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      Direct Conversion of Human Fibroblasts to Induced Serotonergic Neurons

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          Abstract

          Serotonergic (5HT) neurons exert diverse and widespread functions in the brain. Dysfunction of the serotonergic system gives rise to a variety of mental illnesses including depression, anxiety, obsessive compulsive disorder, autism and eating disorders. Here we show that human primary fibroblasts were directly converted to induced serotonergic (i5HT) neurons by the expression of Ascl1, Foxa2, Lmx1b and FEV. The transdifferentiation was enhanced by p53 knockdown and appropriate culture conditions including hypoxia. The i5HT neurons expressed markers for mature serotonergic neurons, had Ca 2+− dependent 5HT release and selective 5HT uptake, exhibited spontaneous action potentials and spontaneous excitatory postsynaptic currents. Application of serotonin significantly increased the firing rate of spontaneous action potentials, demonstrating the functional utility of i5HT neurons for studying serotonergic neurotransmission. The availability of human i5HT neurons will be very useful for research and drug discovery on many serotonin-related mental disorders.

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          Suppression of induced pluripotent stem cell generation by the p53-p21 pathway.

          Hyenjong Hong, Kazutoshi Takahashi, Tomoko Ichisaka … (2009)
          Induced pluripotent stem (iPS) cells can be generated from somatic cells by the introduction of Oct3/4 (also known as Pou5f1), Sox2, Klf4 and c-Myc, in mouse and in human. The efficiency of this process, however, is low. Pluripotency can be induced without c-Myc, but with even lower efficiency. A p53 (also known as TP53 in humans and Trp53 in mice) short-interfering RNA (siRNA) was recently shown to promote human iPS cell generation, but the specificity and mechanisms remain to be determined. Here we report that up to 10% of transduced mouse embryonic fibroblasts lacking p53 became iPS cells, even without the Myc retrovirus. The p53 deletion also promoted the induction of integration-free mouse iPS cells with plasmid transfection. Furthermore, in the p53-null background, iPS cells were generated from terminally differentiated T lymphocytes. The suppression of p53 also increased the efficiency of human iPS cell generation. DNA microarray analyses identified 34 p53-regulated genes that are common in mouse and human fibroblasts. Functional analyses of these genes demonstrate that the p53-p21 pathway serves as a barrier not only in tumorigenicity, but also in iPS cell generation.
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            Linking the p53 tumor suppressor pathway to somatic cell reprogramming

            Teruhisa Kawamura, Jotaro Suzuki, Yunyuan Wang … (2009)
            Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes1–8, but the low frequency and tendency to induce malignant transformation9 compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting reprogramming efficiency in somatic cells. We show that reprogramming factors can activate the p53 pathway. Reducing signaling to p53 by expressing a mutated version of one of its negative regulators, by deleting or silencing p53 or its target gene, p21, or by antagonizing apoptosis enhanced three factor (Oct4/Sox2/Klf4)-mediated reprogramming of mouse fibroblasts. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline transmitting chimeric mice using only Oct4 and Sox2. Furthermore, silencing of p53 significantly increased the reprogramming efficiency of human somatic cells. These results provide insights into reprogramming mechanisms and suggest new routes to more efficient reprogramming while minimizing the use of oncogenes.
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              Immortalization eliminates a roadblock during cellular reprogramming into iPS cells.

              Jochen Utikal, Jose M. Polo, Matthias Stadtfeld … (2009)
              The overexpression of defined transcription factors in somatic cells results in their reprogramming into induced pluripotent stem (iPS) cells. The extremely low efficiency and slow kinetics of in vitro reprogramming suggest that further rare events are required to generate iPS cells. The nature and identity of these events, however, remain elusive. We noticed that the reprogramming potential of primary murine fibroblasts into iPS cells decreases after serial passaging and the concomitant onset of senescence. Consistent with the notion that loss of replicative potential provides a barrier for reprogramming, here we show that cells with low endogenous p19(Arf) (encoded by the Ink4a/Arf locus, also known as Cdkn2a locus) protein levels and immortal fibroblasts deficient in components of the Arf-Trp53 pathway yield iPS cell colonies with up to threefold faster kinetics and at a significantly higher efficiency than wild-type cells, endowing almost every somatic cell with the potential to form iPS cells. Notably, the acute genetic ablation of Trp53 (also known as p53) in cellular subpopulations that normally fail to reprogram rescues their ability to produce iPS cells. Our results show that the acquisition of immortality is a crucial and rate-limiting step towards the establishment of a pluripotent state in somatic cells and underscore the similarities between induced pluripotency and tumorigenesis.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9607835
                Journal ID (pubmed-jr-id): 20545
                Journal ID (nlm-ta): Mol Psychiatry
                Journal ID (iso-abbrev): Mol. Psychiatry
                Title: Molecular psychiatry
                ISSN (Print): 1359-4184
                ISSN (Electronic): 1476-5578
                Publication date Nihms-submitted: 23 June 2015
                Publication date (Electronic): 28 July 2015
                Publication date (Print): January 2016
                Publication date PMC-release: 01 July 2016
                Volume: 21
                Issue: 1
                Pages: 62-70
                Affiliations
                [1 ] Department of Neurology & Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
                [2 ] Veterans Affairs Western New York Healthcare System, Buffalo, NY 14215, USA
                [3 ] Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York 14214, USA
                Author notes
                [* ] To whom correspondence should be addressed: Jian Feng, Ph.D., Department of Physiology and Biophysics, State University of New York at Buffalo, 124 Sherman Hall, Buffalo, NY 14214, Phone: 1-716-829-2345, Fax: 1-716-829-2699, jianfeng@ 123456buffalo.edu
                Shengdi Chen, M.D., Department of Neurology & Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China, Phone: 86-21-6445-4473, Fax: 86-21-6445-4473, chen_sd@ 123456medmail.com.cn
                Article
                Manuscript ID: NIHMS701897
                DOI: 10.1038/mp.2015.101
                PMC ID: 4518549
                PubMed ID: 26216300
                SO-VID: 923bc95a-bb2e-41f1-ab6f-9ecef94bb289
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                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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                ScienceOpen disciplines: Molecular medicine
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                ScienceOpen disciplines: Molecular medicine

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