Direct Conversion of Human Fibroblasts into Neuronal Restricted Progenitors

Abstract

Background: Neuronal restricted progenitors have not been generated from fibroblasts by transdifferentiation. Results: Human induced neuronal restricted progenitors (hiNRPs) were efficiently generated from fibroblasts by transfection of three defined factors: Sox2, c-Myc, and either Brn2 or Brn4. Conclusion: Unipotent neuronal restricted progenitors can be rapidly and efficiently produced from fibroblasts. Significance: This novel method will provide a new source of neurons for cellular replacement therapy of human neurodegenerative diseases.

Fast and Efficient Neural Conversion of Human Hematopoietic Cells

“…While recent work identified MASH1 as the most important driver of neural conversion in fibroblasts (Chanda et al, 2014), we observed only marginal induction of MASH1 expression in CB-iNCs (Figure 2A). In contrast, BRN2 was progressively activated in CB-iNCs during the neural conversion (Figure 2A), suggesting an involvement of BRN2 in this process, in line with other recent reports (Lujan et al, 2012;Zou et al, 2014).…”

“…These data are in line with previous works showing that forced expression of SOX2 alone or in combination with other transcription factors can convert mouse and human fibroblasts into neural stem cells (Ring et al, 2012) or multipotent neural progenitors (Lujan et al, 2012). Noteworthy, SOX2 and BRN2 have been recently used to convert fibroblasts into NPCs (Lujan et al, 2012;Zou et al, 2014). Furthermore, SOX2 has been shown to co-occupy with BRN2 (a POU factor) a large set of distal enhancers in NPCs and regulate together a subset of genes important for neural fate (Lodato et al, 2013;Miyagi et al, 2006).…”

How to make a hippocampal dentate gyrus granule neuron

“…In a single culture, these may include dopaminergic neurons marked by tyrosine hydroxylase (TH), glutamatergic neurons marked by vesicular glutamate transporter, interneurons marked by γ-aminobutyric acid, and motor neurons marked by choline acetyltransferase (Ambasudhan et al, 2011;Pang et al, 2011;Qiang et al, 2011;Yoo et al, 2011). In a similar way, neurons differentiated from iNPCs thus far also seem to contain multiple neuronal subtypes (Han et al, 2012;Ring et al, 2012;Wang et al, 2013;Zou et al, 2014). It is clear from these studies that the method of NPC production and the precise patterning cues that are provided have a direct bearing on the potential of the cells to reliably differentiate into specialized cell types.…”

Skin-derived neural precursors competitively generate functional myelin in adult demyelinated mice

“…In search of an accessible, renewable, and nonimmunogenic source of myelin-forming cells, reprogramming strategies were designed to generate rodent or primate induced pluripotent stem cell-derived NPCs (iPS-NPCs) or oligodendrocyte progenitor cells (iPS-OPCs) (6)(7)(8). Alternatively, somatic cells were directly reprogrammed into NPCs (iNPCs) (9)(10)(11)(12)(13) or OPCs (iOPCs) (14,15). Few of these studies addressed the capacity of the derived cells to differentiate into oligodendrocytes in vitro or in vivo after engraftment in models of congenital dysmyelination (8,14,15).…”