Using human pluripotent stem cells to untangle neurodegenerative disease mechanisms

Abstract

Human pluripotent stem cells, including embryonic (hES) and induced pluripotent stem cells (hiPS), retain the ability to self-renew indefinitely, while maintaining the capacity to differentiate into all cell types of the nervous system. While human pluripotent cell-based therapies are unlikely to arise soon, these cells can currently be used as an inexhaustible source of committed neurons to perform high-throughput screening and safety testing of new candidate drugs. Here, we describe critically the available methods and molecular factors that are used to direct the differentiation of hES or hiPS into specific neurons. In addition, we discuss how the availability of patient-specific hiPS offers a unique opportunity to model inheritable neurodegenerative diseases and untangle their pathological mechanisms, or to validate drugs that would prevent the onset or the progression of these neurological disorders.

Fig. 1

Scheme illustrating the principal steps for differentiating hESCs or iPS cells into neurons. hESCs human embryonic stem cells, hiPS human induced pluripotent stem cells, hNPs human neural precursor cells, DA dopaminergic neurons, MN motor neurons, PNS peripheral nervous system derivatives, EB embryoid body

Fig. 2

TGF-β superfamily and Wnt signalling pathways showing signalling proteins associated with TGF-β (a) and Wnt (b) pathway regulation. a Two major signalling pathways of the TGF-β superfamily. Right the signalling pathway of BMPs, while signalling pathways of TGF-β, activin, and nodal are shown on the left. Ligand binding promotes the assembly of heteromeric complexes, which activate Smads after phosphorylation. Activated Smad complexes translocate into the nucleus, where they regulate transcription of target genes involved in puripotency. b When Wnt is present, the axin complex is inhibited by Dishevelled (Dvl), leading to cytosolic accumulation of β-catenin, which is transported into the nucleus where it bind to Tcf and activates target genes involved in self-renewal. Blunted red arrows represent inhibitory pathways