Exercise has been shown to influence nearly every tissue type in the body, including the hematopoietic system. The means by and the extent to which exercise is able to do this is unknown. Here, we investigated the effects of skeletal muscle and exercise on several components of hematopoiesis. Firstly, we investigated exercise induced changes in skeletal muscle endocrine signalling. We demonstrated that exercise increased skeletal muscle hypoxia, leading to HIF1α and HIF2α stability, resulting in increased expression of erythropoietin. As well, myoblasts in culture were shown to express and release erythropoietin in response to hypoxia. Secondly, we measured mobilization of hematopoietic cells during exercise. We demonstrated that exercise greatly increased the number of hematopoietic stem cells in circulation. The quantity of mobilization was dependent on exercise intensity, did not depend on fitness levels, and was at peak immediately post exercise. Thirdly, we measured levels of extramedullary hematopoiesis following exercise. Exercise increased spleen hematopoietic stem cell content. Furthermore, expression of genes associated with hematopoietic homing, adhesion, quiescence, and growth were all increased in the spleen following exercise. Finally, we examined bone marrow in the appendicular and axial skeleton of aged animals. Here, exercise increased bone marrow cellularity and reduced bone marrow adiposity in the appendicular skeleton of aged mice. However, lumbar vertebral marrow cellularity and skeletal muscle expression of hematopoietic cytokines in these mice was unaffected by exercise. Taken together, these results demonstrate that exercise is a potent mediator of hematopoietic homeostasis. Several themes recurrent in these and other studies lead to insight in how exercise is able to exert influence on hematopoiesis, namely: tissue specific changes in hematopoietic growth and homing factor expression, the ability of mechanical forces felt during exercise to alter the bone marrow niche microenvironment, and increased flux of hematopoietic stem cells through their various bodily niches. / Thesis / Doctor of Philosophy (PhD) / Exercise affects many different tissue types throughout the body. The hematopoietic system, through which the body produces blood cells, is no exception. How exercise as a stimulus is able to influence this system is poorly understood. Here, we demonstrate that exercise is able to stimulate skeletal muscle to produce erythropoietin, a potent hematopoietic growth factor. As well, we demonstrate that exercise is capable of mobilizing hematopoietic stem cells from the bone marrow to the blood. We then describe how exercise is able to increase hematopoietic activity outside the bone marrow. Finally, we show that exercise affects marrow in only certain bone marrow cavities. Our findings demonstrate that exercise is able to influence hematopoiesis in a myriad of ways. As well, our findings highlight potential commonalities in the means by which exercise exerts these influences.

Thesis (Ph. D.)--West Virginia University, 2006. / Title from document title page. Document formatted into pages; contains x, 180 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references.

This study examined how the monoblast-like human histiocytic lymphoma cell line U937 can be induced by phorbol 12-myristrate 13-acetate (PMA) to undergo differentiation. In order to study the mechanism of action of CSF-1, a CSF-1 receptor gene (c-fms) was transfected into U937 cells. Exogenous CSF-1 treatment induced an autocrine response in this CSF-1 was determined and all events were shown to be time dependent. CSF-1 stimulation also enhanced proto-oncogene c-jun and c-myc gene expression. Complementary DNA coding for Jun or Fos was introduced into U937 cells by transfection. The transfection did not generate a high level of CSF-1 gene expression which suggests that Fos and Jun alone are insufficient to induce CSF-1 synthesis.

No description available.

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references (p. 112-126).

Thesis (Ph. D.)--University of Chicago, Dept. of Pathology, August 2001. / Includes bibliographical references. Also available on the Internet.

