Blood diseases and cancers can in some cases be cured by transplantation of the stem cells that develop into the various types of blood cells. At present stem cell transplantation relies on the use of donated cells from the bone marrow or umbilical cord blood, but locating and obtaining suitable donated cells is in many cases difficult or impossible; this problem is especially prominent in some minority groups. This project aims to explore methods that may lead to the use of human embryonic stem (hES)-derived blood stem cells as a substitute for donated cells in blood stem cell transplantation. Preliminary work demonstrates that cells with the characteristics of blood cell precursors can be isolated from hES cells that have been allowed to differentiate in culture, but we need to know much more about these cells before their use in patients could be considered. We will carry out a series of investigations of these cells, as an approach to the goal of using them in clinical stem cell transplantation. Because the current methods of deriving the stem cells from hES cells are cumbersome and small-scale, we will work to develop methods that will allow large-scale preparation with simplified procedures suitable for clinical work. We will investigate the development of a variety of marker proteins on the surface of the stem cells as they develop, thereby aiding isolation of subtypes of cells, and also helping us to understand how they may interact with the immune system of the recipient individual. We will use an established model in which human blood cells can develop in the mouse in order to assess the ability of the hES-derived cells to develop into the many types of blood cell. Work to date has focused on one type of hES-derived blood cell precursor. In order to expand the possible utility of these cells, we will seek new types of blood cell precursors in populations of cells derived from hES cells. This proposal has the potential to lead to the production of cells that can be used in clinical blood stem cell transplantation, which would transform the procedure and make it available to many more individuals.
Statement of Benefit to California:
Very large numbers of individuals in California are afflicted with diseases that can be cured or ameliorated by transplantation of blood stem cells; these include, for example, sickle cell disease and leukemia. Nevertheless the application of blood stem cell transplantation is limited because stem cells must be donated by individuals, and because it is necessary to match certain characteristics of the donor’s and host’s immune systems. Blood stem cells can be derived from human embryonic stem (hES) cells. Such hES-derived cells could become a substitute for donated stem cells, but before this is possible it will be necessary to know much more about their characteristics, and to develop means of producing them in quantities sufficient for clinical use. The experiments we propose are an approach to the goal of making hES-derived stem cells that can be used in clinical blood stem cell transplantation. Successful completion of these experiments will allow us to make judgments about the feasibility of using these hES-derived cells in patients, and may thus contribute to the goal of making blood stem cell transplantation available to a much broader group of patients.