Stem Cells

Amplifying Stem Cells

Science Signaling  14 Sep 2010:
Vol. 3, Issue 139, pp. ec279
DOI: 10.1126/scisignal.3139ec279

The success of hematopoietic stem cell (HSC) transplantation into human patients for treating bone and blood diseases depends on the number of stem cells in the graft (see the Perspective by Sauvageau and Humphries). Culturing HSCs with a cocktail of cytokines (thrombopoietin, stem cell factor, interleukin-6, and the ligand of the Flt3 receptor tyrosine kinase) before transplantation can induce proliferation, but the increase in cell number is rapidly followed by loss of multipotency, which is accompanied by loss of the cell surface markers CD34 and CD133. Boitano et al. identified the purine derivative StemRegenin 1 (SR1) in a screen for small molecules that could stimulate HSC expansion without hastening differentiation. Culturing human HSCs collected from peripheral blood with the cytokine cocktail plus SR1 increased the number of CD34+ and CD133+ cell populations as compared to control cells treated with cytokines alone. SR1 treatment had no effect in the absence of cytokines, and removing SR1 from the culture medium induced differentiation of the cells. Addition of SR1 did not increase proliferation of cytokine-treated HSCs but instead increased the proportion of cells that were CD34+ by suppressing differentiation. The number of multilineage colonies formed by HSCs also increased with SR1 as compared to controls, further supporting the notion that SR1 maintained HSCs in a multipotent state. SR1 increased both short- and long-term engraftment of human umbilical cord blood CD34+ HSCs into mice as compared to uncultured or control HSCs cultured with cytokines alone. SR1 inhibited the aryl hydrocarbon receptor (AhR), a nuclear receptor that has been implicated in pathways that regulate hematopoiesis. Two AhR antagonists mimicked the effects of SR1 on cultured HSCs, and SR1 blocked the transcriptional response to the AhR agonist dioxin. Short hairpin RNA–mediated knockdown of AhR also mimicked SR1 treatment, and SR1 had no effect on HSCs harboring a constitutively active version of AhR. Thus, modulating AhR activity may be a useful strategy for improving clinical outcome of HSC transplantation.

A. E. Boitano, J. Wang, R. Romeo, L. C. Bouchez, A. E. Parker, S. E. Sutton, J. R. Walker, C. A. Flaveny, G. H. Perdew, M. S. Denison, P. G. Schultz, M. P. Cooke, Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 329, 1345–1348 (2010). [Abstract] [Full Text]

G. Sauvageau, R. K. Humphries, The blood stem cell Holy Grail? Science 329, 1291–1292 (2010). [Summary] [Full Text]