Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver
Hiromi Gunshin, … , Sylvie Robine, Nancy C. Andrews
Hiromi Gunshin, … , Sylvie Robine, Nancy C. Andrews
Published May 2, 2005
Citation Information: J Clin Invest. 2005;115(5):1258-1266. https://doi.org/10.1172/JCI24356.
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Article Hematology

Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver

Abstract

Solute carrier family 11, member 2 (SLC11A2) is the only transmembrane iron transporter known to be involved in cellular iron uptake. It is widely expressed and has been postulated to play important roles in intestinal iron absorption, erythroid iron utilization, hepatic iron accumulation, placental iron transfer, and other processes. Previous studies have suggested that other transporters might exist, but their physiological significance remained uncertain. To define the activities of Slc11a2 in vivo, we inactivated the murine gene that encodes it globally and selectively. We found that fetal Slc11a2 is not needed for materno-fetal iron transfer but that Slc11a2 activity is essential for intestinal non-heme iron absorption after birth. Slc11a2 is also required for normal hemoglobin production during the development of erythroid precursors. However, hepatocytes and most other cells must have an alternative, as-yet-unknown, iron uptake mechanism. We previously showed that Slc11a2 serves as the primary portal for intestinal iron entry in hemochromatosis. However, inactivation of murine Hfe ameliorates the phenotype of animals lacking Slc11a2.

Authors

Hiromi Gunshin, Yuko Fujiwara, Angel O. Custodio, Cristina DiRenzo, Sylvie Robine, Nancy C. Andrews

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Hematopoietic Slc11a2 is required for normal erythropoiesis. (A) Hemoglo...
Hematopoietic Slc11a2 is required for normal erythropoiesis. (A) Hemoglobin isoform analysis demonstrating the presence of HSC-derived hemoglobin in the peripheral blood 8 weeks after fetal liver transfer. The blood samples were as follows: lanes 1 and 2, Slc11a2–/– HSC recipients; lanes 3 and 4, wild-type HSC recipients; lane 5, C57BL/6 mice; lane 6, 129S6/SvEvTac mice; lanes 7 and 8, recipients before transfer. After fetal liver transfer, recipients produced diffuse alleles of hemoglobin β chain (Hbbd) characteristic of the 129S6/SvEvTac background but not single alleles of Hbb (Hbbs) characteristic of the C57BL/6 background. (B) Flow cytometry of peripheral blood before (left) and 8 weeks after (right) fetal liver transfer. Before HSC transfer, 100% of recipient cells had both CD45.1 and CD45.2 markers characteristic of their mixed C57BL/6 and 129S6/SvEvTac background (left). After fetal liver transfer, hematopoietic cells primarily expressed only the CD45.2 marker associated with the 129S6/SvEvTac background, which was consistent with the hemoglobin analysis. Approximately 5.2–8.6% of cells were double stained for CD45.1 and CD45.2 markers, which indicates a low level of residual chimerism. Wild-type blood morphology was normal (C) and distinctly different from that of recipients of Slc11a2–/– HSCs (D). Original magnification, ×60. The recipients of Slc11a2–/– HSCs had hypochromic, microcytic cells with anisocytosis and poikilocytosis. (E) Hemoglobin (HGB) levels were persistently lower in Slc11a2–/– HSC recipients compared with animals that received Slc11a2+/– HSCs. (F) Non-heme liver iron content (adjusted taking into account whole liver and body weight) was increased in animals that received Slc11a2–/– HSCs. Values are shown as a percent of the values determined for Slc11a2+/– HSC recipients.