Bone marrow stromal cell transplantation

Bone marrow is the seat of hematopoiesis. Proliferation and differentiation of hematopoietic progenitors are controlled by the medullary microenvironment which is constituted by stromal cells acting through growth factors, and adhesion molecules. The medullary stromal cells that have primary functions in the control of normal hematopoiesis could be used to locally produce growth factors that would allow the stimulation of hematopoiesis. The study presented in this report first aims to assess the ability of these cells to implant in the bone marrow, then to consider the use of stromal cells as vectors to produce local growth factors to stimulate hematopoiesis. The SCID and NOD-SCID mice are immuno-tolerant, the subcutaneous transplantation of human fetal bone fragments allows the maintenance of human hematopoiesis in vivo in its own microenvironment for several months (SCID or NOD-SCID-hu) mice. NOD-SCID-hu mice were used as hosts for the study of stromal cell transplantation. Three types of stromal cells were used in this study: - a human line (MRC-5) expressing the gene for β-galactosidase, - a murine stromal line (MSS) that was transfected to produce IL3-hu and cells derived from human stromal precursors that have been retrovirally transduced and express CD2m. These cells were injected directly into human grafts, or intravenously into NOD-SCID-hu mice. Genetically modified stromal cells have been implicated in human fetal bone grafts but also in the bone marrow, liver and spleen of mice. MSS cells produced detectable IL3-hu in mouse key serum and their implantation in human grafts was correlated with stimulation of human hematopoiesis. This study has also shown that human medullary stromal cells can be retrovirally transduced and can be transplanted. These cells could therefore be proposed as a vector for locally producing a molecule of therapeutic interest