Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress

Howard Hughes Medical Institute, Department of Internal Medicine, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA.
Nature Cell Biology (Impact Factor: 19.68). 10/2010; 12(10):999-1006. DOI: 10.1038/ncb2101
Source: PubMed


To better understand the mechanisms that regulate stem cell identity and function, we sought to identify genes that are preferentially expressed by stem cells and critical for their function in multiple tissues. Prdm16 is a transcription factor that regulates leukaemogenesis, palatogenesis and brown-fat development, but which was not known to be required for stem cell function. We demonstrate that Prdm16 is preferentially expressed by stem cells throughout the nervous and haematopoietic systems and is required for their maintenance. In the haematopoietic and nervous systems, Prdm16 deficiency led to changes in the levels of reactive oxygen species (ROS), depletion of stem cells, increased cell death and altered cell-cycle distribution. In neural stem/progenitor cells, Prdm16 binds to the Hgf promoter, and Hgf expression declined in the absence of Prdm16. Addition of recombinant HGF to Prdm16-deficient neural stem cells in cell culture reduced the depletion of these cells and partially rescued the increase in ROS levels. Administration of the anti-oxidant, N-acetyl-cysteine, to Prdm16-deficient mice partially rescued defects in neural stem/progenitor cell function and neural development. Prdm16 therefore promotes stem cell maintenance in multiple tissues, partly by modulating oxidative stress.

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Available from: Boaz P Levi, Jul 18, 2014
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    • "Adult stem cells have widely been identified in different tissues/ organs, and known to persist throughout the lifetime for maintaining the homeostasis of organism, including the physiological turnover and the repair/regeneration in case of damage [1]. Several instructive genetic mouse models have recently demonstrated the unique susceptibility of stem cells to perturbations in metabolic or redox homeostasis [2] [3] [4]. In contrast, many recent studies have found that these adult stem cells likely to be highly resistant to various stresses, including oxidative stress [5] [6]. "
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    ABSTRACT: Although stem cells are generally thought to be resistant to oxidative stress, the fact and in detail molecular mechanism are still to be clearly identified. We herein tried to understand the overall characterization of redox regulatory signaling in hematopoietic stem cells. We purified c-kit-positive hematopoietic stem/progenitor cells from the bone marrow of healthy mice, and then evaluated their redox regulatory property. Compared to the c-kit-negative matured mononuclear cells, c-kit-positive stem/progenitor cells showed lower basic levels of intracellular reactive oxygen species, faster clearance of the accumulated intracellular reactive oxygen species, and higher resistant to oxidative stress. An overall view on the gene expression profile associated with redox regulation showed to be widely differed between cell types. We confirmed that the c-kit-positive stem/progenitor cells expressed significantly higher of Nox1 and catalase, but less of lactoperoxidase than these matured mononuclear cells. Our data suggests that stem cells keep specific redox regulatory property for defensing against oxidative stress.
    Biochemical and Biophysical Research Communications 10/2014; 454(3). DOI:10.1016/j.bbrc.2014.10.090 · 2.30 Impact Factor
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    • "In addition, excessive ROS drives stem cells out of quiescence and eventually lead to depletion of stem-cell reserves (Rossi et al, 2008). Animal models of precocious stem-cell depletion or dysfunction consistently emphasize the role of key molecules involved in oxidative defense in maintaining stem-cell reserves: Atm (Ito et al, 2004), Tsc1 (Chen et al, 2008), Prdm16 (Chuikov et al, 2010), and FoxO3 (Miyamoto et al, 2007; Yalcin et al, 2008; Paik et al, 2009; Renault et al, 2009). Furthermore, stem cells have intrinsic antioxidant and stress-resistance systems that maintain low levels of ROS (Ivanova et al, 2002; Ramalho-Santos et al, 2002). "
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    ABSTRACT: Forkhead Box O (FoxO) transcription factors act in adult stem cells to preserve their regenerative potential. Previously, we reported that FoxO maintains the long-term proliferative capacity of neural stem/progenitor cells (NPCs), and that this occurs, in part, through the maintenance of redox homeostasis. Herein, we demonstrate that among the FoxO3-regulated genes in NPCs are a host of enzymes in central carbon metabolism that act to combat reactive oxygen species (ROS) by directing the flow of glucose and glutamine carbon into defined metabolic pathways. Characterization of the metabolic circuit observed upon loss of FoxO3 revealed a drop in glutaminolysis and filling of the tricarboxylic acid (TCA) cycle. Additionally, we found that glucose uptake, glucose metabolism and oxidative pentose phosphate pathway activity were similarly repressed in the absence of FoxO3. Finally, we demonstrate that impaired glucose and glutamine metabolism compromises the proliferative potential of NPCs and that this is exacerbated following FoxO3 loss. Collectively, our findings show that a FoxO3-dependent metabolic programme supports redox balance and the neurogenic potential of NPCs.
    The EMBO Journal 09/2013; 32(19). DOI:10.1038/emboj.2013.186 · 10.43 Impact Factor
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    • "Cells lacking expression of PRDM16 exhibit increased cell death so overexpression is expected to lead to an over-representation of clones with proviral insertions near PRDM16. PRDM16 may be in a gene network involving MDS1/EVI1, GATA2, and other genes that affect HSCs [65,66]. Thus, dysregulation of the PRDM16 gene locus could have an effect on the signaling pathways for other genes involved in normal hematopoiesis, expanding the effects of dysregulation of the PRDM16 gene. "
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    ABSTRACT: Hematopoietic stem cell (HSC) therapy using replication-incompetent retroviral vectors is a promising approach to provide life-long correction for genetic defects. HSC gene therapy clinical studies have resulted in functional cures for several diseases, but in some studies clonal expansion or leukemia has occurred. This is due to the dyregulation of endogenous host gene expression from vector provirus insertional mutagenesis. Insertional mutagenesis screens using replicating retroviruses have been used extensively to identify genes that influence oncogenesis. However, retroviral mutagenesis screens can also be used to determine the role of genes in biological processes such as stem cell engraftment. The aim of this review is to describe the potential for vector insertion site data from gene therapy studies to provide novel insights into mechanisms of HSC engraftment. In HSC gene therapy studies dysregulation of host genes by replication-incompetent vector proviruses may lead to enrichment of repopulating clones with vector integrants near genes that influence engraftment. Thus, data from HSC gene therapy studies can be used to identify novel candidate engraftment genes. As HSC gene therapy use continues to expand, the vector insertion site data collected will be of great interest to help identify novel engraftment genes and may ultimately lead to new therapies to improve engraftment.
    09/2013; 2013(Suppl 3). DOI:10.4172/2157-7633.S3-004
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