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February 16, 2021

Pumping the blood with more oxygen

The Kenji Osafune laboratory shows how the combination of human iPS cells and mice can reveal clues for increasing the production of red blood cells.

Erythropoietin, or EPO, has made a name in the media as the hormone of choice for doping endurance athletes. In medical circles, EPO is recognized as the key hormone for elevating oxygen levels in the blood by increasing the production of red blood cells. By using human iPS cells, CiRA Prof. Kenji Osafune and his colleagues report in a new study that retinoic acid, a cheap and safe drug, can increase EPO levels in anemic mice.

"EPO is the hormone responsible for producing red blood cells. However, we do not understand well how it is produced," explained Osafune.

In the adult body, the kidneys are the organ that produces EPO. However, in the fetal and neonatal stages of life, the liver is also a source of the hormone. This has important implications for iPS cell research, since cells made from iPS cells are normally fetal-like.

"We generated EPO-producing cells by applying a hepatic differentiation protocol to iPS cells. Liver is a potential new target for treating anemia," Osafune said.

The body is naturally programmed to increase red blood cells when oxygen levels are low, or hypoxic. So too are Osafune's EPO-producing cells, which the study showed also produce EPO in hypoxia if they are treated with retinoic acid.

Retinoic acid is a well-known metabolite of vitamin A and involved in many types of physiological processes including the fetal liver producing EPO. Moreover, retinoic acid is remarkably safe and cheap.

There already exist treatment options for anemia, including recombinant EPO, but these risk cardiovascular problems.

"Recently, inhibitors of PHD [prolyl hydroxylase domain-containing protein] have been explored. PHD is a critical regulator for EPO production. Inhibitors stabilize HIF [hypoxia-inducible factor], but HIF if unchecked can cause other problems like cancer," noted Osafune.

Interestingly, PHD inhibitors and retinoic acid had an additive effect on EPO-producing cells. The same additive benefits were found when treating anemic mice with the two factors. The observations provide new insights on how retinoic acid enhances EPO and provides new drug targets that could avoid the concerns of HIF.

Because the benefits were seen in human cells and living mice, Osafune believes the combination of the two systems could bring faster knowledge on the physiological factors responsible for producing EPO in the human body.

"The cells allow us to identify candidate factors quickly. Then we can test those candidates confidently in mice. Understanding the main mechanisms regulating EPO production will bring us new treatments for anemia and related diseases," he said.

Paper Details
  • Journal: Scientific Reports
  • Title: Retinoic acid regulates erythropoietin production cooperatively with hypoxia-inducible factors in human iPSC-derived erythropoietin-producing cells
  • Authors: Naoko Katagiri1, Hirofumi Hitomi2, Shin-Ichi Mae1, Maki Kotaka1, Li Lei3,
    Takuya Yamamoto4,5,6,7, Akira Nishiyama3 and Kenji Osafune1
  • Author Affiliations:
    1. Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
    2. Department of iPS Stem Cell Regenerative Medicine, Kansai Medical University, Osaka, Japan.
    3. Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
    4. Department of Life Science Frontiers, CiRA, Kyoto University, Kyoto, Japan.
    5. Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.
    6. AMED-CREST, AMED, Tokyo, Japan.
    7. Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan.
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