THE ROLE OF BMP SIGNALING AND ENDOGLIN IN REGULATION OF HEMATOPOIESIS
Abstract: Hematopoiesis, the formation of blood cells, ultimately depends on a rare population of hematopoietic stem cells (HSCs), which can both self-renew to maintain the HSC pool, and differentiate into all mature blood lineages. HSC fate decisions are governed by a complex combination of numerous signals, although the molecular mechanisms are not fully understood. This thesis describes the role of two important regulatory candidates, Bone Morphogenetic Proteins (BMP) and Endoglin in adult hematopoiesis. Several publications have described the importance of BMP signaling in specification of hematopoietic tissue in developing embryos. In Article I and II, we investigate the full role of BMP signaling in adult mice, using single and double Cre-based conditional knockout mice for the BMP signaling mediators Smad1 and Smad5. We demonstrate that BMP signaling deficient bone marrow (BM) competes normally with wild-type cells and display unperturbed self-renewal and differentiation capacity when transplanted into lethally irradiated recipients. Thus, despite its crucial role in initial patterning of hematopoiesis, BMP signaling is not required to maintain adult hematopoiesis. Endoglin is a TGF-β accessory receptor recently demonstrated to identify functional long-term HSCs, although little is known regarding its function in these cells. We have investigated the role of endoglin in hematopoiesis by both knocking down, and over-expressing its levels using viral vectors. Interestingly, our study suggests a pivotal role for endoglin in adult erythropoietic development. However, transplantation of transduced BM stem and progenitor cells reveals that neither endoglin suppression nor over-expression affects the ability of HSCs to long-term repopulate recipient marrow.
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