This renewal application proposes to examine two fundamental issues in hematopoietic stem cell (HSC) biology, namely the relationship between cell cycle status of these cells and maintenance of their hematopoietic potential and how the dynamics between mitotic quiescence and HSC potential change during hematopoietic development. In the previous funding period, we surveyed the hematopoietic potential of cycling and quiescent HSC from human hematopoietic tissues through ontogeny and established that in adult tissues, a hierarchy of hematopoietic potential can be assembled based on the mitotic status of HSC. However, this hierarchical order does not predominate during fetal development where mitotically quiescent and cycling HSC, sustain long-term hematopoiesis. We examined if extrinsic factors can modulate the fate of primitive hematopoietic progenitors and determined that, with appropriate intervention, hematopoietic function and self-renewal can be maintained through successive in vitro divisions. These modulators included unidentified factors from committed progeny of HSC thus corroborating our proposed instructional clonal activation as a model for maintenance of steady state hematopoiesis and the stem cell pool. New information gathered to date, prompt us to pursue new and challenging concepts regarding our ability to extrinsically modulate HSC fate and the outcomes of the interaction between stem cells and their hematopoietic microenvironment at different stages of development. To better understand these critical issues in stem cell biology, two specific aims will be examined. First we will investigate if microenvironmental cues in fetal but not adult hematopoietic tissues induce dividing stem cells to retain their reconstitution potential while traversing through all phases of cell cycle. Second, we will investigate if stem cell fate can be modulated by factors elaborated by different hematopoietic and non-hematopoietic cell types including endothelial and myo-epithelial cells and more differentiated, lineage committed hematopoietic cells. Testing these specific aims should yield valuable information regarding normal hematopoiesis and the mechanisms that regulate stem cell fate. These studies are critical for assessing the impact of the interaction of stem cells with their hematopoietic microenvironment on stem cell function throughout ontogeny. ? ?
| Hooker, R A; Chitteti, B R; Egan, P H et al. (2015) Activated leukocyte cell adhesion molecule (ALCAM or CD166) modulates bone phenotype and hematopoiesis. J Musculoskelet Neuronal Interact 15:83-94 |
| Cheng, Ying-Hua; Streicher, Drew A; Waning, David L et al. (2015) Signaling pathways involved in megakaryocyte-mediated proliferation of osteoblast lineage cells. J Cell Physiol 230:578-86 |
| Wang, Lin; Zhang, Huajia; Rodriguez, Sonia et al. (2014) Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-?B-dependent manner. Cell Stem Cell 15:51-65 |
| Chitteti, Brahmananda Reddy; Kobayashi, Michihiro; Cheng, Yinghua et al. (2014) CD166 regulates human and murine hematopoietic stem cells and the hematopoietic niche. Blood 124:519-29 |
| Chitteti, Brahmananda R; Cheng, Ying-Hua; Kacena, Melissa A et al. (2013) Hierarchical organization of osteoblasts reveals the significant role of CD166 in hematopoietic stem cell maintenance and function. Bone 54:58-67 |
| Bethel, Monique; Chitteti, Brahmananda R; Srour, Edward F et al. (2013) The changing balance between osteoblastogenesis and adipogenesis in aging and its impact on hematopoiesis. Curr Osteoporos Rep 11:99-106 |
| Cheng, Ying-Hua; Hooker, R Adam; Nguyen, Khanh et al. (2013) Pyk2 regulates megakaryocyte-induced increases in osteoblast number and bone formation. J Bone Miner Res 28:1434-45 |
| Chitteti, Brahmananda Reddy; Bethel, Monique; Voytik-Harbin, Sherry L et al. (2013) In vitro construction of 2D and 3D simulations of the murine hematopoietic niche. Methods Mol Biol 1035:43-56 |
| Chitteti, Brahmananda R; Bethel, Monique; Kacena, Melissa A et al. (2013) CD166 and regulation of hematopoiesis. Curr Opin Hematol 20:273-80 |
| Culang-Reinlieb, Michelle E; Sneed, Joel R; Keilp, John G et al. (2012) Change in cognitive functioning in depressed older adults following treatment with sertraline or nortriptyline. Int J Geriatr Psychiatry 27:777-84 |
Showing the most recent 10 out of 38 publications
