Cellular programming and reprogramming: sculpting cell fate for the production of dopamine neurons for cell therapy

Abstract

Pluripotent stem cells are regarded as a promising cell source to obtain human dopamine neurons in sufficient amounts and purity for cell replacement therapy. Importantly, the success of clinical applications depends on our ability to steer pluripotent stem cells towards the right neuronal identity. In Parkinson disease, the loss of dopamine neurons is more pronounced in the ventrolateral population that projects to the sensorimotor striatum. Because synapses are highly specific, only neurons with this precise identity will contribute, upon transplantation, to the synaptic reconstruction of the dorsal striatum. Thus, understanding the developmental cell program of the mesostriatal dopamine neurons is critical for the identification of the extrinsic signals and cell-intrinsic factors that instruct and, ultimately, determine cell identity. Here, we review how extrinsic signals and transcription factors act together during development to shape midbrain cell fates. Further, we discuss how these same factors can be applied in vitro to induce, select, and reprogram cells to the mesostriatal dopamine fate.

Figure 1

Cell identity is represented as the resultant of the integration of signals that the receptive, undifferentiated cell is exposed to, in a temporal and spatial coordinated fashion.

Figure 2

During embryogenesis ventral midbrain dopamine neurons are born at the intersection of three signaling molecules, Shh, Wnt1 and Fgf8, that pattern the neural tube along rostrocaudal, dorsoventral and mediolateral axes. Sagittal and coronal views at the midbrain and spinal cord levels of the mouse embryo showing the expression patterns of these morphogens at E9.5. FP: floor plate; IsO: isthmic organizer; MB: midbrain; NC: notochord; OV: otic vesicle; RP: roof plate; SC: spinal cord; ZLI: zona limitans intermedia.

Figure 3

Customized rendering of the epigenetic landscape for ventral midbrain dopamine neurons representing the developmental program (downhill, black lines) and the reprogramming pathways back to pluripotency (red lines) and across mature fates (blue lines).