| 1. |
- Johard, Helena, et al.
(författare)
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HCN Channel Activity Balances Quiescence and Proliferation in Neural Stem Cells and Is a Selective Target for Neuroprotection During Cancer Treatment
- 2020
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Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 18:10, s. 1522-1533
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Tidskriftsartikel (refereegranskat)abstract
- Children suffering from neurologic cancers undergoing chemotherapy and radiotherapy are at high risk of reduced neurocognitive abilities likely via damage to proliferating neural stem cells (NSC). Therefore, strategies to protect NSCs are needed. We argue that induced cell-cycle arrest/quiescence in NSCs during cancer treatment can represent such a strategy. Here, we show that hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels are dynamically expressed over the cell cycle in NSCs, depolarize the membrane potential, underlie spontaneous calcium oscillations and are required to maintain NSCs in the actively proliferating pool. Hyperpolarizing pharmacologic inhibition of HCN channels during exposure to ionizing radiation protects NSCs cells in neurogenic brain regions of young mice. In contrast, brain tumor-initiating cells, which also express HCN channels, remain proliferative during HCN inhibition.
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| 2. |
- Omelyanenko, Anna
(författare)
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Ionic modulators of stem cell state
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tissue generation during development and maintenance throughout life relies on the proliferation and sequential specification of a group of cells. Stem cells are defined by the properties of self-renewal (division to produce daughter cells equipotent to the mother) and differentiation (division where at least one daughter is of a more restricted potential). In adult systems, two additional states - quiescence, a dormant state of infrequent proliferation, and activation, a state of increased proliferation, are described. Regulation of these states is a key determinant of health and fitness on a tissue and organism level, as it ensures proper development and regeneration. The aim of this thesis is to investigate how another key system at the cellular level – regulation of ion availability – can modulate cell states of embryonic and adult stem cells. In paper I the effect of lithium chloride (LiCl) on juvenile mouse neural stem progenitor cells (NSPCs) from the subgranular zone (SGZ) of the hippocampus was investigated. Under maintenance conditions, treatment with LiCl increased NSPC proliferation, reducing the fraction of cells in G0/G1. Pre-treatment of NSPCs with LiCl prior to ionizing radiation (IR) exposure reduced DNA damage response activation, and attenuated the IR-induced G1 block, restoring proliferation, although cell death was not reduced. In paper II the effect of ZD7288, a specific blocker of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, on mouse embryonic stem cell (ESCs) was examined. The blocker attenuated proliferation by extending G1 and S phases. This did not compromise pluripotency, but facilitated spontaneous serum-induced differentiation while reducing the efficiency of directed differentiation towards the neuronal lineage. In paper III expression of HCN family channels and effects of their inhibition in adult NSPCs were described. Hcn2 and Hcn3 are expressed throughout the NSPC hierarchy, but only functional in S and G2/M phases. HCN inhibition or knockdown attenuated proliferation due to a reversible G0/G1 accumulation which was accompanied by alterations in activation marker expression, metabolism, and the molecular clock network. A small molecular agonist of Rev-erb-α, a clock component, recapitulated the proliferative effects. HCN inhibition-induced G0/G1 block was shown to have a protective effect during IR exposure of juvenile mice, reducing apoptosis and maintaining proliferation. In conclusion, lithium, which is proposed to inhibit a number of enzymes by replacing magnesium as a cofactor, and HCN currents, which are involved in regulation of the electrochemical state of the cell, were shown to modulate stem cell state. This suggests that further investigation of these and other ionic modulators is warranted, both for therapy development and in the interests of basic science.
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| 3. |
- Zanni, Giulia, et al.
(författare)
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Lithium increases proliferation of hippocampal neural stem/progenitor cells and rescues irradiation-induced cell cycle arrest in vitro.
- 2015
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Radiotherapy in children causes debilitating cognitive decline, partly linked to impaired neurogenesis. Irradiation targets primarily cancer cells but also endogenous neural stem/progenitor cells (NSPCs) leading to cell death or cell cycle arrest. Here we evaluated the effects of lithium on proliferation, cell cycle and DNA damage after irradiation of young NSPCs in vitro.NSPCs were treated with 1 or 3 mM LiCl and we investigated proliferation capacity (neurosphere volume and bromodeoxyuridine (BrdU) incorporation). Using flow cytometry, we analysed apoptosis (annexin V), cell cycle (propidium iodide) and DNA damage (γH2AX) after irradiation (3.5 Gy) of lithium-treated NSPCs.Lithium increased BrdU incorporation and, dose-dependently, the number of cells in replicative phase as well as neurosphere growth. Irradiation induced cell cycle arrest in G1 and G2/M phases. Treatment with 3 mM LiCl was sufficient to increase NSPCs in S phase, boost neurosphere growth and reduce DNA damage. Lithium did not affect the levels of apoptosis, suggesting that it does not rescue NSPCs committed to apoptosis due to accumulated DNA damage.Lithium is a very promising candidate for protection of the juvenile brain from radiotherapy and for its potential to thereby improve the quality of life for those children who survive their cancer.
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