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Blood, 15 May 2008, Vol. 111, No. 10, pp. 4836-4837.
Where the Epo cells areNATIONAL INSTITUTES OF HEALTH
In this issue of Blood, Obara and colleagues report on their use of a GFP transgene to mark kidney Epo-producing cells in mice. These cells in the interstitial space express neuronal markers, and their number correlates with plasma Epo levels and increases with hypoxic induction.
Known Epo gene-regulatory elements include binding sites for hypoxia-inducible factor (HIF) and for hepatocyte nuclear factor-4 (HNF-4). The importance of the HIF protein in regulation of Epo production was recently underscored by the discovery of a gain-of-function mutation in the HIF2 Renal Epo-producing interstitial cells exhibit dendritelike processes and express neural-specific markers. Although the range of Epo expression per cell has not yet been determined, the number of Epo-producing cells correlates with plasma Epo concentration, supporting the hypothesis that Epo production by a subset of interstitial cells is regulated in an on/off fashion.3 Hypoxia and anemia, due to bleeding, increased Epo and GFP expression in the kidney. The number of renal Epo-expressing cells also increased, further indicating that Epo induction was not exclusively through increased Epo expression in those interstitial cells already expressing Epo and marked by GFP. Whether local variation in oxygen tension or some other factor induces Epo-producing cells in the unstressed microenvironment, and the extent of heterogeneity of Epo expression per cell, are issues that remain unresolved. In the liver, Epo-producing hepatocytes lack neural markers, are evident by embryonic day 9.5, persist through birth, and are again detected in adult liver after hypoxia or anemic stress. Further investigation to determine the extent to which endogenous human Epo expression parallels these observations of mouse Epo in the kidney and liver is warranted.
Increasing evidence suggests physiologic function of Epo beyond erythropoiesis. For example, Epo expression in the brain, and its apparent neuroprotective activity in culture and animal models, have led to investigation of the use of Epo therapy for ischemic stroke.4 Localization and enumeration of Epo-expressing cells in the brain under normal and ischemic conditions would offer insight into endogenous Epo activity in this organ. Obara and colleagues observe GFP-expressing cells only in the kidney and liver: either additional sequences are required for Epo production in other tissues, or GFP expression is below the level of their detection method. Increased understanding of the nature and function of Epo-producing cells in the kidney, liver, and other organs may be useful in broadening cell-type specificity for new therapeutic strategies designed to enhance endogenous Epo expression.5 Examination of the GFP transgenic mouse may also provide new insight into factors that affect endogenous Epo production, such as the fate of kidney Epo-producing cells in renal disease.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests.
REFERENCES
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| Copyright © 2008 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
subunit leading to familial erythrocytosis.
