Scientists reprogram blood cells into blood-forming stem cells

Researchers have reprogrammed mature blood cells from mice into blood-forming hematopoietic stem cells (HSCs), using a cocktail of eight genetic switches called transcription factors.

The reprogrammed cells, which the researchers have dubbed induced HSCs (iHSCs), have the functional hallmarks of HSCs, are able to self-renew like HSCs, and can give rise to all of the cellular components of the blood like HSCs.

The research team, led by Derrick J. Rossi, PhD, of Boston Children's Program in Cellular and Molecular Medicine, including lead author Jonah Riddell, PhD, screened gene expression in 40 different types of blood and blood progenitor cells from mice. From this screen they identified 36 transcription factors-genes that control when other genes are turned on and off-that are expressed exclusively in HSCs, not in cells that arise from them.

In a series of mouse transplantation experiments, Rossi's team found that six-Hlf, Runx1t1, Pbx1, Lmo2, Zfp37 and Prdm5-of the 36 factors, plus two additional factors not originally identified in their screen-Mycn and Meis1-were sufficient to robustly reprogram two kinds of blood progenitor cells (pro/pre B cells and common myeloid progenitor cells) into iHSCs.

Rossi's team reprogrammed their source cells by exposing them to viruses containing the genes for all eight factors and a molecular switch that turned the factor genes on in the presence of doxycycline. They then transplanted the exposed cells into recipient mice and activated the genes by giving the mice doxycycline.

The resulting iHSCs were capable of generating the entire blood cell repertoire in the transplanted mice, showing that they had gained the ability to differentiate into all blood lineages. Stem cells collected from those recipients were themselves capable of reconstituting the blood of secondary transplant recipients, proving that the eight-factor cocktail could instill the capacity for self-renewal-a hallmark property of HSCs.

Taking the work a step further, Rossi's team treated mature mouse myeloid cells with the same eight-factor cocktail. Again, when transplanted into mice, iHSCs were generated that produced all of the blood lineages and could regenerate the blood of secondary transplant recipients.

The study has been published online in the journal Cell.