Recombinant human bone morphogenetic protein-2 induces a hematopoietic microenvironment in the rat that supports the growth of stem cells.
In the mammalian bone marrow, stromal components support the growth and differentiation of blood cells. To study this complex system, we used a rat model in which ectopic hematopoietic tissue was induced to form after subcutaneous implantation of recombinant human bone morphogenetic protein (rhBMP-2). We showed that this organoid contained clonogenic precursors of both erythroid and myeloid lineages and progenitors competent to regenerate splenic lymphopoiesis. Furthermore, stem cells derived from ectopic foci conferred both short-term (30 day) and long-term (>6-month) protection in vivo against radiation-induced marrow aplasia. Lead shielding of the ectopic marrow in situ also permitted endogenous recovery of hematopoiesis after sublethal irradiation. Extending previous observations that most fibroblastoid cells of the marrow stain with the anti-ST3 antibody (but minimally with anti-ST4), whereas those growing from nonhematopoietic tissues react with anti-ST4, we found that analogous cells of the ectopic foci stained predominantly with anti-ST3. The ability to induce formation of a hematopoietic microenvironment from mesenchymal precursors may make possible the development of new strategies for the treatment of primary disorders of stem cells and irreversible stromal injury.
An
J
J
Division of Hematology/Medical Oncology, Royal Victoria Hospital, Montréal, Québec, Canada.
Rosen
V
V
Cox
K
K
Beauchemin
N
N
Sullivan
A K
AK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology; D001483:Base Sequence; D016026:Bone Marrow Transplantation; D019485:Bone Morphogenetic Proteins; D016025:Bone Transplantation; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D003238:Connective Tissue / Q000187:drug effects; D003239:Connective Tissue Cells; D004343:Drug Implants; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008969:Molecular Sequence Data; D009940:Organoids / Q000473:pathology; D010641:Phenotype; D011506:Proteins / Q000494:pharmacology*; D011828:Radiation Chimera; D051381:Rats; D011914:Rats, Inbred BN; D011994:Recombinant Proteins / Q000494:pharmacology; D012867:Skin; D016042:Transplantation, Heterotopic
D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D019485:Bone Morphogenetic Proteins; D004343:Drug Implants; D011506:Proteins; D011994:Recombinant Proteins