Clonal diversity of the stem cell compartment

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Abstract
Hematopoietic stem cells are functionally heterogeneous even when isolated as phenotypically homogenous populations. How this heterogeneity is generated is incompletely understood. Several models have been formulated to explain the generation of diversity. All of these assume the existence of a single type of hematopoietic stem cell that generates heterogeneous daughter stem cells in response to extrinsic or intrinsic (stochastic) signals. This view has encouraged the idea that stem cells can be instructed to adapt their function. Newer data, however, challenge this concept. Here, we summarize these findings and discuss their implication for applications of stem cells. Hematopoietic stem cells that differ in function have been documented during development and within the adult stem cell compartment. The differences in function are stably inherited to daughter stem cells when these cells proliferate to self-renew. Collectively, the data show that the adult stem cell compartment consists of a limited number of distinct classes of stem cells. The most important stem cell functions, including self-renewal and differentiation capacity, are preprogrammed through epigenetic or genetic mechanisms. Thus, stem cells are much more predictable than previously thought. Changes in the stem cell compartment through disease or aging can be interpreted as shifts in its clonal composition, rather than a modification of individual hematopoietic stem cells.