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bioRxiv · 10.1101/506345

The role of Selenoprotein N in the differentiation of erythroid progenitors during stress erythropoiesis

Paulson, R. F.·Nettleford, S. K.·Liao, C.·Chen, Y.·Hao, S.·Blatzinger, M.·Thami-Braye, M.·Lescure, A.·Prabhu, K. S.
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Abstract

Low serum Se is independently associated with anemia in elderly population, dialysis patients, sickle-cells patients, and hypothyroidism patients. Previous work from our laboratory showed that dietary Se deficiency in mice showed mild anemia indicating activation of stress-erythropoietic mechanisms. Unlike steady state erythropoiesis that is primarily responsible for homeostasis to produce new erythrocytes at a constant rate, stress erythropoiesis predominates when the bone marrow cannot generate sufficient erythrocytes. During such a process, short-term reconstituting hematopoietic stem cells (CD34+Kit+Sca1+Linneg) migrate to the spleen leading to the proliferation and differentiation of stress-erythroid progenitors (SEPs). These cells lead to stress burst forming unit-erythroid cells (BFU-E) followed by terminal differentiation to erythrocytes. Recent studies demonstrate deficits in selenoproteins block the expansion and development of stress BFU-E with defects in terminal differentiation. Analysis of selenoprotein expression showed that selenoprotein W (SelenoW) was highly expressed in developing SEPs. CRISPR-Cas9 knockout of SelenoW blocked the proliferation of immature SEPs in murine and human stress erythropoiesis cultures demonstrating a central role for SelenoW in stress erythropoiesis. Using the two-culture system to generate SEPs, selenoprotein N (SelenoN) expression increased as the progenitors transition from self-renewing \"stem cell like\" progenitors to form committed erythroid progenitors. SelenoN-/- mice showed significantly slower erythroid recovery following phenylhydrazine (PHZ)-induced acute hemolytic anemia. As in the muscle satellite cells where SelenoN regulates cellular Ca2+ signaling, SelenoN may also regulate Ca2+ signaling in SEPs to modulate pathways of differentiation. In summary, these data suggest that multiple selenoproteins, including SelenoN and SelenoW, coordinately regulate stress erythropoiesis.

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Paulson, R. F., Nettleford, S. K., Liao, C., Chen, Y., Hao, S., Blatzinger, M., Thami-Braye, M., Lescure, A., Prabhu, K. S.. 2018-12-25. The role of Selenoprotein N in the differentiation of erythroid progenitors during stress erythropoiesis. https://doi.org/10.1101/506345

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