write.
The UT Southwestern scientists' latest work, focused on reprogramming glial cells, was founded on their previous studies indicating that ectopic SOX2 can reprogram resident striatal glial cells in the adult mouse brain into neuronal progenitors, which then differentiate into mature neurons when the animals are treated with the small molecule valproic acid. Using this type of approach the team hoped to induce glial cells in the adult mouse brain to differentiate into dopaminergic neurons.
They developed a cocktail of genes—which they hoped would reprogram glial cells into dopaminergic neurons—including the stem cell factor, SOX2, plus for transcription factors NURR1, LMX1A, and FOXA2, and also administered the compound valproic acid. The genes were delivered by viral vector directly into the striatum, a region of the brain that is rich in GABA-producing medium spiny neurons, a nerve cell type that controls motor function. Dopamine-producing neurons are generally located elsewhere in the brain, but do put out connections that control the striatal medium spiny neurons.
As the team hoped, the procedure resulted in the development of dopaminergic neuron-like cells in the treated region of the brain, but what they hadn’t bargained for was that the new neurons weren’t derived from glial cells, but from the direct conversion of medium spiny neurons. “We got the new cells we wanted,” Dr. Zhang states, “but they did not originate from glial cells.”
Further rounds of experiments showed that while the iDALS retained some characteristics of the original cells, they expressed features typical of dopaminergic neurons, demonstrated characteristic electrophysiological properties and spontaneous action potential firing patterns, and formed connections with other neurons. “Rather than originating from glia, the new dopamine cells came from local, existing mature neurons without passing through a stem cell state,” Dr. Zhang states. “This is a mature-cell-to-mature-cell transformation.”
The team now aims to further characterize the cells and their genetic basis in the lab. “Taken together, these results indicate that iDALS are functionally mature and possess electrophysiological properties resembling endogenous DA neurons,” the researchers conclude. “Expanding the repertoire of cells that can be phenotypically reprogrammed in vivo, the results of this study show that striatal neurons in the adult mouse brain can be converted to a phenotype resembling DA neurons.”