Human hematopoiesis in SCID mice implanted with human adult cancellous bone.
The persistence of hematopoietic cells from human adult cancellous bone fragments implanted subcutaneously into CB-17 scid/scid mice was studied. Recipient mice received either no pretreatment (control group) or pretreatment with 3 Gy total-body irradiation and anti-asialo GM1 sera (ASGM1; pretreated group) before implantation. Pretreated severe combined immunodeficient (SCID) mice implanted with human bone were subsequently given ASGM1 every 7 days for the duration of the experiments. At 12 weeks postimplantation, flow cytometry of cells from pretreated and control animal tissues detected human CD45+ cells in the mouse spleen (mean, 7.8% and 3.4% positive cells, pretreated and control animals, respectively), bone marrow (BM; mean, 16.5% and 4.8% positive cells, respectively), and blood (mean, 5.5% and < 2% positive cells, respectively), and in the implanted human bone (73% and 8.9% positive cells, respectively). At 12 weeks, pretreated mice had human granulocyte-macrophage colony-forming cells (GM-CFC) and burst-forming units-erythrocyte (BFU-E) in the implanted human bone in the murine BM and in some of the spleens. The spleens also had extensive infiltration of human B cells and macrophages. Mean serum levels of human IgG in pretreated animals were 14 micrograms/mL during weeks 6 to 12, compared with trace levels (< 1 microgram/mL) in control mice. Bone from patients with acute myeloblastic leukemia (AML) was also implanted in pretreated SCID mice, and retrieved at 8 weeks for analysis. Comparison of preimplantation and implanted samples showed that the original histology was maintained, and massive infiltration of human CD68+ cells was observed in the mice spleens and BM. Implantation of AML bone in SCID mice facilitates analysis of in situ AML cell interaction with stromal cells in the leukemic state, and therapies against AML can be tested in this system, especially the selective killing of AML cells in the presence of other BM cells. Furthermore, this model requires no exogenous administration of cytokines to maintain human hematopoiesis with both normal or AML bone. Because the structure and function of both normal and diseased human adult bone is maintained, this animal model should facilitate investigation of both normal human hematopoiesis and hematopoietic malignancies.
Sandhu
J S
JS
Department of Surgery, University of Toronto, Ontario, Canada.
Clark
B R
BR
Boynton
E L
EL
Atkins
H
H
Messner
H
H
Keating
A
A
Hozumi
N
N
D000208:Acute Disease; D000818:Animals; D016025:Bone Transplantation / Q000473:pathology*; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D016130:Immunophenotyping; D007951:Leukemia, Myeloid / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D013154:Spleen / Q000166:cytology; D014183:Transplantation, Heterologous
D007074:Immunoglobulin G; D017493:Leukocyte Common Antigens