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Stem Cells. 2019 Apr 1. doi: 10.1002/stem.3011. [Epub ahead of print]

Notch Signaling in Nestin-Expressing Cells in the Bone Marrow Maintains Erythropoiesis via Macrophage Integrity.

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Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Department of Transfusion Medicine, University of Tsukuba Hospital, Tsukuba, Japan.
Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
School of Medical Sciences, University of Tsukuba, Tsukuba, Japan.
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan.


Notch signaling plays pivotal roles in both hematopoietic stem/progenitor and their niche cells. Myeloproliferative phenotypes are induced by disruption of Notch signaling in nonhematopoietic bone marrow (BM) cells. Nestin-expressing cells in the BM reportedly represent a component of the hematopoietic stem cell niche. We established mice in which rare Nestin-expressing cells in the BM were marked by green fluorescent protein, and Notch signaling was conditionally disrupted in these cells specifically. We observed impairment of erythropoiesis in the BM accompanying splenomegaly with BM hematopoietic programs in other lineages undisturbed. Transplantation experiments revealed that the microenvironmental rather than the hematopoietic cells were attributable to these phenotypes. We further found that the erythroid-island-forming ability of BM central macrophages was compromised along with the transcriptional upregulation of interleukin-6. Various Inflammatory conditions hamper BM erythropoiesis, which often accompanies extramedullary hematopoiesis. The mouse model demonstrated here may be of relevance to this common pathophysiologic condition. Stem Cells 2019.


Bone marrow stromal cells; Erythroid differentiation; Erythropoiesis; Nestin; Notch


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