Direct somatic lineage conversion

Tanabe, Koji; Haag, Daniel; Wernig, Marius

doi:10.1098/rstb.2014.0368

Cited by 25 publications

(22 citation statements)

References 108 publications

(85 reference statements)

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“…During normal development, the only cells with the potential to change lineage identity are uncommitted stem and progenitor cells. Most reprogramming studies use heterogeneous fibroblasts as donor cells, raising the question as to whether the transdifferentiation capability is limited to undifferentiated progenitor cells (29). Our results unequivocally show that terminally differentiated cells can be transdifferentiated into another, distantly related somatic lineage.…”

Section: Discussionmentioning

confidence: 50%

Transdifferentiation of human adult peripheral blood T cells into neurons

Tanabe

Ang

Chanda

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Human cell models for disease based on induced pluripotent stem (iPS) cells have proven to be powerful new assets for investigating disease mechanisms. New insights have been obtained studying single mutations using isogenic controls generated by gene targeting. Modeling complex, multigenetic traits using patient-derived iPS cells is much more challenging due to line-to-line variability and technical limitations of scaling to dozens or more patients. Induced neuronal (iN) cells reprogrammed directly from dermal fibroblasts or urinary epithelia could be obtained from many donors, but such donor cells are heterogeneous, show interindividual variability, and must be extensively expanded, which can introduce random mutations. Moreover, derivation of dermal fibroblasts requires invasive biopsies. Here we show that human adult peripheral blood mononuclear cells, as well as defined purified T lymphocytes, can be directly converted into fully functional iN cells, demonstrating that terminally differentiated human cells can be efficiently transdifferentiated into a distantly related lineage. T cell-derived iN cells, generated by nonintegrating gene delivery, showed stereotypical neuronal morphologies and expressed multiple pan-neuronal markers, fired action potentials, and were able to form functional synapses. These cells were stable in the absence of exogenous reprogramming factors. Small molecule addition and optimized culture systems have yielded conversion efficiencies of up to 6.2%, resulting in the generation of >50,000 iN cells from 1 mL of peripheral blood in a single step without the need for initial expansion. Thus, our method allows the generation of sufficient neurons for experimental interrogation from a defined, homogeneous, and readily accessible donor cell population.

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Section: Discussionmentioning

confidence: 50%

Transdifferentiation of human adult peripheral blood T cells into neurons

Tanabe

Ang

Chanda

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…This direct reprogramming process is often referred to as “trans-differentiation.” In fact, trans-differentiation was first successfully demonstrated in 1987 when a single gene MyoD was reported to directly convert fibroblasts into myoblasts (Davis et al, 1987). Today, skin fibroblast cells can be directly trans-differentiated into many cell types including cardiomyocytes and neurons (Sadahiro et al, 2015; Tanabe et al, 2015; Vierbuchen et al, 2010; Xu et al, 2015) (Fig. 1).…”

Section: Ips Cell Technology and Trans-differentiation In Vitromentioning

confidence: 99%

In Vivo Reprogramming for CNS Repair: Regenerating Neurons from Endogenous Glial Cells

Chen

2016

Neuron

133

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Neuroregeneration in the central nervous system (CNS) has proven to be difficult despite decades of research. The old dogma that CNS neurons cannot be regenerated in the adult mammalian brain has been overturned; however, endogenous adult neurogenesis appears to be insufficient for brain repair. Stem cell therapy once held promise for generating large quantities of neurons in the CNS, but immunorejection and long-term functional integration remain major hurdles. In this perspective, we discuss the use of in vivo reprogramming as an emerging technology to regenerate functional neurons from endogenous glial cells inside the brain and spinal cord. Besides the CNS, in vivo reprogramming has been demonstrated successfully in the pancreas, heart and liver, and may be adopted in other organs. Although challenges remain for translating this technology into clinical therapies, we anticipate that in vivo reprogramming may revolutionize regenerative medicine by using a patient’s own internal cells for tissue repair.

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“…A faster approach to utilising primary human cells is direct reprogramming to the differentiated cell type of interest, thereby bypassing the generation of true pluripotent cells as intermediates ( Vierbuchen and Wernig, 2011 ; Tanabe et al, 2015 ). This approach generally exploits knowledge about transcriptional and hormonal regulation of differentiation, and potentially offers the advantages of fast dynamics and high efficiency, making relatively rapid screening of numerous individuals feasible ( Vierbuchen and Wernig, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of human dermal fibroblasts directly reprogrammed to adipocyte-like cells as a metabolic disease model

Chen

Goh

Rocha

et al. 2017

Disease Models &Amp; Mechanisms

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Adipose tissue is the primary tissue affected in most single gene forms of severe insulin resistance, and growing evidence has implicated it as a site at which many risk alleles for insulin resistance identified in population-wide studies might exert their effect. There is thus increasing need for human adipocyte models in which to interrogate the function of known and emerging genetic risk variants. However, primary adipocyte cultures, existing immortalised cell lines and stem-cell based models all have significant biological or practical limitations. In an attempt to widen the repertoire of human cell models in which to study adipocyte-autonomous effects of relevant human genetic variants, we have undertaken direct reprogramming of skin fibroblasts to adipocyte-like cells by employing an inducible recombinant lentivirus overexpressing the master adipogenic transcription factor PPARγ2. Doxycycline-driven expression of PPARγ2 and adipogenic culture conditions converted dermal fibroblasts into triglyceride-laden cells within days. The resulting cells recapitulated most of the crucial aspects of adipocyte biology in vivo, including the expression of mature adipocyte markers, secreted high levels of the adipokine adiponectin, and underwent lipolysis when treated with isoproterenol/3-isobutyl-1-methylxanthine (IBMX). They did not, however, exhibit insulin-inducible glucose uptake, and withdrawal of doxycycline produced rapid delipidation and loss of adipogenic markers. This protocol was applied successfully to a panel of skin cells from individuals with monogenic severe insulin resistance; however, surprisingly, even cell lines harbouring mutations causing severe, generalised lipodystrophy accumulated large lipid droplets and induced adipocyte-specific genes. The direct reprogramming protocol of human dermal fibroblasts to adipocyte-like cells we established is simple, fast and efficient, and has the potential to generate cells which can serve as a tool to address some, though not all, aspects of adipocyte function in the presence of endogenous disease-causing mutations.

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Direct somatic lineage conversion

Cited by 25 publications

References 108 publications

Transdifferentiation of human adult peripheral blood T cells into neurons

Transdifferentiation of human adult peripheral blood T cells into neurons

In Vivo Reprogramming for CNS Repair: Regenerating Neurons from Endogenous Glial Cells

Evaluation of human dermal fibroblasts directly reprogrammed to adipocyte-like cells as a metabolic disease model

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