Direct Conversion of Human Fibroblasts into Neural Progenitors Using Transcription Factors Enriched in Human ESC-Derived Neural Progenitors

Hou, Pei Shan; Chuang, Ching Yu; Yeh, C; Chiang, Wei Fan; Liu, Hsiao Jung; Lin, Teng Nan; Kuo, Hung‐Chi

doi:10.1016/j.stemcr.2016.11.006

Cited by 34 publications

(48 citation statements)

References 35 publications

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“…iNSCs are particularly suited for characterizing neural cells in health and disease, as well as during neural development. Moreover, treatment of patient-derived neuronal cultures with GSK3b inhibitors resulted in a significant reduction of pTAU aggregates [37]. Importantly, the iNSC-derived neuronal cell cultures recapitulated cellular hallmarks of the disease, including increased levels of amyloid ß and phosphorylated TAU (pTAU) in neuronal cell bodies and processes [37].…”

Section: Functional Characterization Of Insc-derived Neuronsmentioning

confidence: 99%

“…The unexpected reprogramming activity of this non-neurogenic TF critically depends on its interaction with RBPJ to activate downstream TFs involved in NSC specification. In 2017, Hou et al [37] reported two reprogramming protocols exploiting either six or seven TFs for direct OSKM-and BSKM-independent conversion of human fibroblasts into iNSCs. In 2017, Hou et al [37] reported two reprogramming protocols exploiting either six or seven TFs for direct OSKM-and BSKM-independent conversion of human fibroblasts into iNSCs.…”

Section: Transcription Factors Employed In Insc Generationmentioning

confidence: 99%

“…In fact, it causes activation of at least six families of TF genes, including Sox and POU domain family members, thus making possible SOX2 and OCT4 activation during the Ptf1a-induced transdifferentiation procedure [38]. In contrast, the seven TFs (FOXG1, GATA3, NR2F1, PAX6, SALL2, TFAP2A, and ZFP42) gave rise to iNSCs of both hindbrain and the peripheral nervous system (PNS) [37]. To some extent, the establishment of regional identity of iNSCs appeared to depend on which set of TFs was chosen.…”

Section: Transcription Factors Employed In Insc Generationmentioning

confidence: 99%

“…The unique properties of iNSCs (self-renewal, clonality, and multipotency) and the fact that they can be generated from somatic cellular sources make them powerful model systems to study human physiology and pathology in vitro and in vivo. Importantly, the iNSC-derived neuronal cell cultures recapitulated cellular hallmarks of the disease, including increased levels of amyloid ß and phosphorylated TAU (pTAU) in neuronal cell bodies and processes [37]. For example, Hou et al [37] have reported the generation of iNSCs derived from fibroblasts of patients suffering from Alzheimer's disease (AD), a fatal neurodegenerative disease of unknown etiology [84].…”

Section: Functional Characterization Of Insc-derived Neuronsmentioning

confidence: 99%

“…Importantly, the iNSC-derived neuronal cell cultures recapitulated cellular hallmarks of the disease, including increased levels of amyloid ß and phosphorylated TAU (pTAU) in neuronal cell bodies and processes [37]. The authors showed that treatment of HDderived neuronal cells with an A2AR agonist reduced neuronal DNA damage in neurons, one of the hallmarks of HD [37]. The same group has also generated iNSCs from Huntington's disease (HD) patients.…”

Section: Functional Characterization Of Insc-derived Neuronsmentioning

confidence: 99%

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Take the shortcut – direct conversion of somatic cells into induced neural stem cells and their biomedical applications

et al. 2019

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Second-generation reprogramming of somatic cells directly into the cell type of interest avoids induction of pluripotency and subsequent cumbersome differentiation procedures. Several recent studies have reported direct conversion of human somatic cells into stably proliferating induced neural stem cells (iNSCs). Importantly, iNSCs are easier, faster, and more cost-efficient to generate than induced pluripotent stem cells (iPSCs), and also have a higher level of clinical safety. Stably, self-renewing iNSCs can be derived from different cellular sources, such as skin fibroblasts and peripheral blood mononuclear cells, and readily differentiate into neuronal and glial lineages that are indistinguishable from their iPSC-derived counterparts or from NSCs isolated from primary tissues. This review focuses on the derivation and characterization of iNSCs and their biomedical applications. We first outline different approaches to generate iNSCs and then discuss the underlying molecular mechanisms. Finally, we summarize the preclinical validation of iNSCs to highlight that these cells are promising targets for disease modeling, autologous cell therapy, and precision medicine. Take the shortcut: from iPSC to iNSCForced expression of lineage-specific transcription factors (TFs) has been shown to reprogram the developmental potential of various somatic cell types e.g. by inducing pluripotency [1]. The seminal breakthrough of fibroblast reprogramming into iPSCs offers a novel experimental tool to generate patient-specific cells for developmental studies and diverse biomedical applications, such as disease modeling and cell therapy. Since then, efficiency and robustness of reprogramming protocols have been substantially improved, but the derivation of patient-specific iPSCs remains a lengthy and cumbersome procedure. Moreover, clinical applications require subsequent redifferentiation of iPSCs into the cell type of interest, which is inefficient and risky because transplanted undifferentiated iPSCs are tumorigenic. In the shadow of iPSC-type reprogramming, second-generation reprogramming paradigms have been developed to bypass the pluripotency state Abbreviations

