Recent studies have demonstrated localization of hematopoietic stem cells in unexpected peripheral sites. For example, hematopoietic activity in the absence of extramedullary hematopoiesis has been described in skeletal and cardiac muscle. The accumulation and maintenance of hematopoietic cells in tissues such as muscle is difficult to explain. One hypothesis is that primitive hematopoietic cells normally circulate at low frequencies because they play a role in the innate immune response. Consistent with this hypothesis, several pro-inflammatory cytokines have strong co-stimulatory effects on hematopoietic cell proliferation and mobilization. This application seeks to test the hypothesis that bone marrow-related mechanisms can play an important role in peripheral inflammatory responses. The investigator will develop an experimental model to test the hypothesis that mobilization of hematopoietic cells from bone marrow into the peripheral blood is a mechanism which evolved to provide accumulation of these cells in peripheral tissues, where local production of cytokines directs them to expand and differentiate into myeloid cells during the normal response to inflammatory stimuli. As a first aim, experiments will determine if hematopoietic stem and progenitor cells mobilize from the bone marrow in response to peripheral inflammation.
The second aim of the study is to determine if mobilized or transplanted hematopoietic cells accumulate and differentiate within peripheral sites of inflammation. Peripheral inflammatory sites will be analyzed to determine if cells with hematopoietic activity accumulate and differentiate in situ to produce myeloid cells that contribute to the inflammatory response. We will also test the hypothesis that transplanted hematopoietic cells can accumulate in existing sites of peripheral inflammation and contribute to the generation of inflammatory responses in these sites. The results of this study may suggest approaches to limit pathological inflammation that sometimes impacts bone marrow transplant recipients.
| Spangrude, Gerald J; Cho, Scott; Guedelhoefer, Otto et al. (2006) Mouse models of hematopoietic engraftment: limitations of transgenic green fluorescent protein strains and a high-performance liquid chromatography approach to analysis of erythroid chimerism. Stem Cells 24:2045-51 |
