TY - JOUR
T1 - Human extramedullary bone marrow in mice
T2 - A novel in vivo model of genetically controlled hematopoietic microenvironment
AU - Chen, Ye
AU - Jacamo, Rodrigo
AU - Shi, Yue Xi
AU - Wang, Rui Yu
AU - Battula, Venkata Lokesh
AU - Konoplev, Sergej
AU - Strunk, Dirk
AU - Hofmann, Nicole A.
AU - Reinisch, Andreas
AU - Konopleva, Marina
AU - Andreeff, Michael
PY - 2012/5/24
Y1 - 2012/5/24
N2 - 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 1α 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.
AB - 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 1α 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.
UR - http://www.scopus.com/inward/record.url?scp=84861524484&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84861524484&partnerID=8YFLogxK
U2 - 10.1182/blood-2011-11-389957
DO - 10.1182/blood-2011-11-389957
M3 - Article
C2 - 22490334
AN - SCOPUS:84861524484
SN - 0006-4971
VL - 119
SP - 4971
EP - 4980
JO - Blood
JF - Blood
IS - 21
ER -