The hematopoietic stem cell niche

Hematopoiesis is a hierarchical organized process that has its origin in the long-term repopulating hematopoietic stem cell (LT-HSC). Due to a process called asymetrical division this cell creates a new HSC and a short-term repopulating cell which leads only to transient repopulation of a lethally irradiated host when transplanted.

Several transcription factors have been identified that are required for the establishment of definitive hematopoietic stem cells (like AML1, CBFβ and HIF-1α) but once definitive hematopoiesis has been established might be dispensable for hematopoietic stem cell maintenance. Despite the tremendous advances in the field, our knowledge about the molecular mechanisms of hematopoietic stem cell self-renewal is still very limited. Schofield proposed in the 70th that the hematopoietic stem cell resides in a specific niche which provides a special microenvironment.

 The hematopoietic stem cell niche is located in the endosteal space where HSC reside in close proximity to osteoblasts and stroma cells which provide special growth factors like VEGF, SDF and Notch ligand to the HSC. It has also been suggested that the HSC stem cell niche is hypoxic but experimental evidence for this hypothesis remains scarce. The major molecular response to low oxygen tension is the induction of a transcription factor called hypoxia inducible factor-1 alpha (HIF-1α). HIF-1α heterodimerizes with HIF-1α to form a transcription factor complex which binds to hypoxia response elements (HRE) and activates genes involved in glucose metabolism, angiogenesis, cell proliferation/survival and invasion/metastasis. Which effect hypoxia and the regulation of HIF-1alpha target genes has on HSC self-renewal and maintenance is poorly understood.

Our lab investigates whether under physiologic conditions the HSC stem cell niche is hypoxic and how the molecular response to hypoxia might contribute to hematopoietic stem cell self-renewal. Additionally, we investigate the role of hypoxia-induced VEGF expression on murine hematopoietic stem cells.