Deciphering erythroblastic islands in mice and humans during development and stress

About This Grant

(PLEASE KEEP IN WORD, DO NOT PDF) Terminal differentiation of erythroid cells occurs in the erythroid-specific niches. The most studied erythroid niche is the erythroblastic island (EBI), which comprises a central macrophage surrounded by developing erythroblasts. While studies over the past decades have identified many genes that are functionally important for EBI, the field faces major caveats. Current knowledge of EBI is predominantly derived from studies of in vitro reconstitution of mixed cell populations that do not recapitulate in vivo niches. In addition, the EBI compositions in human hematopoietic tissues are unknown. In this project, we aim to uncover the anatomy, composition, and functions of EBIs in mice and humans using unbiased approaches through multiple spatial mapping technologies. Through spatial transcriptomic studies, we revealed a higher positive spatial correlation between erythroid cells and C1q+ macrophages than with other macrophages, suggesting that C1q+ macrophages are likely the EBI macrophages in mice. This strong positive correlation between C1q+ macrophages and erythroid cells was also observed in newborn bone marrow and adult spleen under physiologic and stress conditions. We applied the same technologies to human hematopoietic tissues. In contrast to mice, we did not observe a strong positive correlation between erythroid cells and C1q+ or other macrophages in the human hematopoietic tissues. Instead, there is a strong association between erythroid progenitors and maturing erythroid cells. This erythroid self-assembled EBI structure was recapitulated in a human induced pluripotent stem cell (iPSC)-derived bone marrow organoid model. Furthermore, we identified ICAM4 as a critical erythroid surface protein that maintains erythroid-centered EBIs in humans. These preliminary studies uncover unique erythroid niches in mice and humans. Based on this evidence, we hypothesize that mouse and human EBIs have distinct structures and molecular features that help sustain terminal erythropoiesis. In this project, we propose to investigate the composition of macrophage-centered EBIs and the mechanisms of C1q in EBI macrophages in hematopoietic tissues in mice. The same approaches will be used to study ICAM4 and erythroid self-assembled EBIs in humans. Furthermore, EBI responses and their molecular mechanisms under stress and disease conditions in mice and humans will also be investigated. The success of this project will not only advance the understanding of red cell biology but also offer invaluable insights into hematopoiesis as a whole.