Stromal Cell Regulation of Stem Cell Maintenance

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Stromal cells in the microenvironment provide all signals necessary for stem cell proliferation and differentiation in vivo. However, the nature of these signals and the mechanisms by which stromal cells regulate stem cells remain to be defined. To understand how stromal cells interact with stem cells, in collaboration with the Lemischka group we analyzed a large panel of genetically and developmentally matched stromal cell lines. We found that a) stromal cell lines that maintain high levels of stem cells are very rare; b) the ability to support stem cells was not correlated with known effector molecules made by the stromal cell lines; c) those stromal cell lines that supported stem cells can support all types of stem cells indicating that a single stromal cell line is capable of maintaining the entire stem cell compartment. Overall, the data indicate that most stromal cell lines favor differentiation of stem cells over stem cell maintenance. However, a few rare stromal cells can form niches that selectively maintain primitive stem cell, likely by producing yet to be discovered molecules.

More recently, we have found that stromal cell lines that fail to support stem cells do so by two distinct mechanisms. Some stromal cell lines produce negative regulator molecules that overwhelm the positive molecules produced by supportive stromal cells fail to make the necessary positive regulator molecules. Others, fail to make the necessary set of positive regulator molecules. Interestingly, some of the latter lines, synergize with supportive stromal cells to increase recovery of HSC after culture. Thus, HSC maintenance likely requires the concerted action of many different molecules. Based on these data we developed a model of stromal cell controlled stem cell decisions.

Mesanchymal Stem Cells/Stromal Cells

Stromal Cell Regulation of Stem Cell Maintenance

Establishment of Stroma: Role of M-SCF

Regulation of Stroma Function: Role of CD44