In this study, we show that removal of a quorum sensing subtype of stromal macrophage expands the support capacity of ex vivo bone marrow culture. Notably, this system maintains much of the remaining paracrine signaling of the organ, unlike traditional macrophage ablation or cytokine supplemented media and does not place undue stress on the HSPC itself. Recent studies have independently identified alternatively activated macrophages that suppress hematopoiesis in in vitro culture. We have identified for the first time, a small molecule capable of preferentially killing those cells, thus providing a method to both culture unaltered HSPC ex vivo for long periods of time and significantly expand transient progenitor cells to assist transplantation efficiency. Our culture system in unique in its ability to maintain cultured HSPC in the physiological micro-environment of the bone marrow
We found the small molecule “999” capable of expanding hematopoietic capacity of stroma culture by selectively eliminating an MHCII-Hi subpopulation of stromal macrophages that suppress HSPC growth. Removal of these macrophages enables long-term HSC ex vivo stability and massive expansion of the MPP and its progeny. Cultures expanded in this manner have increased engraftment potential and behave physiologically normal upon transplantation.
This investigation has also helped to uncover the role of TGFB in bone marrow quiescence signaling. The MHCII-HI target cells express TGFB and through it, signal quiescence to the HSPC, likely as a form of quorum sensing. Targeted acute elimination of that signal leads to unabashed expansion of MPP.
Furthermore, macrophage polarization in the tumor microenvironment has also been show to promote tumor formation and often leads to poor prognosis. Molecular tools such as 999 that have the ability to alter macrophage polarization ratios may prove to be valuable synergistic tools for oncologists in conjunction with current therapies.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/D8NC61CB |
| Date | January 2016 |
| Creators | Churchill, Michael John |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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