Heme oxygenase-1 protects bone marrow mesenchymal stem cells from iron overload through decreasing reactive oxygen species and promoting IL-10 generation
Introduction
Many blood system diseases, such as β-thalassemia, myelodysplastic syndrome (MDS), lead to hemoglobin reduction inducing severe anemia. Repeated blood transfusion is needed to alleviate anemia. However, the treatment often accumulates excessive iron in the body, resulting in iron overload (IO) [1]. Iron is an important element of growth and survival, but IO reduces hematopoiesis by reactive oxygen species (ROS)-mediated signaling proteins and excessive iron deposition, thereby promoting the apoptosis of bone marrow (BM) monocytes. Heme oxygenase-1 (HO-1) is the major rate-limiting enzyme in the metabolism of heme. It catalyzes the degradation of hemoglobin to free iron, carbon monoxide and bilirubin [8], [9], [10], [11], [12]. HO-1 elevation can protect cells by significantly reducing ROS production. Meanwhile, HO-1 can relieve IO in tissue by reducing cellular labile iron pool (LIP) level. Bone marrow mesenchymal stem cells (BMMSCs) are pluripotent non-hematopoietic progenitor cells with regenerative, anti-inflammatory and immunomodulatory capacities, and they differentiate into mesodermal cells (osteoblasts, chondrocytes, adipocytes, heart cells, etc.), ectodermal origin of cells neurons and endodermal origin of cells (hepatic oval cells) [7], [13], [14]. Interleukin 10 (IL-10) is secreted by BMMMSCs and produced by regulating anti-inflammatory effects [19], [20], [21], [22]. Increased secretion of IL-10 is a key factor in protecting cells from IO injury, which promotes the secretion of intracellular hepcidin to reduce intracellular iron content [45]. However, the relationship between HO-1 and IL-10 in the case of IO is still unknown. We found that HO-1 regulated the secretion of hepcidin by regulating IL-10 and thus affected intracellular iron content, while HO-1 regulated ROS to reduce tissue damage caused by IO. Although HO-1 can protect against iron-induced liver and spleen injuries [15], [16], [17], [18], how HO-1 protects BMMSCs from IO-related ROS or regulates IL-10 under IO condition is still unclear. In this study, we investigated the relationship between IL-10 and HO-1 upon IO.
Section snippets
Ethics statement
This study was approved by the Institutional Animal Care and Use Committee of PUMC and the methods were carried out in accordance with the approved guidelines. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. The experiment followed the Helsinki Declaration and passed the Guizhou Medical University ethical review (ethical approval number: 2017-13).
Reagents
Deferasirox was purchased from Novartis. RPMI 1640 was purchased from Gibco
Up-regulation of HO-1 protected BMMSCs from IO damage by reducing intracellular iron content in vitro
BMMSCs, as important components of BM microenvironment, can effectively secrete a variety of cytokines to protect BM cells from damage by external stimuli. In this study, HO-1 first increased in the culture of BMMSCs with excess iron, confirming that it protected cells. We hypothesized that HO-1 overexpression in BMMSCs protected cells from IO, and stimulated BMMSCs to secrete cytokines to protect BM cells. We extracted mouse BM cells and identified them as BMMSCs by morphological observation,
Discussion
Iron is an essential element for growth and survival, but IO is a disease characterized by excessive iron deposition in tissues and damage to vital organs including the heart, liver, and kidney [2], [3], [5], [15], [37], [38]. In clinical studies, patients with MDS and anemia, who need repeated blood transfusion, suffer from iron accumulation and finally IO. IO impairs the proliferation of erythroid progenitor cells from patients with MDS [6], [35], [36]. Chai et al. verified that IO undermined
Acknowledgments
This research was supported in part by the National Natural Science Foundation of China (#81360501, #81470006, #81660616), the International Cooperation Project of Guizhou Province (#2011-7010), the Social Project of Guizhou Province (#2011-3012), and the Provincial Governor Special Fund of Guizhou Province (#2010-84).
Conflicts of interest
The authors declare no conflict of interest.
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