Functional consequences of stem and progenitor cell heterogeneity

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OVERALL PROJECT SUMMARY This program brings together five hematopoiesis investigators who have been working collaboratively to address the fundamental question of how individual hematopoietic stem and progenitor cells (HSPC) are regulated to contribute to the production of blood under homeostatic and stress conditions. It creates a collective of complementary technologies developed in the investigator's laboratories to track individual clones in vivo and thereby to model how distinct clonal behaviors contribute to hematopoietic output under varying conditions. Furthermore, it employs innovative tools for manipulating specific molecular regulators of gene expression to test which molecules drive specific HSPC behaviors. These are tested in the context of inflammatory and genotoxic stress and are evaluated for their ability to alter the competitive relationship of normal HSPC with clones bearing blood disease associated alleles known to accumulate in the aging human. The cross comparison of models, species, time in development and molecular parameters (mRNA, meDNA, ncRNA, chromatin state) shared through an established common database and analytic tools provide a uniquely powerful means of defining with high resolution the process of hematopoiesis. By providing a mechanism to sustain interaction, share data and techniques and create a forum for resolution of conflicting data, this PO1 will facilitate the creation of a hematopoiesis `roadmap' whereby interventions at specific molecular waypoints can modulate blood cell production to enhance hematopoietic regeneration and limit aberrant clonal outgrowth in settings of disease.