Notch signaling in Nestin-expressing cells in the bone marrow maintains erythropoiesis via macrophage integrity.

Notch signaling plays pivotal roles in both hematopoietic stem/progenitor and their niche cells. Myeloproliferative phenotypes are induced by disruption of Notch signaling in non-hematopoietic 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. SIGNIFICANCE STATEMENT: Notch signaling plays a crucial role in both hematopoietic stem cells (HSCs) and their niche cells. Nestin-expressing mesenchymal stromal cells (MSCs) in a bone marrow (BM) reported as a component of HSC niche. We found Notch signaling in Nestin-expressing MSCs regulates erythroid differentiation in the BM. Disruption of Notch signaling in Nestin-expressing MSCs induced the upregulation of IL-6 in central macrophages and IL-6 can cause the impairment of erythroid island forming capacity in central macrophages. Our results suggest the erythropoiesis in the BM is regulated by interaction between the central macrophages and Nestin-expressing MSCs. © AlphaMed Press 2019.