Transplantable functional hematopoiesis from embryonic stem cells – one step closer

by Alexey Bersenev on February 23, 2008

in Journal club

Blogging on Peer-Reviewed ResearchOne of most potentially attractive alternative sources of hematopoietic stem cells (HSCs) is embryonic stem (ES) cells. Compared to traditional sources of HSCs for transplantation (such as bone marrow, cord blood or mobilized peripheral blood), ES cells have some advantages.
The first advantage is a low level of HLA expression. It makes ES-derived HSCs less immunogenic and may allow many patients who can’t find matched donors to receive transplants. The other advantage is the possibility of ex vivo expansion of HSCs, because ES cells have virtually unlimited potential to divide and theoretically could be used for large-scale production of blood cells.

Few research groups around the world have published protocols of HSCs derivation from ES cells in mice and humans. Initial attempts of HSC isolation from ES cells displays in vitro capacity to generate multilineage blood cells but demonstrated very poor engraftment and chimerism in vivo.

Attempts to generate HSCs from ES cells have been hampered by the finding that ES cell-derived hematopoietic cells migrate and engraft poorly when transplanted. Given that the functional potential of a candidate HSC population can be assayed only in a transplant setting, this characteristic of ES cell-derived HSCs has complicated an already challenging experimental pursuit.

(PNAS 2006; 103:12213-12214)

The problem of weak transplantable hematopoiesis from ES cells was partially solved in a Canadian study, published in J. Exp. Med. in 2004.

Somatic and hESC-derived hematopoietic cells have similar phenotype and in vitro clonogenic progenitor activity.
However, in contrast with somatic cells, hESC (human embryonic stem cell)-derived hematopoietic cells failed to reconstitute intravenously transplanted recipient mice.
Direct femoral injection allowed recipient survival and resulted in multilineage hematopoietic repopulation, providing direct evidence of HSC function. However, hESC-derived HSCs had limited proliferative and migratory capacity compared with somatic HSCs

This scheme summarized some general approaches to generate blood cells from ES cells (T-cells in particular):

In the recent report, prepublished in Blood journal, it was demonstrated for the first time that ES cell-derived HSCs can be used to create a functional immune system.

Previous studies have not investigated well whether ES cell-derived bone marrow in donor mice could rescue normal immunity. An international team of scientists led by Nicholas Zavazava from University of Iowa tested how immune cells arising from ES cell-derived HSCs respond to viruses or vaccines.

The authors used the protein HOXB4, which induced hematopoietic differentiation from ES cells and led to robust multilineage HSCs engraftment in vivo. All types of immune cells (T-, B-, NK and DC) were generated in vivo from donor HSCs. T-cells of donor’s origin were able to respond effectively to the virus, injected into mice. Another assay shows that ES cell-derived antigen-presenting cells (DC) were able to functionally present antigen to T-cells and B-cells, which were then able to produce antigen-specific antibody.

In addition, the authors pointed out that none of the 70 transplanted mice followed for more than 200 days developed any tumors. This is one more advantage of this study, which lead us one step closer to the possibility of clinical application of the ES cell-derived hematopoietic progenitors.

Blood Epub. Dec. 4; 2007; DOI 10.1182/blood-2007-10-117366
ASH Press Release

PS: I plan to interview Dr. Zavazava next week. If you have any questions or suggestions according this study, please let me know.

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