RETRACTED: Directed Conversion of Alzheimer's Disease Patient Skin Fibroblasts into Functional Neurons

Abstract

SUMMARY Directed conversion of mature human cells, as from fibroblasts to neurons, would be of potential clinical utility for neurological disease modeling and as cell therapeutics. Here we describe the efficient generation of induced neuronal (hiN) cells from adult skin fibroblasts of unaffected individuals and Alzheimer’s patients, using virally transduced transcription regulators and extrinsic support factors. hiN cells from unaffected individuals display morphological, electrophysiological, and gene expression profiles that typify glutamatergic forebrain neurons, and are competent to integrate functionally into the rodent CNS. hiN cells from familial Alzheimer disease (FAD) patients with Presenilin-1 or -2 mutations exhibit altered processing and localization of amyloid precursor protein (APP) and increased production of Aβ, relative either to hiN cells from unaffected individuals or to the source patient fibroblasts. These findings demonstrate directed conversion of human fibroblasts to a neuronal phenotype and reveal cell type-selective pathology in hiN cells derived from FAD patients.

Direct lineage conversion: induced neuronal cells and induced neural stem cells

“…However, the same combination of factors does not elicit the same outcome in human fibroblasts, generating neurons with limited functional properties . This result was also confirmed by Qiang et al (2011) who showed that ABM factors had little effect on reprogramming human cells and instead caused apoptotic cell death. Pang et al (2011) therefore screened 20 additional factors in combination with ABM and found that the co-expression of ABM and the basic helix-loop-helix (bHLH) transcription factor NeuroD1 is sufficient to generate functional neuronal cells from human fibroblasts.…”

Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro

“…However, the basic culture conditions for growing neurons in vitro have not been updated to reflect fundamental principles of brain physiology. Currently, most human neuronal cultures are grown in media based on DMEM/F12 (4,5,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24), Neurobasal (25)(26)(27)(28)(29)(30), or a mixture of DMEM and Neurobasal (DN) (31)(32)(33)(34). To promote neuronal differentiation and survival, a variety of supplements, such as serum, growth factors, hormones, proteins, and antioxidants, are typically added to these basal media.…”

Specification of functional neurons and glia from human pluripotent stem cells

“…In addition, although both adult and fetal neural stem cells in theory are able to be amplified using mitogens such as FGF2 or EGF, these neural stem cells always undergo undesired differentiation and tend to lose their potential to generate the appropriate type of cells for cell replacement therapy (Wright et al, 2006). Functional neurons (Vierbuchen et al, 2010;Ambasudhan et al, 2011;Marro et al, 2011;Pang et al, 2011;Qiang et al, 2011;Yoo et al, 2011), and lately subtype-specific neurons such as dopaminergic neurons (Caiazzo et al, 2011;Pfisterer et al, 2011) and motor neurons (Son et al, 2011) have been converted directly from other type of somatic cells of mouse and human by introducing pro-neuronal transcription factors or micro-RNA. The neurons generated through these procedures were called induced neurons (iNs) and the process was termed transdifferentiation.…”