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Section: Functional Characterization Of Insc-derived Neuronsmentioning

confidence: 99%

Section: Transcription Factors Employed In Insc Generationmentioning

confidence: 99%

Section: Transcription Factors Employed In Insc Generationmentioning

confidence: 99%

Section: Functional Characterization Of Insc-derived Neuronsmentioning

confidence: 99%

Section: Functional Characterization Of Insc-derived Neuronsmentioning

confidence: 99%

See 3 more Smart Citations

Take the shortcut – direct conversion of somatic cells into induced neural stem cells and their biomedical applications

et al. 2019

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Studying Human Neurological Disorders Using Induced Pluripotent Stem Cells: From 2D Monolayer to 3D Organoid and Blood Brain Barrier Models

Logan

Arzua

Canfield

et al. 2019

Comprehensive Physiology

103

145

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Neurological disorders have emerged as a predominant healthcare concern in recent years due to their severe consequences on quality of life and prevalence throughout the world. Understanding the underlying mechanisms of these diseases and the interactions between different brain cell types is essential for the development of new therapeutics. Induced pluripotent stem cells (iPSCs) are invaluable tools for neurological disease modeling, as they have unlimited self-renewal and differentiation capacity. Mounting evidence shows: 1) various brain cells can be generated from iPSCs in 2-dimensional (2D) monolayer cultures; 2) further advances in 3D culture systems have led to the differentiation of iPSCs into organoids with multiple brain cell types and specific brain regions. These 3D organoids have gained widespread attention as in vitro tools to recapitulate complex features of the brain, and 3) Complex interactions between iPSC-derived brain cell types can recapitulate physiological and pathological conditions of blood-brain barrier (BBB). As iPSCs can be generated from diverse patient populations, researchers have effectively applied 2D, 3D and BBB models to recapitulate genetically complex neurological disorders and reveal novel insights into molecular and genetic mechanisms of neurological disorders. In this review, we describe recent progress in the generation of 2D, 3D and BBB models from iPSCs and further discuss their limitations, advantages, and future ventures. This review also covers the current status of applications of 2D, 3D and BBB models in drug screening, precision medicine, and modeling a wide range of neurological diseases (e.g., neurodegenerative diseases, neurodevelopmental disorders, brain injury, and neuropsychiatric disorders).

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Direct conversion of human fibroblasts into therapeutically active vascular wall-typical mesenchymal stem cells

Steens

Unger

Klar

et al. 2019

Cell. Mol. Life Sci.

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Cell-based therapies using adult stem cells are promising options for the treatment of a number of diseases including autoimmune and cardiovascular disorders. Among these, vascular wall-derived mesenchymal stem cells (VW-MSCs) might be particularly well suited for the protection and curative treatment of vascular damage because of their tissue-specific action. Here we report a novel method for the direct conversion of human skin fibroblasts towards MSCs using a VW-MSC-specific gene code (HOXB7, HOXC6 and HOXC8) that directs cell fate conversion bypassing pluripotency. This direct programming approach using either a self-inactivating (SIN) lentiviral vector expressing the VW-MSC-specific HOX-code or a tetracyclinecontrolled Tet-On system for doxycycline-inducible gene expressions of HOXB7, HOXC6 and HOXC8 successfully mediated the generation of VW-typical MSCs with classical MSC characteristics in vitro and in vivo. The induced VW-MSCs (iVW-MSCs) fulfilled all criteria of MSCs as defined by the International Society for Cellular Therapy (ISCT). In terms of multipotency and clonogenicity, which are important specific properties to discriminate MSCs from fibroblasts, iVW-MSCs behaved like primary ex vivo isolated VW-MSCs and shared similar molecular and DNA methylation signatures. With respect to their therapeutic potential, these cells suppressed lymphocyte proliferation in vitro, and protected mice against vascular damage in a mouse model of radiation-induced pneumopathy in vivo, as well as ex vivo cultured human lung tissue. The feasibility to obtain patient-specific VW-MSCs from fibroblasts in large amounts by a direct conversion into induced VW-MSCs could potentially open avenues towards novel, MSC-based therapies.

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Direct Conversion of Human Fibroblasts into Neural Progenitors Using Transcription Factors Enriched in Human ESC-Derived Neural Progenitors

Cited by 34 publications

References 35 publications

Take the shortcut – direct conversion of somatic cells into induced neural stem cells and their biomedical applications

Take the shortcut – direct conversion of somatic cells into induced neural stem cells and their biomedical applications

Studying Human Neurological Disorders Using Induced Pluripotent Stem Cells: From 2D Monolayer to 3D Organoid and Blood Brain Barrier Models

Direct conversion of human fibroblasts into therapeutically active vascular wall-typical mesenchymal stem cells

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