HSC Diversity, in aging, ontogeny, and transformation



 DESCRIPTION (provided by applicant): The blood system provides oxygen and nourishment to the body, and also contains cells that protect against infections, cancers, and blood loss. The appropriate production of all blood cells derives from a tiny fraction [~1 in 20,000] of blood forming cells in the adult bone marrow called blood forming stem cells. These stem cells are the only blood forming cells that can make more blood forming stem cells, a property called self-renewal. The stem cell transitions through many intermediate steps before giving rise to mature blood cell types-which are generally classified into two groups: myeloid (red blood cells [RBCs], platelets, granulocytes and macrophages) and lymphoid (B, T and NK cells) cells. At each successive step, there is a cell that becomes increasingly specialized by including some fates and excluding others. We wish to inquire why some blood forming stem cells, predominant in young mice and people, at the single cell level make roughly equivalent numbers of lymphoid and myeloid cells (balanced); and why other single stem cells, predominant in aged mice and humans, make very few new lymphoid cells, and make many more myeloid cells (myeloid-bias). Our preliminary evidence favors the hypothesis that a balanced stem cell is always balanced, no matter the age of the individual, while a myeloid biased stem cell is always biased; and these myeloid biased stem cells have a selective advantage in the aging individual. The experiments we describe provide multiple ways to answer this question in humans and mice. For example, in mice we have developed a method wherein we can determine the location and life history of single cells and their clonal progeny without the need to isolate them outside the body to study their properties. We bring all of these approaches to study how stem cells get their bias, move through the body, and how they are affected-and how their progenitor daughter cells are affected in normal blood formation, in genetic diseases of the blood, and in the development of preleukemias and leukemias. A number of blood diseases such as loss of oxygen carrying RBCs, or critical blood-clotting elements, or infection fighting cells can occur, usually due to inherited or acquired genetic abnormalities. We have shown, for example, that in human preleukemias the genetic changes that characterize these diseases, all occur in the single stem cells, some of which expand to make clones. Some clones eventually accumulate more mutations, so it is possible to determine the order of mutations for a particular patient and the patient's disease. In some preleukemias, such as in myelodysplastic syndrome [MDS], where there is a deficiency of one or more types of the mature blood cells, the individual mutations and order of addition of those mutations give strong clues about the cause of that cell's deficiency. When the preleukemic MDS clone progresses to acute leukemia, we have identified the kinds of mutations consistent with the progression and wild growth of the leukemia. Thus following the stages of normal blood cell development and analyzing the associated genetic changes can lead to better understanding of the cancer [or other blood diseases] and lead to new effective therapies.