Age-specific differentiation of multipotent progenitors

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PROJECT SUMMARY/ABSTRACT The foundation of this project is based on the clinical observation that adults and children are affected by different blood disorders, many of which show typical age biases. Accumulating evidence supports the notion that the scripted changes that occur normally in the hematopoietic system during development and aging create transient, age-specific hematopoietic substrates in which these diseases develop. The blood forming system undergoes a controlled maturation process wherein the prioritized lineage outputs, mechanisms of lineage restriction, and rates of hematopoietic stem cell (HSC) self-renewal change from early development through maturation of the organism. Postnatally, as the hematopoietic system ages, these changes continue with a progressive myeloid bias and further diminishment of HSC self-renewal. These temporal changes in the mechanisms of blood formation appear to be regulated both intrinsically and extrinsically, as both the anatomic location and cellular composition of the hematopoietic microenvironment change with time in concert with the function of HSCs. Our prior K08-supported research has identified a novel potential mechanism of epigenetic control of the transition from the transient, juvenile state of hematopoiesis to mature adult hematopoiesis. Here, we will investigate molecular mechanisms regulating the shifting lineage biases that occurs during hematopoietic maturation.