Deficiency of Antioxidative Paraoxonase 2 (Pon2) Leads to Increased Number of Phenotypic LT-HSCs and Disturbed Erythropoiesis

Deficiency of Antioxidative Paraoxonase 2 (Pon2) Leads to Increased Number of Phenotypic LT-HSCs and Disturbed Erythropoiesis

Background. Long-term hematopoietic stem cells (LT-HSCs) reside in bone marrow niches with tightly controlled reactive oxygen species (ROS) levels. ROS increase results into LT-HSC differentiation and stem cell exhaustion. Paraoxonase 2 (PON2) has been shown to be important for ROS control. Objectiv...

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Published in:Oxidative medicine and cellular longevity Vol. 2021; no. 1; p. 3917028
Main Authors: Spiecker, Lisa, Witte, Ines, Mehlig, Julia, Shah, Viral, Meyerhöfer, Markus, Haehnel, Patricia S., Petermann, Victoria, Schüler, Andrea, More, Piyush, Cabezas-Wallscheid, Nina, Horke, Sven, Pautz, Andrea, Daiber, Andreas, Sasca, Daniel, Kindler, Thomas, Kleinert, Hartmut
Format: Journal Article
Language:English
Published: United States Hindawi 2021
Hindawi Limited
Subjects:
Animals
Antioxidants - metabolism
Apoptosis
Aryldialkylphosphatase - deficiency
Aryldialkylphosphatase - metabolism
Cell culture
Cell Differentiation - physiology
Cell Line
Erythropoiesis - physiology
Hematology
Hematopoietic Stem Cells - enzymology
Hematopoietic Stem Cells - metabolism
Mice
Oxidative stress
Penicillin
Phenotype
Reactive Oxygen Species - metabolism
Stem cells
Germany
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Summary:Background. Long-term hematopoietic stem cells (LT-HSCs) reside in bone marrow niches with tightly controlled reactive oxygen species (ROS) levels. ROS increase results into LT-HSC differentiation and stem cell exhaustion. Paraoxonase 2 (PON2) has been shown to be important for ROS control. Objectives. We investigate the effects of inactivation of the PON2 gene on hematopoietic cell differentiation and activity. Methods and Results. In young mice with inactivated Pon2 gene (Pon2-/-, <3 months), we observed an increase of LT-HSCs and a reduced frequency of progenitor cells. In competitive transplantations, young Pon2-/- BM outcompeted WT BM at early time points. ROS levels were significantly increased in Pon2-/- whole BM, but not in Pon2-/- LT-HSCs. In more differentiated stages of hematopoiesis, Pon2 deficiency led to a misbalanced erythropoiesis both in physiologic and stress conditions. In older mice (>9 months), Pon2 depletion caused an increase in LT-HSCs as well as increased levels of granulocyte/macrophage progenitors (GMPs) and myeloid skewing, indicating a premature aging phenotype. No significant changes in ROS levels in old Pon2-/- LT- and short-term (ST-) HSCs were observed, but a significant reduction of spontaneous apoptotic cell death was measured. RNA-seq analysis in Pon2-/- LT-HSCs identified overrepresentation of genes involved in the C-X-C chemokine receptor type 4 (Cxcr4) signaling, suggesting compensatory mechanisms to overcome ROS-mediated accelerated aging in hematopoietic progenitor cells. Conclusions. In summary, our current data indicate that PON2 is involved in the regulation of HSC functions.
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Academic Editor: Liren Qian
ISSN:1942-0900
1942-0994
DOI:10.1155/2021/3917028