The GOD of Hematopoietic Stem Cells: A Clonal Diversity Model of the Stem Cell Compartment

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Abstract
Hematopoietic stem cells (HSC) show heterogeneous behavior even when isolated asphenotypically homogeneous populations. The cellular and molecular mechanisms that controlthe generation of diversity (GOD) in the HSC compartment are not well understood, but havebeen the focus of much debate. There is increasing evidence that the most important HSCfunctions, self-renewal and differentiation, are epigenetically preprogrammed and thereforepredictable. Indeed, recent data show that the adult HSC compartment consists of a limitednumber of functionally distinct subsets of HSC. This contradicts older models of HSC behavior,which postulated a single type of HSC that can be continuously molded into different subtypes ofHSC. We propose a clonal diversity model where the adult HSC compartment consists of a fixednumber of different types of HSC, each with epigenetically preprogrammed behavior. Aging ordisease may change the overall function of the HSC population. The model predicts that thesechanges reflect the relativ...