Iron overload enhances human mesenchymal stromal cell growth and hampers matrix calcification

• Published in: Biochimica et biophysica acta Vol. 1860; no. 6; pp. 1211 - 1223
• Main Authors: Borriello, Adriana, Caldarelli, Ilaria, Speranza, Maria Carmela, Scianguetta, Saverio, Tramontano, Annunziata, Bencivenga, Debora, Stampone, Emanuela, Negri, Aide, Nobili, Bruno, Locatelli, Franco, Perrotta, Silverio, Oliva, Adriana, Della Ragione, Fulvio
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2016
• Subjects: apoptosis; bone marrow; bone metabolism; calcification; Calcification, Physiologic; Cell Differentiation; cell growth; Cell Proliferation; Cells, Cultured; culture media; cyclins; endocrine glands; heart; hematopoiesis; Humans; interphase; Iron; Iron overload; Iron Overload - pathology; liver; MAP Kinase Signaling System - physiology; Mesenchymal stromal cells; Mesenchymal Stromal Cells - physiology; Mineralization; mitogen-activated protein kinase; morbidity; mortality; osteoblasts; Osteoblasts - physiology; Osteogenesis; pancreas; patients; reactive oxygen species; Reactive Oxygen Species - metabolism; stromal cells; Iron overload; TfR; ARS; hBM-MSCs; FAC; Iron; AP; Tf; SAC; OC; Mineralization; ROS; Mesenchymal stromal cells; DCF-DA; SM; qPCR; PNPP; OM; Osteogenesis
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2016.01.025

Iron overload syndromes include a wide range of diseases frequently associated with increased morbidity and mortality. Several organs are affected in patients with iron overload including liver, heart, joints, endocrine glands, and pancreas. Moreover, severe bone and hemopoietic tissue alterations are observed. Because of the role of bone marrow mesenchymal stromal cells (BM-MSCs) in bone turnover and hematopoiesis, iron effects on primary BM-MSCs cultures were evaluated. Primary human BM-MSCs cultures were prepared and the effects of iron on their proliferation and differentiation were characterized by biochemical analyses and functional approaches. Addition of iron to the culture medium strongly increased BM-MSCs proliferation and induced their accelerated S phase entry. Iron enters BM-MSCs through both transferrin-dependent and transferrin-independent mechanisms, inducing the accumulation of cyclins E and A, the decrease of p27Kip1, and the activation of MAPK pathway. Conversely, neither apoptotic signs nor up-regulation of reactive oxygen species were observed. Iron inhibited both differentiation of BM-MSCs into osteoblasts and in vitro matrix calcification. These effects result from the merging of inhibitory activities on BM-MSCs osteoblastic commitment and on the ordered matrix calcification process. We demonstrated that BM-MSCs are a target of iron overload. Iron accelerates BM-MSCs proliferation and affects BM-MSCs osteoblastic commitment, hampering matrix calcification. Our study reports, for the first time, that iron, at concentration found in overloaded patient sera, stimulates the growth of BM-MSCs, the BM multipotent stromal cell component. Moreover, iron modulates the physiological differentiation of these cells, affecting bone turnover and remodeling. •Bone marrow mesenchymal stromal cells (BM-MSCs) are the osteoblasts precursors and key hematopoietic niche components.•Iron enters BM-MSCs through transferrin-dependent and -independent mechanisms.•Iron, at concentrations detected in sera of iron overloaded patients, stimulates in vitro the proliferation of BM-MSCs.•Iron-dependent growth stimulation is associated with cyclins E and A increase, p27 decrease and MAPK pathway activation.•Iron impairs BM-MSCs osteoblastic differentiation acting both on cell commitment and matrix calcification process.