ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO0486

Pro-Inflammatory Signaling Alters Hematopoiesis in Anemic Mice

Session Information

Category: Anemia and Iron Metabolism

  • 200 Anemia and Iron Metabolism

Authors

  • Thomas, Jane Joy, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Courbon, Guillaume, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Martin, Aline, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • David, Valentin, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

Iron deficiency anemia (IDA) is a common complication of Chronic Kidney Disease (CKD), associated with accelerated disease progression and death. IDA is the direct result of low circulating iron and total body iron stores, which are unable to meet the demands of erythropoiesis. To date, the effects of low iron bioavailability and anemia on hematopoiesis at the single cell level remain unexplored.

Methods

To investigate the effects of IDA on hematopoiesis, we fed three-week old mice a control or an iron deficient diet for 3 weeks. As expected, mice fed on a low-iron diet developed IDA, evidenced by low hematocrit count and severely reduced hemoglobin. We next analyzed the developing hematopoietic progenitors and identified molecular markers that are predictive of the cell differentiating status using single cell RNA sequencing of bone marrow (BM) and peripheral blood (PB) cells from control and IDA mice.

Results

We found that IDA increased the number of hematopoietic stem cells and restricted erythroid progenitors in BM and in PB. In contrast, IDA disrupted terminal erythroid differentiation, and particularly the differentiation of orthochromatic erythroblasts into reticulocytes. Compared to control mice, orthochromatic erythroblasts from IDA mice differentiated into an “alternate” reticulocyte cluster, overabundant in BM but quasi-absent in PB. Analysis of differentially expressed genes showed that iron deficiency increased pro-inflammatory signaling and resulted in the expression of pro-apoptotic markers in this alternate cluster, including the expression of Ddit3 (+12 fold),Trib3 and Atf4 (+13 fold).
The effects of IDA were not restricted to the erythroid lineage. IDA reduced the number of differentiated myeloid cells such as macrophages and neutrophils. Importantly, cells from IDA mice showed increased BM megakaryopoietic differentiation and higher number of circulating megakaryopoietic cells in PB. In contrast, IDA reduced lymphoid differentiation and thus, lowered the number of mature B cells, highlighting the importance of iron in adaptive humoral immune responses.

Conclusion

In aggregate, our data suggest that iron deficiency anemia alters hematopoiesis through inflammation-induced expansion of progenitors and apoptotic signaling in mature cell populations. Our results might help develop targeted therapies in CKD patients to correct anemia and improve outcomes.

Funding

  • NIDDK Support