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THE ROLE OF CONNEXIN-43-MEDIATED GAP JUNCTION INTERCELLULAR COMMUNICATION IN BLOOD FORMATION

KASTL, BRYAN DARYL
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1148139809

Abstract Details

2006, MS, University of Cincinnati, Allied Health Sciences : Transfusion and Transplantation Medicine.
Blood cell formation is a highly regulated process that depends on the proliferation and differentiation of hematopoietic stem cells (HSC). HSC are located in the endosteal area of the bone marrow (BM) cavity and their function depends on an intimate relation with osteoblasts and stromal (O/S) cells. The factors involved in this intercellular interaction are not known. We proposed that direct cell-to-cell intercellular communication (IC) at the endosteum is crucial for normal hematopoiesis, specifically under stress conditions. The best known form of IC is through channels called gap junctions (GJ), which allow the passage of small, charged molecules, including secondary messengers that may trigger intracellular signaling responses. GJ are formed by hexamers of proteins called connexins (Cx). One of these, connexin-43 (Cx43), is ubiquitously expressed and is the Cx most prevalent in BM. Cx43 is normally expressed at low levels in BM but administration of 5-fluorouracil (5-FU), a chemotherapy drug, has been shown to increase Cx43-expression in BM approximately 100-fold. Using an inducible, conditional Cx43 knock-out murine model, we found that Cx43 is critical for adult hematopoiesis after 5-FU administration. Here we analyzed the microlocalization of BM Cx43-expression after 5-FU administration, and confirmed that under stress conditions, Cx43-expression is predominantly located in the endosteum. Next, the hematopoietic function of Cx43-deficient mice was analyzed. We observed that Cx43-deficient mice displayed a major impairment in hematological recovery after 5-FU administration, which included myelo-, erythro- and thrombopoiesis. This correlated with a significant depletion of the cellularity and the myelo-erythroid progenitor content of the BM and spleen in Cx43-deficient mice. This depletion did not affect the HSC population, which concomitantly became enriched in BM. Competitive repopulation of Cx43-deficient HSC showed impaired short-term, but not long-term repopulation when compared to wild-type (WT) counterparts. Although a proliferation defect of Cx43-deficient mice cannot be ruled out, we found no significant decrease in the proliferation status of BM and spleen HSC in vivo in Cx43-deficient mice on Day 9 after 5-FU administration. Since Cx43 is expressed by O/S and HSC, we analyzed the effect of Cx43-deficiency in full hematopoietic chimeras, where either the O/S or the HSC were deficient in Cx43. The results suggest that HSC from WT Cx43 mice transplanted into mice with a Cx43-deficient expression in O/S cells induces significant monocytopenia and lymphopenia (p&lt0.05) in peripheral blood. Further, chimeric mice that express Cx43 in O/S cells and transplanted with Cx43-deficient HSC displayed leukopenia with neutropenia, monocytopenia and lymphocytopenia. This suggests that Cx43-expression plays a crucial role in both the HSC and O/S cell components. In summary, Cx43-expression in the BM endosteum appears to play a major role in the hematopoietic response to stress conditions.
Dr. Jose Cancelas (Advisor)
66 p.
Hematopoiesis; Cx43; Connexin; Gap Junction

Recommended Citations

Citations

  • KASTL, B. D. (2006). THE ROLE OF CONNEXIN-43-MEDIATED GAP JUNCTION INTERCELLULAR COMMUNICATION IN BLOOD FORMATION [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1148139809

    APA Style (7th edition)

  • KASTL, BRYAN. THE ROLE OF CONNEXIN-43-MEDIATED GAP JUNCTION INTERCELLULAR COMMUNICATION IN BLOOD FORMATION. 2006. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1148139809.

    MLA Style (8th edition)

  • KASTL, BRYAN. "THE ROLE OF CONNEXIN-43-MEDIATED GAP JUNCTION INTERCELLULAR COMMUNICATION IN BLOOD FORMATION." Master's thesis, University of Cincinnati, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1148139809

    Chicago Manual of Style (17th edition)

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This open access ETD is published by University of Cincinnati and OhioLINK.