High dose chemotherapy followed by stem cell transplantation (SCT) is routinely used for treatment of patients with hematological malignancies and solid tumors. Patients receiving SCT have significant periods of neutropenia and thrombocytopenia and prolonged periods of depressed immune cells, particularly recipients of cord blood (CB) grafts. Ex vivo expansion of hematopoietic grafts could provide more rapid engraftment and decrease graft failure of CB recipients. Despite extensive studies to determine the hematopoietic cells that are responsible for rapid hematopoietic recovery, there is debate to which cells provide recovery of neutrophils, platelets and immune cells. Therefore there is debate as to which cells should be expanded ex vivo. We hypothesize that i) distinct mature precursor cells are responsible for neutrophil, platelet and lymphoid engraftment, ii) intermediate engraftment is provided by committed and/or multipotential precursors, and iii) long term engraftment is provided by totipotent hematopoietic stem cells (HSC). Using a mouse transplant model we will determine the cells providing short term engraftment, intermediate cell engraftment and long term durable engraftment These studies will evaluate the contribution of candidate stem cell populations to both short term and long term engraftment The goal of this project is to identify and characterize the murine cells responsible for recovery of each lineage of hematopoietic cells. In addition, mouse ex vivo expansion studies will be conducted to characterize the growth factor cocktails that stimulate optimal generation of each of these populations. We also hypothesize that ex vivo expanded cells require additional growth factors when infused in vivo and we will determine the growth factors that provide optimal engraftment of expanded cells in vivo. These studies will be combined to identify the optimal numbers of each population and optimal timing of transplantation and growth factor treatment We propose that these studies will lead to better defined mouse grafts that provide optimal engraftment and will then provide the basis for evaluating human hematopoietic grafts for equivalent populations and further ex vivo expansion studies.
| Xiang, Ying; Wang, Jin-fu (2004) [Effect of Chinese drugs on proliferation and differentiation of hemopoietic stem/progenitor cells] Zhongguo Zhong Xi Yi Jie He Za Zhi 24:666-9 |
