Bone marrow transplants offer a way to cure leukemia, sickle cell disease, and a variety of other life-threatening blood disorders.There are two major problems, however: One is many patients don’t have a well-matched donor to provide the marrow needed to reconstitute their blood with healthy cells. Another is even with a well-matched donor, rejection or graft versus host disease can occur, and lifelong immunosuppression may be needed.
A much more powerful option would be to develop a means for every patient to serve as their own bone marrow donor. To address this challenge, researchers have been trying to develop reliable, lab-based methods for making the vital, blood-producing component of bone marrow: hematopoietic stem cells (HSCs).
Two new studies by NIH-funded research teams bring us closer to achieving this feat. In the first study, researchers developed a biochemical “recipe” to produce HSC-like cells from human induced pluripotent stem cells (iPSCs), which were derived from mature skin cells. In the second, researchers employed another approach to convert mature mouse endothelial cells, which line the inside of blood vessels, directly into self-renewing HSCs. When these HSCs were transplanted into mice, they fully reconstituted the animals’ blood systems with healthy red and white blood cells.
As reported in Nature, both teams took advantage of earlier evidence showing that HSCs are formed during embryonic development from budding endothelial cells in the aorta. Those HSCs ultimately find their way into the bone marrow, where they produce a lifetime supply of blood cells. However, the biochemical signals, or recipes, driving that natural conversion of endothelial cells into HSCs weren’t known.
George Daley from Boston Children’s Hospital and Dana-Farber Cancer Institute, Boston, and colleagues examined the scientific literature for clues of a possible recipe. Their search produced a list of 26 transcription factors—proteins that bind DNA to influence the expression of other genes—that they thought might have potential to yield HSCs.
To test them out, the researchers first used a previously defined protocol to convert human iPSCs into endothelial cells similar to those known to produce HSCs during development. They then tested the capacity of those 26 transcription factors in different combinations to coax endothelial cells into producing HSC-like cells. They ultimately narrowed down the recipe to a combination of seven transcription factors that were sufficient to convert the iPSC-derived endothelial cells to immature HSC-like cells.
In the parallel study, Raphael Lis and Shahin Rafii from Weill Cornell Medicine, New York, began with readily accessible endothelial cells taken from the organs of adult mice. Bypassing the pluripotent state, in which stem cells are still capable of producing several different cell types, the researchers showed that expression of only four transcription factors was sufficient to convert the adult endothelial cells into long-lasting HSCs.
Both groups relied on external signals to encourage the immature HSCs or HSC-like cells to mature into self-renewing stem cells that no longer needed any assistance from the researchers to continue growing and producing various types of blood cells. Daley’s team matured those human HSC-like cells by transplanting them directly into the bone marrow of living mice. Lis and Rafii instead grew the emerging mouse HSCs on a layer of endothelial cells in a dish, where they acquired the attributes of fully functional HSCs, and later were transplanted into mice.
In the mice, stem cells generated using both approaches took up residence in the bone marrow as expected. Importantly, Rafii’s team showed they could infuse the lab-derived HSCs, nurtured on the endothelial tissue, directly into a mouse, just as a person would now receive a bone marrow transplant. The cells gave rise to all major blood lineages, including red blood cells, B cells, and T cells. They could also be isolated again and engrafted into a second recipient—an important test of their regenerative capacity.
Importantly, Lis and Rafii found no evidence of cancer for many months after mice were transplanted with the lab-derived HSCs. They also note that, while their new findings were in animals, they already have some evidence from a previous study to suggest a similar approach might work in human cells .
Both sets of experiments relied on genes inserted randomly into the genome using viruses to drive transcription factor expression. Daley and Rafii say they are now working on other ways to supply those signals, which they hope could work even more effectively and without the potential health risks associated with viral insertion.
These lab-derived HSCs already hold vast potential for screening new drug candidates for the treatment of blood disorders. While more work is needed to perfect making them and to evaluate their safety, these advances also stand as encouraging signs that adult stem cell therapies for people with various blood disorders could be achievable in the coming years.
 Haematopoietic stem and progenitor cells from human pluripotent stem cells. Sugimura R, Jha DK, Han A, Soria-Valles C, da Rocha EL, Lu YF, Goettel JA, Serrao E, Rowe RG, Malleshaiah M, Wong I, Sousa P, Zhu TN, Ditadi A, Keller G, Engelman AN, Snapper SB, Doulatov S, Daley GQ. Nature. 2017 May 17. [Epub ahead of print]
 Conversion of adult endothelium to immunocompetent haematopoietic stem cells. Lis R, Karrasch CC, Poulos MG, Kunar B, Redmond D, Duran JGB, Badwe CR, Schachterle W, Ginsberg M, Xiang J, Tabrizi AR, Shido K, Rosenwaks Z, Elemento O, Speck NA, Butler JM, Scandura JM, Rafii S. Nature. 2017 May 17. [Epub ahead of print]
 Reprogramming human endothelial cells to haematopoietic cells requires vascular induction. Sandler VM, Lis R, Liu Y, Kedem A, James D, Elemento O, Butler JM, Scandura JM, Rafii S. Nature. 2014 Jul 17;511(7509):312-318.
Blood and Bone Marrow Transplant (National Heart, Lung, and Blood Institute/NIH)
Stem Cell Basics (NIH)
Daley Lab (Boston Children’s Hospital)
Shahin Rafii (Weill Cornell Medicine, New York City)
NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; National Cancer Institute.