Abstract
We examined gap junction communication in an in vitro model of hematopoiesis, using the murine bone marrow stroma cell line S-17, and primary cultures of murine marrow-derived blood cell precursors. S-17 cells express several connexins, the major one being connexin 43. Connexin expression and formation of functional gap junctions is modulated by stroma cell density. Transfection of S-17 cells with a vector containing connexin 43 sense or anti-sense sequences increased or decreased, respectively, connexin 43 synthesis and intercellular dye coupling. Under these conditions, modulation of gap junction-mediated communication modified the growth pattern of stroma itself, as well as the ability of the stroma to sustain hematopoiesis. Increased connexin 43 expression was associated with a delay in differentiation of blood cells, resulting in increased production of hematopoietic precursors, while decreased connexin 43 expression elicited an accelerated differentiation of myeloid blood cell precursor cells. These results suggest that connexin-mediated coupling in the stroma modulates the ratio between proliferation and differentiation of hematopoietic precursors. We therefore propose that increased gap junction communication in the stroma elicits an enhanced production of immature bone marrow cells through the delay in their terminal differentiation, inducing consequently an extended proliferation period of blood cell precursors.
Highlights
Gap junctions are specialized cell membrane structures that form ion channels interconnecting the cytoplasm of adjacent cells
Connexin expression was monitored in early confluence and post-confluence of S-17 cultures
We have shown, in an in vitro experimental model of hematopoiesis, that a bone marrow stroma cell line expresses several connexins, the major one being Cx43, and forms functionally competent gap junctions
Summary
Gap junctions are specialized cell membrane structures that form ion channels interconnecting the cytoplasm of adjacent cells. All the lineages are derived from a small population of totipotent hematopoietic stem cells, which follow a programmed progressive restriction of their proliferating capacity, generating the terminally differentiated mature blood cells. The early part of the proliferation cascade involves the generation of totipotent or multipotent cells, while the later one produces the most differentiated cells (Johnson 1984). At each step of this cascade, hematopoietic cells respond in a different manner to various growth factors, cytokines, or inhibitors of proliferation and differentiation present in the bone marrow environment. Chronological order of hematopoiesis is spatially ordered, providing a defined microenvironment to the cells that are at a specific developmental stage, inducing the step of their commitment and differentiation (Metcalf 1993)
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