The SOX (Sry-related HMG box) genes belong to a family of transcription factors containing a High-Mobility-Group box domain. In an initial screen, SOX7 was uniquely down-regulated in myeloid malignancies compared with most cases of precursor B-cell acute lymphoblastic leukemia (ALL) and normal bone marrow cell, leading us to examine the expression and function of SOX7 during normal hematopoietic differentiation and in acute lymphoblastic leukemia. By studying human umbilical cord blood (UCB), SOX7 expression in different hematopoietic lineages was evaluated by RT-PCR. SOX7 was preferentially expressed in CD34+CD38- compared with CD34+CD38+ population and in CD34-CD19+ compared with CD34-CD33+ cells. SOX7 expression was down-regulated in colonies in CFU assay and in engrafting myeloid cells in NOD/SCID mouse transplantation. Transfecting SOX7 siRNA into CD34+ cells reduced cell growth and the CD34+CD33+ population in 3-day culture; induced cell-cycle arrest at G1 phase; reduced clonogenic activities but had no effect on apoptosis. Overall engraftment into NOD/SCID mice were not affected but the engrafting myeloid populations were reduced. In acute lymphoblastic leukemia, SOX7 was robustly expressed, compared with that in normal UCB and acute myeloid leukemia (AML). In 5 ALL patients in whom the coding sequence of SOX7 was examined, 3 of them showed mutations (amino acid change) in the SOX C-terminal transactivation domain. No mutation was observed in the β-catenin binding site. Knockdown of SOX7 with specific siRNA significantly increased appoptosis and decreased cell proliferation. SOX7 knockdown by shRNA in a precursor B-cell ALL cell line Nalm20 significantly reduced its engraftment into NOD/SCID mice. In summary, SOX7 is preferentially expressed in early hematopoietic stem and progenitor cells and is important for the maintenance of myeloid progenitor. It is also expressed in the primitive population of ALL and is important for leukemia initiation in ALL. The present study has generated important information about the regulation of normal hematopoiesis and acute lymphoblastic leukemia / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

During embryogenesis, hematopoietic cells arise from the lateral plate mesoderm (LPM) following gastrulation. The transcriptional program required for this LPM to blood switch is not fully understood. Previous work on a zebrafish mutant with a deletion in the cdx4 gene demonstrated the importance of this caudal transcription factor in the LPM to blood transition. To explain how cdx4 regulates embryonic hematopoiesis, two main approaches were taken in this thesis. The first part of the thesis describes a chemical genetics screen that identified cdx4 interacting pathways. To find small molecules that could rescue the loss of red blood cells caused by the cdx4 deletion, cdx4 mutant embryos were incubated with 2640 compounds from the beginning of the gastrula stage to the 10-somite stage. Two related psoralen compounds, Bergapten (Ber) and 8-methoxypsoralen (8-MOP), rescued the erythroid progenitors in the cdx4 mutants. This rescue is closely linked to the compounds' effects on anteriorposterior patterning, reminiscent of retinoic acid pathway compounds. The second part of my thesis identifies a Cdx4-Sall4 transcriptional module in the LPM. Chromatin-immunoprecipitation coupled to sequencing (ChIP-seq) and microarray analysis revealed that Cdx4 directly regulates cdx4 and a zinc finger transcription factor spalt-like 4 (sall4) transcription. Sall4 ChIP-seq showed that Sall4 also binds to its own locus and to the cdx4 locus, suggesting an auto- and cross-regulation between two transcription factors. In addition, Cdx4 and Sall4 bind to common genomic regions proximal to mesodermal progenitor (tbx16 and mespa) and hematopoietic genes (scl, gata2a, and ldb1a), indicating Cdx4 and Sall4 co-regulate key genes that are required for LPM and blood specification. sall4 knockdown in the cdx4 mutants demonstrated that Sall4 synergizes with Cdx4 in regulating embryonic hematopoiesis. These findings suggest that auto- and cross-regulation of Cdx4 and Sall4 establish a stable circuit in the LPM that facilitates the activation of blood-specific program as development proceeds. How undifferentiated germ layers transition into various tissues is a key question in developmental biology. My thesis establishes a model based on LPM to blood transition, which is also applicable to other studies on germ layer specification.

No description available.

Thesis (doctoral)--Københavns universitet.