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      Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium

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          Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age.

          A diminished capacity to maintain tissue homeostasis is a central physiological characteristic of ageing. As stem cells regulate tissue homeostasis, depletion of stem cell reserves and/or diminished stem cell function have been postulated to contribute to ageing. It has further been suggested that accumulated DNA damage could be a principal mechanism underlying age-dependent stem cell decline. We have tested these hypotheses by examining haematopoietic stem cell reserves and function with age in mice deficient in several genomic maintenance pathways including nucleotide excision repair, telomere maintenance and non-homologous end-joining. Here we show that although deficiencies in these pathways did not deplete stem cell reserves with age, stem cell functional capacity was severely affected under conditions of stress, leading to loss of reconstitution and proliferative potential, diminished self-renewal, increased apoptosis and, ultimately, functional exhaustion. Moreover, we provide evidence that endogenous DNA damage accumulates with age in wild-type stem cells. These data are consistent with DNA damage accrual being a physiological mechanism of stem cell ageing that may contribute to the diminished capacity of aged tissues to return to homeostasis after exposure to acute stress or injury.
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            Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing.

            Mammalian ageing is associated with reduced regenerative capacity in tissues that contain stem cells. It has been proposed that this is at least partially caused by the senescence of progenitors with age; however, it has not yet been tested whether genes associated with senescence functionally contribute to physiological declines in progenitor activity. Here we show that progenitor proliferation in the subventricular zone and neurogenesis in the olfactory bulb, as well as multipotent progenitor frequency and self-renewal potential, all decline with age in the mouse forebrain. These declines in progenitor frequency and function correlate with increased expression of p16INK4a, which encodes a cyclin-dependent kinase inhibitor linked to senescence. Ageing p16INK4a-deficient mice showed a significantly smaller decline in subventricular zone proliferation, olfactory bulb neurogenesis, and the frequency and self-renewal potential of multipotent progenitors. p16INK4a deficiency did not detectably affect progenitor function in the dentate gyrus or enteric nervous system, indicating regional differences in the response of neural progenitors to increased p16INK4a expression during ageing. Declining subventricular zone progenitor function and olfactory bulb neurogenesis during ageing are thus caused partly by increasing p16INK4a expression.
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              Subepithelial telocytes are an important source of Wnts that supports intestinal crypts

              Tissues with rapid cellular turnover, such as the mammalian hematopoietic system or the intestinal epithelium, are dependent upon stem and progenitor cells, which through proliferation provide differentiated cells to maintain organismal health. Stem and progenitor cells, in turn, are thought to rely upon signals and growth factors provided by local niche cells to support their function and self-renewal. Several cell types have been proposed to provide the signals required for the proliferation and differentiation of the ISC in the crypt 1–6 . Here, we identify subepithelial telocytes as an important source of Wnt proteins, without which intestinal stem cells cannot proliferate and support epithelial renewal. Telocytes are large but rare mesenchymal cells that are marked by Foxl1 and PDGFRα expression and form a subepithelial plexus that extends from the stomach to the colon. While supporting the entire epithelium, Foxl1+ telocytes compartmentalize the production of Wnt ligands and inhibitors to enable localized pathway activation. Conditional gene ablation of Porcupine (Porcn), which is required for functional maturation of all Wnt proteins, in Foxl1+ telocytes causes rapid cessation of Wnt signaling to intestinal crypts, followed by loss of stem and transit amplifying cell proliferation and impaired epithelial renewal. Thus, Foxl1+ telocytes are an important source of niche signals to intestinal stem cells.
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                Author and article information

                Journal
                Nature
                Nature
                Springer Science and Business Media LLC
                0028-0836
                1476-4687
                July 10 2019
                Article
                10.1038/s41586-019-1383-0
                31292548
                f19512a3-ee2c-4c99-b489-58b3a289b39d
                © 2019

                http://www.springer.com/tdm

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