Forcing Differentiation

Durham, NC -

Classically hematopoietic stem cells were known to differentiate into myeloid (monocyte and granulocyte) and lymphoid (T cell, B cell, NK cell) lineages. More recent studies have demonstrated differentiation into cardiomyocytes, neurons, and other tissue cells. The signals associated with hematopoietic stem cell differentiation into myeloid and lymphoid cells are currently under intense investigation.

In a recent study (Hsu et al. Activation of MEK/ERK signaling pathway is involved in the myeloid lineage commitment. Blood. 2007 May 29) the ability of common lymphoid progenitor cells to differentiate into myeloid cells was disected at a molecular level.

Normally, common lymphoid progenitor cells differentiate into lymphoid cells, however, if IL-2 receptor is transfected into these cells and IL-2 is administered, the common lymphoid progenitors can differentiate into the myeloid lineage. IL-7 receptor is expressed on common lyphoid progenitors but can not induce myeloid differentiation, despite the fact that the IL-2 receptor and IL-7 receptor share a common gamma chain.

The investigators found that by genetically fusing the IL-2 receptor beta chain to the IL-7 receptor, it is possible to induce common lymphoid progenitors to differentiate into myeloid lineage cells. Therefore, the beta component of the IL-2 receptor chain seems to be important in shifting the differentiation of common lymphoid progenitor cells into myeloid cells. The investigators went deeper and found that it is the specific A-region of the IL-2 receptor beta chain that is important in induction of differentiation. Furthermore, it was found that Shc binding to the A-region of the IL-2 receptor beta chain activates the MEK/ERK pathway, which in turn activates MAP kinase.

The importance of the MEK/ERK pathway in the differentiation of common lymphoid progenitors, but not hematopoietic stem cells, along the myeloid lineage is seen in that inhibiting this pathway chemically blocks myeloid differentiation from the former but not the latter.

This study suggests certain things:

1. It is possible to use small molecule inhibitors to modulate differentiation
2. Not all differentiation into the same cell type occurs through the same pathway (ie hematopoietic stem cells can still become myeloid cells when MEK/ERK is blocked but common lymphoid progenitors can not)
3. Similar studies need to be performed to elucidate the molecular mechanisms of hematopoietic stem cell differentiation into other types of cells that are not hematopoietic (ie cardiac, hepatic, neural, etc).