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      Lens regeneration using endogenous stem cells with gain of visual function

      research-article
      1 , 1 , 2 , 1 , 1 , 1 , 3 , 3 , 4 , 5 , 3 , 6 , 2 , 7 , 2 , 2 , 2 , 3 , 4 , 8 , 2 , 2 , 1 , 1 , 2 , 2 , 4 , 1 , 1 , 2 , 2 , 1 , 1 , 2 , 2 , 1 , 2 , 2 , 1 , 2 , 2 , 2 , 2 , 5 , 7 , 1 , 2 , 3 , 9 , 1
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          Abstract

          The repair and regeneration of tissues using endogenous stem cells represents an ultimate goal in regenerative medicine. To our knowledge, human lens regeneration has not yet been demonstrated. Currently, the only treatment for cataracts, the leading cause of blindness worldwide, is to extract the cataractous lens and implant an artificial intraocular lens. However, this procedure poses notable risks of complications. Here we isolate lens epithelial stem/progenitor cells (LECs) in mammals and show that Pax6 and Bmi1 are required for LEC renewal. We design a surgical method of cataract removal that preserves endogenous LECs and achieves functional lens regeneration in rabbits and macaques, as well as in human infants with cataracts. Our method differs conceptually from current practice, as it preserves endogenous LECs and their natural environment maximally, and regenerates lenses with visual function. Our approach demonstrates a novel treatment strategy for cataracts and provides a new paradigm for tissue regeneration using endogenous stem cells.

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          Most cited references26

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          Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety.

          The glucocorticoid receptor (Gr, encoded by the gene Grl1) controls transcription of target genes both directly by interaction with DNA regulatory elements and indirectly by cross-talk with other transcription factors. In response to various stimuli, including stress, glucocorticoids coordinate metabolic, endocrine, immune and nervous system responses and ensure an adequate profile of transcription. In the brain, Gr has been proposed to modulate emotional behaviour, cognitive functions and addictive states. Previously, these aspects were not studied in the absence of functional Gr because inactivation of Grl1 in mice causes lethality at birth (F.T., C.K. and G.S., unpublished data). Therefore, we generated tissue-specific mutations of this gene using the Cre/loxP -recombination system. This allowed us to generate viable adult mice with loss of Gr function in selected tissues. Loss of Gr function in the nervous system impairs hypothalamus-pituitary-adrenal (HPA)-axis regulation, resulting in increased glucocorticoid (GC) levels that lead to symptoms reminiscent of those observed in Cushing syndrome. Conditional mutagenesis of Gr in the nervous system provides genetic evidence for the importance of Gr signalling in emotional behaviour because mutant animals show an impaired behavioural response to stress and display reduced anxiety.
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            Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells.

            A central issue in stem cell biology is to understand the mechanisms that regulate the self-renewal of haematopoietic stem cells (HSCs), which are required for haematopoiesis to persist for the lifetime of the animal. We found that adult and fetal mouse and adult human HSCs express the proto-oncogene Bmi-1. The number of HSCs in the fetal liver of Bmi-1-/- mice was normal. In postnatal Bmi-1-/- mice, the number of HSCs was markedly reduced. Transplanted fetal liver and bone marrow cells obtained from Bmi-1-/- mice were able to contribute only transiently to haematopoiesis. There was no detectable self-renewal of adult HSCs, indicating a cell autonomous defect in Bmi-1-/- mice. A gene expression analysis revealed that the expression of stem cell associated genes, cell survival genes, transcription factors, and genes modulating proliferation including p16Ink4a and p19Arf was altered in bone marrow cells of the Bmi-1-/- mice. Expression of p16Ink4a and p19Arf in normal HSCs resulted in proliferative arrest and p53-dependent cell death, respectively. Our results indicate that Bmi-1 is essential for the generation of self-renewing adult HSCs.
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              Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells.

              An emerging concept in the field of cancer biology is that a rare population of 'tumour stem cells' exists among the heterogeneous group of cells that constitute a tumour. This concept, best described with human leukaemia, indicates that stem cell function (whether normal or neoplastic) might be defined by a common set of critical genes. Here we show that the Polycomb group gene Bmi-1 has a key role in regulating the proliferative activity of normal stem and progenitor cells. Most importantly, we provide evidence that the proliferative potential of leukaemic stem and progenitor cells lacking Bmi-1 is compromised because they eventually undergo proliferation arrest and show signs of differentiation and apoptosis, leading to transplant failure of the leukaemia. Complementation studies showed that Bmi-1 completely rescues these proliferative defects. These studies therefore indicate that Bmi-1 has an essential role in regulating the proliferative activity of both normal and leukaemic stem cells.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                7 July 2018
                09 March 2016
                17 March 2016
                26 July 2018
                : 531
                : 7594
                : 323-328
                Affiliations
                [1 ]State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
                [2 ]Shiley Eye Institute, Institute for Engineering in Medicine, Institute for Genomic Medicine, University of California, San Diego, La Jolla, California 92093, USA
                [3 ]Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China
                [4 ]Guangzhou KangRui Biological Pharmaceutical Technology Company, Guangzhou 510005, China
                [5 ]Howard Hughes Medical Institute, Children’s Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
                [6 ]Department of Ophthalmology, West China Hospital, Sichuan University, Sichuan 610041, China
                [7 ]Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
                [8 ]Clinical and Translational Research Institute, University of California, San Diego, La Jolla, California 92093, USA
                [9 ]Veterans Administration Healthcare System, San Diego, California 92093, USA
                Author notes
                Correspondence and requests for materials should be addressed to Y.L. ( yzliu62@ 123456yahoo.com ) or K.Z. ( kang.zhang@ 123456gmail.com )
                [*]

                These authors contributed equally to this work.

                Article
                PMC6061995 PMC6061995 6061995 nihpa977394
                10.1038/nature17181
                6061995
                26958831
                c174cdb0-4e09-4b98-a658-86dce2dbba29

                Reprints and permissions information is available at www.nature.com/reprints.

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