The generation of hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) in vitro would represent a major advance in stem cell biology as it would provide an unlimited supply of these cells for transplantation for the treatment of hematological diseases. To be able to derive HSCs from hPSCs, it is essential to recapitulate the developmental pathway in the culture dish that leads to their formation in the early embryo.

The embryonic hematopoietic system is composed of two distinct developmental programs known as primitive and definitive. The primitive program gives rise to primitive erythroblasts, macrophages and megakaryocytes, while the definitive program generates the entire spectrum of blood cells found in the adult, including HSCs. As cells from both programs develop in the hPSC differentiation cultures, important first steps in the search for the HSC are the development of marker sets to distinguish primitive and definitive hematopoietic progenitors, and the identification of signaling pathways that regulate their specification.

A study published in Nature Biotechnology by McEwen Centre Director Dr. Gordon Keller has moved researchers one step closer to being able to generate HSCs in vitro as it identifies a marker, CD235a, that distinguishes primitive and definitive hematopoiesis and it demonstrates that Wnt-β-catenin signaling differentially regulates the development of the two programs. The findings from the study show that CD235a is expressed by KDR+ primitive progenitors that are induced by the combination of activin-nodal signaling and inhibition of the Wnt-β-catenin pathway. Conversely, the KDR+ cells that lack CD235a expression represent the definitive hematopoietic progenitors that are dependent on Wnt-β-catenin signaling for their development.

With these advances, it is now possible to generate hPSC-derived populations consisting entirely of the primitive or definitive hematopoiesis. Access to enriched definitive hematopoietic populations will greatly facilitate the search for HSCs.  

This study was supported by the National Institutes of Health, the Canadian Institutes of Health Research and the Princess Margaret Cancer Foundation. G Keller is a Tier 1 Canada Research Chair in Embryonic Stem Cell Biology.

Wnt signaling controls the specification of definitive and primitive hematopoiesis from human pluripotent stem cells. Sturgeon CM, Ditadi A, Awong G, Kennedy M, Keller G. Nat Biotechnol. 2014 May 18. [Abstract]

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