New Insights into the Hepcidin-Ferroportin Axis and Iron Homeostasis in iPSC-Derived Cardiomyocytes from Friedreich’s Ataxia Patient

Abstract

Iron homeostasis in the cardiac tissue as well as the involvement of the hepcidin-ferroportin (HAMP-FPN) axis in this process and in cardiac functionality are not fully understood. Imbalance of iron homeostasis occurs in several cardiac diseases, including iron-overload cardiomyopathies such as Friedreich’s ataxia (FRDA, OMIM no. 229300), a hereditary neurodegenerative disorder. Exploiting the induced pluripotent stem cells (iPSCs) technology and the iPSC capacity to differentiate into specific cell types, we derived cardiomyocytes of a FRDA patient and of a healthy control subject in order to study the cardiac iron homeostasis and the HAMP-FPN axis. Both CTR and FRDA iPSCs-derived cardiomyocytes express cardiac differentiation markers; in addition, FRDA cardiomyocytes maintain the FRDA-like phenotype. We found that FRDA cardiomyocytes show an increase in the protein expression of HAMP and FPN. Moreover, immunofluorescence analysis revealed for the first time an unexpected nuclear localization of FPN in both CTR and FRDA cardiomyocytes. However, the amount of the nuclear FPN was less in FRDA cardiomyocytes than in controls. These and other data suggest that iron handling and the HAMP-FPN axis regulation in FRDA cardiac cells are hampered and that FPN may have new, still not fully understood, functions. These findings underline the complexity of the cardiac iron homeostasis.

Cells and gene expression programs in the adult human heart

“…We identified six subpopulations of aCM, indicating considerable heterogeneity ( Figure 2B ) particularly between the right and left chambers. Notably, HAMP , a master regulator of iron homeostasis, was significantly enriched in over 50% of RA CM compared to 3% LA CM ( Supplementary Table B4 ) 29 , consistent with prior studies of RA tissues 8 and confirmed by smFISH ( Figure 2G ). HAMP has unknown roles in cardiac biology, but Hamp-null mice have electron transport chain deficits and lethal cardiomyopathy 30 .…”

Cells of the adult human heart

“…We identify five aCM populations (Figure 2e Table 6, 7). HAMP, a master regulator of iron homeostasis, is significantly enriched in over 50% of RA CM vs. 3% LA CM (verified by smFISH, Figure 2g, Extended Data Figure 3c) 23 , implying energetic differences 6 . HAMP has unknown roles in cardiac biology, but Hamp-null mice have electron transport chain deficits and lethal cardiomyopathy 24 .…”

“…3b–d , Supplementary Tables 6 , 7 ). HAMP , a master regulator of iron homeostasis, is considerably enriched in more than 50% of right atrium cardiomyocytes versus 3% left atrium cardiomyocytes (verified by smFISH) 23 (Fig. 2g , Extended Data Fig.…”

Effects of tocotrienol supplementation in Friedreich’s ataxia: A model of oxidative stress pathology

“…HAMP is a key regulator of iron homeostasis, both at the systemic and at the cell level 67 and may be involved in the iron dysregulation occurring in cells of FRDA patients. 68 Here, the increase of HAMP expression should be viewed at the light of its upregulation in inflammation, where HAMP plays a double role in preserving the macrophage iron pool and in downregulating the levels of TNF-α and IL-6 expression. 69 An antioxidant response element has been identified in the promoter of the murine HAMP gene, 70 suggesting that HAMP might be a pivot in the Nrf2-regulated battery of genes acting in OS responses, iron toxicity control, and anti-inflammatory activities.…”