By Diane Krause, MD, PhD
2008-01-01
Dr. Krause indicated no relevant conflicts of interest.
Pronk C, Rossi D, Mansson R, et al. Elucidation of the
phenotypic, functional, and molecular topography of a myeloerythroid
progenitor cell hierarchy. Cell Stem Cell. 2007;1:428-42.
This manuscript defines the surface phenotype of different
hematopoietic stem and progenitor cell subpopulations with higher
resolution than achieved previously. With this further refinement, the
investigators reveal more plasticity within the hematopoietic
differentiation hierarchy than has been previously recognized.
Prior excellent studies have shown enrichment for murine
hematopoietic stem cells (HSCs) and various partially committed
progenitor cells, such as common lymphoid progenitors and common
myeloid progenitors. These investigators further purify these
populations using additional cell surface proteins, including CD105
(endoglin) and CD150 (signaling lymphocytic activation molecule family
member 1, SLAM1), which play roles in signal transduction. HSCs,
previously known to be Lin-Kit+Sca+, were recently shown by Sean
Morrison’s group to be further enriched by selection for CD150
expression. To test the hypothesis that CD105 and CD150 might also be
differentially expressed within hematopoietic progenitor subsets, the
investigators used flow cytometry to sort subpopulations based on
surface expression of lineage markers Sca, Kit, CD150, CD105, and CD41.
They extensively analyzed each subpopulation for morphology, in vitro and in vivo function, and gene expression profile.
Among the important findings presented, they show that the
Lin-Kit+Sca1- population, which was previously known to be enriched for
bipotent megakaryocytic erythroid precursors (MEPs), is CD41- and is
comprised of at least three subpopulations based on CD105 and CD150
expression. The CD105+CD150- and CD105+CD150+ cells within this
population are already erythroid-committed, and the CD105-CD150+ cells
are truly biphenotypic with the ability to differentiate down the
erythroid and megakaryocytic lineages. This CD105-CD150+ population
represents less than 20 percent of the cells previously called MEP and
is referred to as PreMegE. In vitro assays of colonies
expanded from single PreMegE cells, a highly rigorous and
labor-intensive approach, demonstrated that they were biphenotypic
megakaryocytic and erythroid precursors. It remains to be seen whether
the corresponding human hematopoietic subpopulations share the
phenotypes identified.
Additional analysis of the different blood cell types that
differentiated from single cells of the different sorted subpopulations
adds to the complexity of current models of the hematopoietic
hierarchy. For example, Lin-Kit+Sca+CD150+ cells, which are highly
enriched for HSC, would be expected to be polyploid, and thus give rise
to multiple different cell types. However, 25 percent of the time,
these cells differentiated exclusively into megakaryocytes. This
doesn’t fit with our current understanding of hematopoietic lineage
steps and suggests that megakaryocytes may differentiate from HSCs
without going through multiple intermediate stages.
Gene expression analyses were consistent with the lineage commitments observed in vitro.
However, one surprising observation was that common myeloid and common
lymphoid progenitors had many genes in common, which could underlie the
lineage plasticity that has been found during initial phases of lineage
commitment.
The improved ability to identify and purify
specific hematopoietic subpopulations will help investigators to better
understand hematopoietic differentiation in general, and myelopoiesis
specifically. The identification of successive lineage-restricted
progenitors can be used to study the mechanisms of proliferation and
maturation down specific lineages. For example, the highly purified
biphenotypic PreMegE population can be purified to study lineage fate
decisions and to design approaches for enhancing growth and
differentiation of erythrocytes and/or megakaryocytes for in vivo enhancement of these lineages or for transfusion therapy.
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