The therapeutic potential of cell identity reprogramming for the treatment of aging-related neurodegenerative disorders

Abstract

Neural cell identity reprogramming strategies aim to treat age-related neurodegenerative disorders with newly induced neurons that regenerate neural architecture and functional circuits in vivo. The isolation and neural differentiation of pluripotent embryonic stem cells provided the first in vitro models of human neurodegenerative disease. Investigation into the molecular mechanisms underlying stem cell pluripotency revealed that somatic cells could be reprogrammed to induced pluripotent stem cells (iPSCs) and these cells could be used to model Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, and Parkinson disease. Additional neural precursor and direct transdifferentiation strategies further enabled the induction of diverse neural linages and neuron subtypes both in vitro and in vivo. In this review, we highlight neural induction strategies that utilize stem cells, iPSCs, and lineage reprogramming to model or treat age-related neurodegenerative diseases, as well as, the clinical challenges related to neural transplantation and in vivo reprogramming strategies.

Keywords: Alzheimer disease; Amyotrophic lateral sclerosis; Cell identity; Embryonic stem cell; Huntington disease; In vivo reprogramming; Induced neural stem cell; Induced pluripotent stem cell; Neural stem cell; Neurodegeneration; Neuron; Parkinson disease; Regenerative medicine; Reprogramming; Stem cell; Transdifferentiation.

Fig. 1

Neuron induction by diverse cell identity reprogramming strategies. Indirect reprogramming through an iPSC (red): somatic or glial cells adopt a pluripotent state before differentiation into functional subtype-specific neurons or neural progenitor cells that differentiate to yield neurons. Direct reprogramming through a neural progenitor (blue and yellow): somatic or glial cells adopt a unipotent subtype-specific neural progenitor state or tripotent region-specific neural progenitor state. These progenitor cells then differentiate into functional subtype-specific neurons. Direct reprogramming through a tripotent NSC (green): somatic or glial cells adopt a tripotent NSC fate then directly differentiate to neurons, glia or regional neural progenitor cells. Direct reprogramming by transdifferentiation (black): somatic or glial cells adopt a specific neuronal fate without passing through a pluripotent or neural progenitor stage.

Fig. 2

Challenges to clinical translation. Numerous challenges face the clinical application of cell identity reprogramming technologies. In vitro generation of neurons requires a large population of patient-specific source cells for reprogramming and transplantation. Alternatively, in vivo reprogramming strategies typically target large glial cell populations for neuronal induction. The refinement of reprogramming factor delivery, genetic correction of disease-causative mutations, and characterization of induced neurons will be essential to the clinical evaluation of these technologies.