Lineage-biased Stem Cells Detected in Clonal Analysis

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Epigenetic regulation of stem cell lineage commitment and self-renewal: Linage-biased Stem cells detected in clonal analysis.

TSelf-renewal capacity and the ability to regenerate all types of cells in a lineage are defining features of all stem cells, including hematopoietic stem cells (HSC). Decisions whether to self-renew or to differentiate are made on the level of a single HSC. When HSC are examined as populations, the average behavior of these cells is revealed and information on individual decisions is lost. Therefore, a meaningful analysis of HSC behavior must be performed on the clonal level. We developed a simple, yet highly effective method to isolate clonally derived HSC. This allowed us to examine many individual HSC clones.

Amongst the new findings from this clonal analysis was a new type of HSC, called lineage-biased (Lin-bi) HSC. Lin-bi HSC give rise to all cells of all hematopoietic lineages, albeit with a noticeably skewed ratio of myeloid to lymphoid cells in the periphery. To understand the mechanism of Lin-bias, we have focused on myeloid-biased (My-bi) HSC. My-bi HSC generate normal levels of myeloid cells, but have a noticeable block in generating lymphocytes. We found that My-bi HSC have the longest life span (presumably the most self-renewal capacity) of all HSC. Array analysis and functional studies implicate a block in the IL-7 response on the level of immature lymphoid precursors as a major cause of myeloid-bias. A blunted response to the central lymphopoietin IL-7 explains the diminished lymphopoiesis of My-bi HSC. HSC do not express the IL-7 receptor. Yet, epigenetically fixed decisions on the level of the HSC stably generate lymphoid progeny with a blunted response to IL-7. This indicates that the type and number of mature cells that are generated by a differentiating HSC are preprogrammed on the level of the HSC. We are currently exploring how to enhance the output of lymphocytes from My-bi HSC.

Hematopoietic Stem Cells

Lineage-biased Stem Cells Detected in Clonal Analysis

Aging of Hematopoietic Stem Cells

Markers for Hematopoietic Stem Cells

Genes that Control the Size of the Stem Cell Compartment