Role of iron and iron‐related proteins in mesenchymal stem cells: Cellular and clinical aspects

Abstract

Mesenchymal stem cells (MSCs) are located in various tissues where these cells show niche‐dependent multilineage differentiation and secrete immunomodulatory molecules to support numerous physiological processes. Due to their regenerative and reparative properties, MSCs are extremely valuable for cell‐based therapy in tackling several pathological conditions including COVID‐19. Iron is essential for MSC processes but iron‐loading, which is common in several chronic conditions, hinders normal MSC functionality. This not only aggravates disease pathology but can also affect allogeneic and autologous MSC therapy. Thus, understanding MSCs from an iron perspective is of clinical significance. Accordingly, this review highlights the roles of iron and iron‐related proteins in MSC physiology. It describes the contribution of iron and endogenous iron‐related effectors like hepcidin, ferroportin, transferrin receptor, lactoferrin, lipocalin‐2, bone morphogenetic proteins and hypoxia inducible factors in MSC biology. It summarises the excess‐iron‐induced alterations in MSC components, processes and discusses signalling pathways involving ROS, PI3K/AKT, MAPK, p53, AMPK/MFF/DRP1 and Wnt. Additionally, it evaluates the endogenous and exogenous saviours of MSCs against iron‐toxicity. Lastly, it elaborates on the involvement of MSCs in the pathology of clinical conditions of iron‐excess, namely, hereditary hemochromatosis, diabetes, β‐thalassaemia and myelodysplastic syndromes. This unique review integrates the distinct fields of iron regulation and MSC physiology. Through an iron‐perspective, it describes both mechanistic and clinical aspects of MSCs and proposes an iron‐linked MSC‐contribution to physiology, pathology and therapeutics. It advances the understanding of MSC biology and may aid in identifying signalling pathways, molecular targets and compounds for formulating adjunctive iron‐based therapies for excess‐iron conditions, and thereby inform regenerative medicine.

Complex Interactions in Regulation of Haematopoiesis—An Unexplored Iron Mine

“…Bone-marrowderived MSCs (BM-MSCs) influence lineage commitment of haematopoietic stem cells, their mobilisation and exit from the bone marrow thereby influencing organisation of the haematopoietic niche and haematopoiesis. Significance of iron in MSC maintenance is indicated by the fact that those damaged by iron-induced toxicity are unable to support haematopoiesis effectively, as observed in diseases such as β thalassaemia and MDS [48].…”

“…Excess iron levels induce changes in cell signalling pathways and alter different characteristics of MSCs. ROS produced during iron overloading may hinder proliferation of MSCs by arresting the cell cycle at G0/G1 phase [48]. Alternatively, iron overloading may also increase the expression of cell cycle proteins such as cyclin A and E, which stimulates entry of BM-MSCs into the S phase and activates downstream signalling pathways such as the MAP kinase (MAPK) pathway, promoting their proliferation.…”

“…Rescue from the effects of iron overloading may also result from an indirect decrease in ROS levels by reducing levels of its activators such as NOX4 in iron-treated BM-MSCs and iron-loaded mice, as well as by inhibiting p38 MAPK signalling pathway in iron-treated umbilical cord MSCs by iron chelators. Certain intracellular signalling pathways, responsible for mitochondrial fragmentation in iron-loaded BM-MSCs from MDS patients may be attenuated by iron chelators, providing another example of the harmful effects of iron excess conditions on MSC physiology [48].…”

“…Iron chelators may protect BM-MSCs from toxicity by decreasing levels of ROS and inhibiting certain intracellular signaling pathways (p38 MAPK) [48] Mitochondrial fragmentation in iron overloaded BM-MSCs may be reduced by iron chelators such as DFO and NAC.…”

“…Observed in MDS patients. [48] Erythrocytes Hypochromic, microcytic erythrocytes typically observed in IDA patients IDA accounts for 50% of the global burden of anemia. [63] Aberrant overexpression of hepcidin despite low iron stores and serum iron levels, observed in certain anemias.…”