Iron overload impairs normal hematopoietic stem and progenitor cells through reactive oxygen species and shortens survival in myelodysplastic syndrome mice

Jin, Xin; He, Xiaohua; Cao, Xiaoli; Xu, Ping; Xing, Yi; Sui, Song-Nan; Wang, Luqiao; Meng, Jiayuan; Lu, Wenyi; Cui, Rui; Ni, Hongbo; Zhao, Mingfeng

doi:10.3324/haematol.2018.193128

Cited by 57 publications

(45 citation statements)

References 27 publications

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“…16 A previous study showed that iron overload could change the frequency and function of normal hematopoietic stem and progenitor cells, especially in erythroid cells. 17 Our findings are consistent with another study which found that iron overload may postpone hematopoietic recovery following BM transplantation, suggesting that iron overload may affect the hematopoietic microenvironment of BM. 18 Subsequently, observations revealed that colony formation, peripheral RBC counts and HGB concentration were reduced, while platelet counts were increased in response to iron overload after allo-HSCT.…”

Section: Allo-hsct In An Iron-overloaded Mice Negatively Impacts Susupporting

confidence: 93%

Iron overload as a risk factor for poor graft function following allogeneic hematopoietic stem cell transplantation

Lin

Chen

et al. 2020

The Kaohsiung J of Med Scie

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Hematological malignancies are increasingly treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Unfortunately, iron overload is a frequent adverse effect of allo-HSCT and is associated with poor prognosis. In the present study, we investigated hematopoiesis in iron-overloaded mice and elucidated the effects of iron overload on the bone marrow (BM) microenvironment. Ironoverloaded BALB/C mice were generated by injecting 20 mg/mL saccharated iron oxide intraperitoneally. Hematoxylin-eosin staining was performed to evaluate the effects of an iron overload in mice. BM cells obtained from C57BL/6 mice were transplanted into irradiated BALB/C mice (whole-body irradiation of 4 Gy, twice with a 4-hours interval) by tail vein injection. Two weeks after allo-HSCT, the hematopoietic reconstitution capacity was evaluated in recipients by colony-forming assays. Histopathological examinations showed brown-stained granular deposits, irregularly arranged lymphocytes in the liver tissues, and blue-stained blocks in the BM collected from mice received injections of high-dose saccharated iron oxide (20 mg/mL). Ironoverloaded mice showed more platelets, higher-hemoglobin (HGB) concentration, fewer granulocyte-macrophage colony-forming units (CFU-GM), erythrocyte colonyforming units (CFU-E), and mixed granulocyte/erythrocyte/monocyte/megakaryocyte colony-forming units (CFU-mix) than healthy mice. Iron-overloaded recipients presented with reduced erythrocytes and HGB concentration in peripheral blood, along with decreased marrow stroma cells, CFU-GM, CFU-E, and CFU-mix relative to healthy recipients. Taken together, our findings demonstrate that iron overload might alter the number of red blood cells after transplantation in mice by destroying the

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Section: Allo-hsct In An Iron-overloaded Mice Negatively Impacts Susupporting

confidence: 93%

Iron overload as a risk factor for poor graft function following allogeneic hematopoietic stem cell transplantation

Lin

Chen

et al. 2020

The Kaohsiung J of Med Scie

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“…Previous studies have indicated that iron homeostasis is crucial for various kinds of stem cell. For example, iron overload can impact the self‐renewal and function of hematopoietic stem cells and progenitor cells [23,24], whereas iron deficiency impairs the pluripotency of hESCs/hiPSCs [15]. Besides, it has been reported that iron deficiency inhibited the expression of stemness markers and spherogenesis in cancer stem cells [25].…”

Section: Discussionmentioning

confidence: 99%

Iron overload inhibits self‐renewal of human pluripotent stem cells via DNA damage and generation of reactive oxygen species

Han

Chen

et al. 2020

FEBS Open Bio

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Iron overload affects the cell cycle of various cell types, but the effect of iron overload on human pluripotent stem cells has not yet been reported. Here, we show that the proliferation capacities of human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) were significantly inhibited by ferric ammonium citrate (FAC) in a concentration‐dependent manner. In addition, deferoxamine protected hESCs/hiPSCs against FAC‐induced cell‐cycle arrest. However, iron overload did not affect pluripotency in hESCs/hiPSCs. Further, treatment of hiPSCs with FAC resulted in excess reactive oxygen species production and DNA damage. Collectively, our findings provide new insights into the role of iron homeostasis in the maintenance of self‐renewal in human pluripotent stem cells.

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“…Growing evidence has shown that iron homeostasis is critical for stem cells. For example, iron overload can affect the self‐renewal, frequency, and functioning of hematopoietic stem and progenitor cells . Thus far, little is known regarding the role of iron homeostasis in maintaining the biological property of PSCs.…”

Section: Introductionmentioning

confidence: 99%

Iron Homeostasis Determines Fate of Human Pluripotent Stem Cells Via Glycerophospholipids-Epigenetic Circuit

Han

et al. 2019

Stem Cells

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Iron homeostasis is crucial for a variety of biological processes, but the biological role of iron homeostasis in pluripotent stem cells (PSCs) remains largely unknown. The present study aimed to determine whether iron homeostasis is involved in maintaining the pluripotency of human PSCs (hPSCs). We found that the intracellular depletion of iron leads to a rapid downregulation of NANOG and a dramatic decrease in the self-renewal of hPSCs as well as spontaneous and nonspecific differentiation. Moreover, long-term depletion of iron can result in the remarkable cell death of hPSCs via apoptosis and necrosis pathways. Additionally, we found that the depletion of iron increased the activity of lipoprotein-associated phospholipase A2 (LP-PLA2) and the production of lysophosphatidylcholine, thereby suppressing NANOG expression by enhancer of zeste homolog 2-mediated trimethylation of histone H3 lysine 27. Consistently, LP-PLA2 inhibition abrogated iron depletion-induced loss of pluripotency and differentiation. Altogether, the findings of our study demonstrates that iron homeostasis, acting through glycerophospholipid metabolic pathway, is essential for the pluripotency and survival of hPSCs. STEM CELLS 2019;37:489-503 SIGNIFICANCE STATEMENTIron homeostasis is essential for various biological processes. In this study, it was first demonstrated that iron deficiency could severely impair the pluripotency and differentiation of hESCs/ hiPSCs through the downregulation of NANOG by LysoPC-mediated H3K27me3. In addition, long-term iron deficiency reduced the survival and promoted apoptosis in hESCs/hiPSCs. Findings provide novel insights into the underlying mechanisms of iron homeostasis in maintaining the pluripotency and self-renewal of hESCs/hiPSCs

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Iron overload impairs normal hematopoietic stem and progenitor cells through reactive oxygen species and shortens survival in myelodysplastic syndrome mice

Cited by 57 publications

References 27 publications

Iron overload as a risk factor for poor graft function following allogeneic hematopoietic stem cell transplantation

Iron overload as a risk factor for poor graft function following allogeneic hematopoietic stem cell transplantation

Iron overload inhibits self‐renewal of human pluripotent stem cells via DNA damage and generation of reactive oxygen species

Iron Homeostasis Determines Fate of Human Pluripotent Stem Cells Via Glycerophospholipids-Epigenetic Circuit

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