Hans Sieburg Sanford-Burnham Medical Research Institute Hans B Sieburg (1) and Christa E Muller-Sieburg (2) (1) Sanford-Burnham Medical Research Institute, Department of Stem Cells and Regenerative Medicine, 10901 North Torrey Pines Road, La Jolla CA 92037 hsieburg@sbmri.org (2) Sanford-Burnham Medical Research Institute, Department of Stem Cells and Regenerative Medicine, 10901 North Torrey Pines Road, La Jolla CA 92037 ABSTRACT Stem Cells can generate whole organisms (embryonic stem cells) or complete organ systems (adult tissue stem cells), including partially fluidic tissues such the hematopoietic system. The power of each stem cell to (re-)generate on this massive scale depends on the ability to give rise to all cell types by pluri-potent (embryonic), or multi-potent (tissue) differentiation. Since differentiation depletes their compartment, stem cells must be able to proliferate reliably to preserve multi-potency (self-renewal). A large body of evidence collected by us and others over the last decade for mouse and human (reviewed in [1]), demonstrates that hematopoietic stem cells (HSCs) form a heterogeneous population - contrasting the previous belief that all HSCs are the same. Individual HSCs differed remarkably in their self-renewal and differentiation behaviors when their clonal hematopoietic systems were followed in vivo over long periods of time. The data, moreover, show that these behaviors are fixed in the adult organism, thus suggesting that HSC heterogeneity emerges during development. Also, we found that hematopoietic aging manifests as a shift in the composition of the HSC compartment towards lower heterogeneity at the system level, but unaltered capacity at the level of individual HSCs. Together, the current data outline the long-term dynamics of hematopoiesis sufficiently to yield unexpected mathematical and computational predictions. We argue that reevaluating the interpretation of previous experimental and clinical findings in light of HSC heterogeneity is an essential investment into developing improved treatments of blood cancers in adults and the elderly. References [1] Christa E Muller-Sieburg, Hans B Sieburg, Jeff M Bernitz, Giulio Cattarossi Stem cell heterogeneity: implications for aging and regenerative medicine, Blood 119, pp. 3900–3907.