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Editorials
Figure 1. Schematic view of steady-state and stress erythropoiesis in mouse models. Mouse steady-state and stress erythropoiesis occur primarily in the bone marrow and spleen, respectively. Singbrant et al.3 discovered cell surface markers that are common in steady- and stress-burst-forming unit-erythroid progenitors (BFU-E). It remains to be investigated whether and how steady-BFU-E migrate from the bone marrow to the spleen during stress.
ditions with acute anemia. With the relatively more spe- cific markers to enrich steady- and stress-BFU-E, a detailed mechanistic investigation of erythroid lineage commitment becomes more feasible. In this aspect, Singbrant et al.3 found that in addition to genes down- stream of BMP signaling, genes that are regulated by Cbfa2t3 (also known as Eto2) were also upregulated in stress erythroid progenitors. Cbfa2t3 is a transcriptional co-repressor that maintains the primed state of erythroid progenitors and is known to be involved in stress erythro- poiesis.13,14 Future studies on how Cbfa2t3 regulates stress erythropoiesis and whether the Cbfa2t3 transcriptional corepressor complex cross talks with BMP signaling would be interesting to pursue.
One of the key remaining questions is whether these or similar markers can be used to identify human stress ery- throid progenitors. The field of stress erythropoiesis relies heavily on mouse models. Several important differ- ences are present between mouse and human. In mouse, the nature of the hypercellular bone marrow provides limited spaces for the expansion of an erythroid lineage during stress, which forces the spleen to become a major extramedullary erythropoiesis organ. However, this phe- nomenon is not common in humans.15 Although studies have shown that BMP signaling is also involved in human stress erythropoiesis in vitro,10 it is unclear whether the
same is true in vivo. Exploration of markers and signaling pathways in stress erythroid progenitors in human, or other model systems such as rats, would be the necessary next step.
References
1. Hattangadi SM, Wong P, Zhang L, Flygare J, Lodish HF. From stem cell to red cell: regulation of erythropoiesis at multiple levels by mul- tiple proteins, RNAs, and chromatin modifications. Blood. 2011;118(24):6258-6268.
2. Bennett LF, Liao C, Paulson RF. Stress erythropoiesis model systems. Methods Mol Biol. 2018;1698:91-102.
3. Singbrant S, Mattebo A, Sigvardsson M, Strid T, Flygare J. Prospective isolation of radiation induced erythroid stress progenitors reveals unique transcriptomic and epigenetic signatures enabling increased erythroid output. Haematologica. 2020; 105(11):2561-2571.
4. Perry JM, Harandi OF, Paulson RF. BMP4, SCF, and hypoxia cooper- atively regulate the expansion of murine stress erythroid progeni- tors. Blood. 2007;109(10):4494-4502.
5. Lenox LE, Perry JM, Paulson RF. BMP4 and Madh5 regulate the ery- throid response to acute anemia. Blood. 2005;105(7):2741-2748.
6.Porayette P, Paulson RF. BMP4/Smad5 dependent stress erythro- poiesis is required for the expansion of erythroid progenitors during fetal development. Dev Biol. 2008;317(1):24-35.
7.Paulson RF, Shi L, Wu DC. Stress erythropoiesis: new signals and new stress progenitor cells. Curr Opin Hematol. 2011;18(3):139-145. 8. Perry JM, Harandi OF, Porayette P, Hegde S, Kannan AK, Paulson RF. Maintenance of the BMP4-dependent stress erythropoiesis pathway in the murine spleen requires hedgehog signaling. Blood.
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9. Harandi OF, Hedge S, Wu DC, McKeone D, Paulson RF. Murine ery-
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