Key Points Epigenetics and in vivo behavior can distinguish MSCs from different sources. BM-derived MSCs form a hematopoietic niche via a vascularized cartilage intermediate.
The interactions between hematopoietic cells and the bone marrow (BM) microenvironment play a critical role in normal and malignant hematopoiesis and drug resistance. These interactions within the BM niche are unique and could be important for developing new therapies. Here, we describe the development of extramedullary bone and bone marrow using human mesenchymal stromal cells and endothelial colony-forming cells implanted subcutaneously into immunodeficient mice. We demonstrate the engraftment of human normal and leukemic cells engraft into the human extramedullary bone marrow. When normal hematopoietic cells are engrafted into the model, only discrete areas of the BM are hypoxic, whereas leukemia engraftment results in widespread severe hypoxia, just as recently reported by us in human leukemias. Importantly, the hematopoietic cell engraftment could be altered by genetical manipulation of the bone marrow microenvironment: Extramedullary bone marrow in which hypoxia-inducible factor 1␣ was knocked down in mesenchymal stromal cells by lentiviral transfer of short hairpin RNA showed significant reduction (50% ؎ 6%; P ؍ .0006) in human leukemic cell engraftment. These results highlight the potential of a novel in vivo model of human BM microenvironment that can be genetically modified. The model could be useful for the study of leukemia biology and for the development of novel therapeutic modalities aimed at modifying the hematopoietic microenvironment. IntroductionThe relevance of the bone marrow (BM) microenvironment in regulating hematopoietic stem cell (HSC) behavior has only recently been established. [1][2][3][4][5] The maintenance of HSC quiescence and normal hematopoiesis requires complex bidirectional interactions between the BM niche and HSCs. [6][7][8] Moreover, much evidence supports the idea that the BM microenvironment also plays a pivotal role in the initiation and propagation of leukemia. [9][10][11] Leukemic cells have been shown to hijack the homeostatic mechanisms of normal HSCs and take refuge within the BM niche. This mechanism is pivotal during chemotherapy and contributes to disease relapse. 12,13 Although human HSCs can be genetically modified and transplanted into immunodeficient mice, the BM microenvironment is not transplantable. Numerous studies in patients and mice undergoing bone marrow transplantation have failed to demonstrate consistent engraftment of donor BM stroma cells. [14][15][16] A better understanding of the BM niche will not only improve our understanding of HSC self-renewal and hematopoiesis in general but also accelerate the development of new therapeutic modalities and targeted agents for the therapy of hematopoietic malignancies. Although the concept of a BM "niche" was formulated in 1978, it remains largely unidentified owing to technical limitations. 13,[17][18][19] Currently, the xenotransplant NOD/SCID and NOD/SCID/IL-2r␥ null mouse repopulation assays are the most widely used and relevant readout systems for studying human normal and malignant hematopoiesis. H...
Recent studies revealed that mitochondrial Ca2+ channels, which control energy flow, cell signalling and death, are macromolecular complexes that basically consist of the pore-forming mitochondrial Ca2+ uniporter (MCU) protein, the essential MCU regulator (EMRE), and the mitochondrial Ca2+ uptake 1 (MICU1). MICU1 is a regulatory subunit that shields mitochondria from Ca2+ overload. Before the identification of these core elements, the novel uncoupling proteins 2 and 3 (UCP2/3) have been shown to be fundamental for mitochondrial Ca2+ uptake. Here we clarify the molecular mechanism that determines the UCP2/3 dependency of mitochondrial Ca2+ uptake. Our data demonstrate that mitochondrial Ca2+ uptake is controlled by protein arginine methyl transferase 1 (PRMT1) that asymmetrically methylates MICU1, resulting in decreased Ca2+ sensitivity. UCP2/3 normalize Ca2+ sensitivity of methylated MICU1 and, thus, re-establish mitochondrial Ca2+ uptake activity. These data provide novel insights in the complex regulation of the mitochondrial Ca2+ uniporter by PRMT1 and UCP2/3.
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