Hematopoiesis and Gene Therapy of Hematopoietic Stem Cells

The main focus of our research is to develop gene therapy for hematopoietic cells, particularly hematopoietic stem cells. Similarly, there is a strong effort to study the genetic regulation of hematopoietic stem cell proliferation in novel animal models created in the department.

Hematopoietic stem cells are interesting target cells for gene therapy because they have an enormous proliferative capacity and can be used to repopulate the entire hematopoietic system in humans and experimental animals following bone marrow transplantation. Following effective gene transfer into hematopoietic stem cell of a patient, the genetically modified cells can be transplanted back to the patient and will be expected to produce genetically corrected cells of all blood lineages for a long time, perhaps for a lifetime.

To achieve our goals we are developing viral vectors to transfer genes into hematopoietic stem cells. Similarly, we study the target cells for the viral vectors, the hematopoietic stem cells. Of major importance for effective gene transfer of hematopoietic stem cells is their cell cycle stage. Quiescent, nondividing stem cells are difficult targets for gene transfer, but more activated cells and cells that are dividing are generally more susceptible to gene transfer. Therefore, we study the proliferation of hematopoietic stem cells in mutant mice that we have created in the department. These models have forced expression (gain-of-function) or gene deletion (lack-of-function) to modulate cell proliferation within the hematopoietic system. Mice that can be induced to eliminate or block the function of the TGF-b negative growth regulatory pathway have been generated and are used to study how this affects the function, proliferation and development of hematopoietic stem cells. Similar questions are studied in mice that can be induced to overexpress or lack Hox transcription factors which normally stimulate proliferation of hematopoietic stem cells.

Taken together, we focus on the development of gene therapy for hematopoietic stem cells, while simultaneously studying thedevelopment and proliferation of these target cells for gene therapy in novel engineered animal models.