Abstract
BackgroundDirected differentiation of human induced pluripotent stem cells (hiPSC) into functional, region-specific neural cells is a key step to realizing their therapeutic promise to treat various neural disorders, which awaits detailed elucidation.Methodology/Principal FindingsWe analyzed neural differentiation from various hiPSC lines generated by others and ourselves. Although heterogeneity in efficiency of neuroepithelial (NE) cell differentiation was observed among different hiPSC lines, the NE differentiation process resembles that from human embryonic stem cells (hESC) in morphology, timing, transcriptional profile, and requirement for FGF signaling. NE cells differentiated from hiPSC, like those from hESC, can also form rostral phenotypes by default, and form the midbrain or spinal progenitors upon caudalization by morphogens. The rostrocaudal neural progenitors can further mature to develop forebrain glutamatergic projection neurons, midbrain dopaminergic neurons, and spinal motor neurons, respectively. Typical ion channels and action potentials were recorded in the hiPSC-derived neurons.Conclusions/SignificanceOur results demonstrate that hiPSC, regardless of how they were derived, can differentiate into a spectrum of rostrocaudal neurons with functionality, which supports the considerable value of hiPSC for study and treatment of patient-specific neural disorders.
Highlights
Embryonic stem (ES) cells have been derived from mouse, monkey, human, and many other species, and considered as potent candidates for regenerative medicine, and unique tools for understanding of disease mechanisms and screening for effective and safe drugs[1]
TZ1, YZ1, and YK26 were all validated by immunostaining of pluripotency markers and teratoma formation, and all the 4 or 6 transgenes were found silenced in the established human induced pluripotent stem cells (hiPSC) lines, The DNA fingerprints of the hiPSC lines all matched their corresponding parental fibroblast lines and the karotypes of the hiPSC lines were all found normal by G-banding
fibroblast growth factor (FGF) Signaling is Required for Early Neural Induction By using the Xenopus embryo, we have previously demonstrated that inhibition of the bone morphogenetic protein (BMP) pathway is sufficient for neural induction[8] and activation of FGF pathway is required for both neural induction and caudalization[38]
Summary
Embryonic stem (ES) cells have been derived from mouse, monkey, human, and many other species, and considered as potent candidates for regenerative medicine, and unique tools for understanding of disease mechanisms and screening for effective and safe drugs[1]. The key step toward their application in neurological diseases is to direct human ES cell (hESC) differentiation to the neural lineages and to specific neuronal types that are affected under certain pathological conditions[2]. It was reported that FGF alone promotes neural differentiation from hESC, independently of BMP signaling[12]. HESCderived neurons provide an important tool for studying neural genetic disorders and producing therapeutic cell types for their treatment, these applications are only possible after the difficulties of genetically manipulating hESC to model the diseases and the problem of immunorejection of hESC-derived cells by potential recipients are overcome. Directed differentiation of human induced pluripotent stem cells (hiPSC) into functional, region-specific neural cells is a key step to realizing their therapeutic promise to treat various neural disorders, which awaits detailed elucidation
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