Abstract
Degeneration of midbrain dopaminergic (DA) neurons is a key pathological event of Parkinson’s disease (PD). Limited adult dopaminergic neurogenesis has led to novel therapeutic strategies such as transplantation of dopaminergic precursors (DPs). However, this strategy is currently restrained by a lack of cell source, the tendency for the DPs to become a glial-restricted state, and the tumor formation after transplantation. Here, we demonstrate the direct conversion of mouse fibroblasts into induced DPs (iDPs) by ectopic expression of Brn2, Sox2 and Foxa2. Besides expression with neural progenitor markers and midbrain genes including Corin, Otx2 and Lmx1a, the iDPs were restricted to dopaminergic neuronal lineage upon differentiation. After transplantation into MPTP-lesioned mice, iDPs differentiated into DA neurons, functionally alleviated the motor deficits, and reduced the loss of striatal DA neuronal axonal termini. Importantly, no iDPs-derived astroctyes and neoplasia were detected in mouse brains after transplantation. We propose that the iDPs from direct reprogramming provides a safe and efficient cell source for PD treatment.
Highlights
Poorly to pre-patterning morphogens with low differentiation efficiency for specific neuronal subtypes, and are prone to a glial-restricted state[14]
The expressions of tyrosine hydroxylase (TH) and several key factors responsible for midbrain dopaminergic neuron development in 5F-iNPCs were dramatically increased in response to Foxa[2] and Lmx1a overexpression (Fig. S1-E), suggesting that both Foxa[2] and Lmx1a play a positive role in the determination of DA neuronal fate
We reported a novel cocktail of three transcription factors (Brn[2], Sox[2] and Foxa2) that successfully converted mouse skin fibroblasts into neural progenitors
Summary
Poorly to pre-patterning morphogens with low differentiation efficiency for specific neuronal subtypes, and are prone to a glial-restricted state[14]. The factors that directly reprogram somatic cells into neuronal lineage-restricted progenitors have been expanded to the combination of Brn2/Brn[4] and Sox[2] with c-Myc 19. We hypothesize that the specification of midbrain identity and dopaminergic neural fate could be achieved by the ectopic expression of Brn[2] and Sox[2] with Foxa[2] during the direct reprogramming of terminally differentiated cells. We demonstrate that the addition of Foxa[2] into the reprogramming procedure initiated by Brn[2] and Sox[2] successfully converts adult mouse skin fibroblasts into neural progenitors with a midbrain identity and selective dopaminergic differentiation potential. The iDPs can be safely expanded to the desired yield for transplantation, providing a useful cell source for PD treatment
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