Self-renewing hematopoetic progenitor cells

by Alexey Bersenev on September 5, 2013 · 1 comment

in hematopoietic

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The current dogma in stem cell biology is that only true stem cells can self-renew, but not progenitor (committed) cells. For instance, in hematopoiesis, stem cells give rise to multipotent progenitors (MPP) and lineage-committed progenitors through stepwise differentiation process. MPPs are characterized by loss of self-renewal. Even though, the line between stem cells and progenitors sometimes fuzzy, we were sure that we can clearly dissect them by phenotype in hematopoietic tissue. The clear picture got messed up when lineage-biased hematopoietic stem cells (HSC) were described – myeloid and lymphoid. The HSC populations heterogeneity is now commonly accepted. Recently, platelet-biased HSC were discovered and hierarchy of lineage-biased HSCs was proposed.

A new study, published in the last issue of Cell, can break the current dogma about restriction of self-renewal to multipotent stem cell populations. The authors found that “HSC compartment contains myeloid-restricted repopulating progenitors (MyRPs)”, which are not stem cells, not derived from MPPs, but able to self-renew. Some big important conclusions from Nakauchi’s paper:

  • “Lineage commitment takes place in a nonstepwise manner”;
  • Self-renewal capacity is not strictly associated with multipotency;
  • Lineage-restricted progenitors can self-renew
  • The current model of hematopoiesis is outdated.

Nakauchi’s group used the most sophisticated in vivo model, which allows to trace single cell clonally and analyze 5 lineages in readout. In conventional congenic mouse model, usually 3-lineage (T-, B- lymphoid and myeloid) analysis is performed to conclude multipotency. This could be a methodological limitation for high resolution lineage tracing.

To test this hypothesis, we first developed a transgenic mouse line in which not only T and B cells and neutrophils/monocytes but also erythrocytes and platelets are labeled by KusabiraOrange (KuO) fluorescent protein, enabling in vivo tracing of five lineages. Using single-cell transplantation of KuO-mouse bone marrow (BM) cells, we found, in the phenotypically defined HSC compartment, long-term repopulating cells with differentiation potential restricted to myeloid, megakaryocyteerythroid, or megakaryocyte lineages at a single-cell level (common myeloid repopulating progenitors [CMRPs], megakaryocyte-erythroid repopulating progenitors [MERPs], and megakaryocyte repopulating progenitors [MkRPs]), providing evidence for dissociation of self-renewal capacity from multipotency.

It still not very clear to me how to draw the fine line between previously described lineage-biased HSCs (myeloid- and platelet-) and myeloid-restricted repopulating progenitors (MyRPs). Maybe it’s the same thing, but detected by different methodologies with different resolution? Maybe it’s a simple re-naming of HCS lineage-biased populations into progenitors? What do you think?

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Hans Sieburg January 31, 2014 at 8:52 pm

I see several points of confusion, which I hope to diffuse. Self-renewal, which is cell proliferation that conserves differentiation potential, is not limited to stem cells. For example, T and B cells can proliferate and preserve their identity, i.e. they can self-renewal, although committed cells far removed from the (adult) hematopoietic (tissue) stem cell. Consequently, the dogma that you speak of is a myth (arguably promoted by sloppy writing in scientific articles). Next, the finding of lineage-bias by the Muller-Sieburg in 2002 did not mess up the orderly picture (if there was one). Myeloid-, and lymphoid-biased and balanced HSCs are bona fide HSCs, but distinguished by producing normal levels of myeloid cells and < than normal lymphoid cells that have a defect in IL7 responsiveness, producing sub-normal levels of myeloid cells and normal levels of lymphoid cells, and balanced HSC produce lymphoid and myeloid cells at levels found in unseparated bone marrow. Lastly, confusing notation is the name of the game in experimental hematology. Myeloid-restricted progenitors are defined as the top dog on the myeloid cell tree. Comparing the two definitions, myeloid-biased HSCs can and will produce myeloid-restricted progenitor cells, as will lymphoid-biased and balanced HSCs. If one aims to make clear where myeloid-restricted progenitors come from one would correctly say one of "myeloid-restricted progenitors derived from (myeloid-biased, lymphoid-biased, balanced) HSCs".

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