Hepatic Extramedullary Hematopoiesis and Macrophages in the Adult Mouse: Histometrical and Immunohistochemical Studies

Abstract

Fetal liver hematopoiesis in mice disappears approximately 2 weeks after birth; however, under experimental acute anemia extramedullary hematopoiesis occurs in the livers of adult mice. The hematopoietic foci in the liver during extramedullary hematopoiesis contain erythroblasts and macrophages. In this study, the extent of involvement of macrophages in the development and involutional process of the hematopoietic foci in adult mice livers was clarified by experimentally inducing extramedullary hematopoiesis. Hematopoietic cells appeared in the livers 2 days after phenylhydrazine (PHZ) injections. The number and area of the foci increased rapidly, reaching peak values on the sixth day. F4/80-positive macrophages were observed in the sinusoids as well as the hematopoietic foci, and were tightly surrounded by erythroblasts. Sinusoidal macrophages in normal adult livers were positive for F4/80 but negative for ER-HR3. However, in extramedullary hematopoiesis-induced livers, sinusoidal macrophages became positive for ER-HR3 antibodies. The number of ER-HR3-positive macrophages was 9.2 ± 2.9/mm² on the second day after PHZ was administered, and increased to 200.3 ± 4.2/mm² on the sixth day. On the seventh day after the PHZ injections, the number decreased and they were no longer detected at 30 days after PHZ was injected. The present study revealed that erythroblasts accumulate around sinusoidal macrophages to form an erythroblastic island with a central macrophage similar to erythropoiesis in the fetal liver. Furthermore, in line with development and regression of extramedullary hematopoiesis, macrophages express ER-HR3, a hematopoiesis related antigen.

Long-Term Fate of Human Fetal Liver Progenitor Cells Transplanted in Injured Mouse Livers

“…The presence of metaplastic bone formation in one animal raises the concern that hFLMPCs or mesenchymal contaminants may differentiate into undesired lineages in vivo, however. Extramedullary hematopoiesis in livers of anemic adult mice has been described , but usually involves formation of erythroblastic islands rather than bony spicules. It is possible that contaminant mesenchymal progenitors within our fetal liver cultures may have given rise to these metaplastic tissues.…”

Mobilization with granulocyte colony-stimulating factor blocks medullar erythropoiesis by depleting F4/80+VCAM1+CD169+ER-HR3+Ly6G+ erythroid island macrophages in the mouse

“…15 [5,27,28], also identifies erythroid island macrophages in the BM. However, the exact identity of this antigen and whether its expression is necessary to support erythropoiesis remain unknown [44].…”

“…Although the BM is the main site of erythropoiesis in adults in steady-state, the spleen and liver can become important extramedullary erythropoietic organs when the BM is compromised as observed in some hematological neoplasms [28,47]. In conclusion, G-CSF doses used to mobilize HSCs in transplantation donors transiently impair the function of different subsets of tissue supportive macrophages in the mouse BM particularly osteomacs that support bone forming osteoblasts [22,50], HSC nichesupportive macrophages [15][16][17] and erythropoietic island macrophages (herein).…”

From the Cradle to the Grave: The Role of Macrophages in Erythropoiesis and Erythrophagocytosis

“…Additional to retaining HSCs in the spleen, macrophages were found to play a central role in ongoing EMH. Hepatic sinusoidal macrophages were found to form erythroblastic islands upon induction of anemia in mice by injection of phenyl hydrazine ( 70 ). To assess the importance of CD169+ macrophages in EMH of the spleen and bone marrow, a mouse model was used where the diphtheria toxin receptor (DTR) was knocked-in downstream of the Siglec 1 promotor, a protein found specifically in macrophages.…”