Infoscience

Thesis

Novel determinants of the hematopoietic microenvironment in development and homeostasis

The promise of regenerative medicine depends on succeeding at generating sufficient amounts of functional, transplantable tissue by reliably differentiating pluripotent stem cells through the paths of ontogeny, or by efficiently expanding adult stem cells in vitro. For that purpose, the environmental cues responsible for cell fate decisions in vivo need to be deciphered and reproduced in vitro. We have focused on the hematopoietic system as a the best characterized stem cell model system, and present here two novel modulators of the embryonic and adult hematopoietic microenvironment. Firstly, we present data consistent with a negative effect of bone marrow adipocytes in adult hematopoiesis. Adult bone marrow contains numerous adipocytes, whose numbers correlate inversely with the hematopoietic activity of the marrow. In particular, non-hematopoietic skeletal regions are adipocytic in the adult, and fatty infiltration of the hematopoietic red marrow occurs following irradiation or chemotherapy, constituting a diagnostic feature in marrow aplasia. Whether adipocytes participate in hematopoietic regulation or simply expand to fill the marrow space has been unclear. Here we show that OP9-derived adipocytes inhibit hematopoietic expansion in vitro, that murine hematopoiesis is reduced in adipocyte-rich marrow during homeostasis, and that genetically or pharmacologically antagonizing adipocytes after bone marrow transplantation enhances the hematopoietic recovery of the marrow, therefore contradicting the historic dogma that bone marrow adipocytes act as mere space fillers in the hematopoietic milieu. Subsequently, we show that shear stress forces alike those shaping the embryonic vascular system at the time of the onset of a heartbeat enhance the differentiation of competent Flk1+ mesoderm into hematopoietic progenitors from ES cells and from embryo-derived AGM cells, a phenomenon partially dependent on nitric oxide production. Further in vivo relevance of this finding is supported by the fact that Ncx1-/- embryos, which cannot initiate a heartbeat, do not initiate functional hematopoiesis in the AGM region. Both of the environmental determinants presented here constitute novel aspects of hematopoietic biology and have important potential applications in the derivation of hematopoietic stem cells from pluripotent cells and in the biology of bone marrow transplantation, providing further refinement of the hematopoietic niche model in development and homeostasis

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