Methods for the use of stromal cells for therapeutic gene therapy

The logic behind the use of bone marrow stromal cells in gene therapy relies heavily on data that indicate the uniqueness of the bone marrow stromal cell as a differentiated cell phenotype distinct from the embryo fibroblast, adult connective tissue fibroblast, and cells derived from other sites such as the skin, or connective tissue in muscle (Table 1) (1-15). Bone marrow stromal cells comprise the slowly proliferating supportive tissue of the hematopoietic microenvironment. The anatomic localization, biology, physiology, and growth of these cells in tissue culture have been the subject of intense investigation by experimental and clinical hematologists for several years (16-28). A major controversy in basic hematology has been the question of whether bone marrow stromal cells of the hematopoietic microenvironment are transplantable. Classic bone marrow transplantation biology (30-38) has provided significant data to indicate that the hematopoietic stem cell and committed progeny are transplantable in vivo (for review, see refs. 29,39). Techniques to transplant bone marrow stem cells have gained common acceptance in both experimental and clinical hematology. In contrast, transplantation of slowly proliferating stromal cells of the hematopoietic microenvironment has only recently been demonstrated (29,33,40-51), and confirmed by others (52). The use of bone marrow stromal cells in somatic cell gene therapy has recently become a realistic option. for clinical therapeutic management.