Transplantable marrow osteoprogenitors engraft in discrete saturable sites in the marrow microenvironment.
OBJECTIVE
Based on the recognition that marrow contains progenitors for bone as well as blood, we undertook the first trial of bone marrow transplantation (BMT) for a genetic disorder of bone, osteogenesis imperfecta. While we documented striking clinical benefit soon after transplantation, the measured level of osteopoietic engraftment was low. To improve the efficacy of BMT for bone disorders, we sought to gain insight into the cellular mechanism of engraftment of transplantable marrow osteoprogenitors.


METHODS
We transplanted unfractionated bone marrow harvested from green fluorescent protein-transgenic FVB/N mice into lethally irradiated FVB/N recipients. At 3 weeks posttransplantation, we assessed hematopoietic engraftment by flow cytometry and osteopoietic engraftment by immunohistochemical staining for the green fluorescent protein.


RESULTS
We show that engraftment of transplantable marrow osteoprogenitors is saturable with a maximal engraftment of about 15% of all bone cells in the epiphysis and metaphysis of the femur at 3 weeks after transplantation. The number of engrafting sites is not up- or downregulated in response to initial progenitor cell engraftment, and there is no evidence for clonal succession of osteopoietic differentiation of engrafted progenitors.


CONCLUSIONS
Our findings indicate that the capacity for initial osteopoietic engraftment after BMT is limited and "megadose" stem cell transplantation is unlikely to enhance engraftment. Thus, novel strategies to foster osteopoietic chimerism must be developed.
Marino
Roberta
R
Division of Bone Marrow Transplantation, St Jude Children's Research Hospital, Memphis, TN, USA.
Martinez
Caridad
C
Boyd
Kelli
K
Dominici
Massimo
M
Hofmann
Ted J
TJ
Horwitz
Edwin M
EM
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000276:immunology; D016026:Bone Marrow Transplantation; D005434:Flow Cytometry; D006085:Graft Survival / Q000276:immunology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology* / Q000276:immunology / Q000637:transplantation*; D012680:Sensitivity and Specificity
D049452:Green Fluorescent Proteins