Blood-forming stem cells were lab-generated for the first time, using pluripotent stem cells. The relevance of this development is that will allow studying root causes of blood diseases, and treating patients by creating blood cells derived from their own cells, avoiding immune reactions.
In 1998, scientists were able to isolate human embryonic stem (ES) cells, a type of pluripotent stem cells derived from the inner cell mass of a blastocyst (an early-stage embryo). Since then, scientists have tried to use them to generate blood-forming stem cells, with little success. Then, in 2007 scientists were able to induce adult skin cells into pluripotent stem through genetic reprogramming. These induced pluripotent stem cells (iPSCs) have been differentiated in different types of cells like neurons and heart cells; however differentiate them into blood-forming stem cells remained elusive.
Now, a team from Boston Children’s Hospital and another from the Weill Cornell Medicine Center (both in the US) have succeeded in creating blood-forming stem cells by combining both approaches, using iPSCs and ES cells. Both types of pluripotent stem cells were exposed to chemicals that normally signal stem cells to differentiate into specialized tissues in embryonic development. So, these cells differentiated into emogenic endothelium, an early embryonic tissue that eventually gives rise to blood stem cells.
Then, the team identified 26 transcription factors as candidates to push the hemogenic endothelium toward a blood-forming state, of which they identified five (RUNX1, ERG, LCOR, HOXA5, and HOXA9) that combined were able to create blood stem cells. In addition to the factors, the scientists added a lentivirus, as used in some forms of gene therapy.
Finally, the team transplanted the lab-made hemogenic endothelial cells into mice. Weeks later, a small number of the animal models animals carried multiple types of human blood cells in their bone marrow and blood circulation —including red blood cell precursors, myeloid cells (precursors of monocytes, macrophages, neutrophils, platelets, and other cells), and T and B lymphocytes; and some of them were able to mount a human immune response after vaccination. The advance, published in two articles in the journal Nature, marks the culmination of 20 years of work.
Ryohichi Sugimura, study’s first author and a postdoctoral fellow in the Daley Lab said that “this step opens up an opportunity to take cells from patients with genetic blood disorders, use gene editing to correct their genetic defect, and make functional blood cells.” Additionally, “this also gives us the potential to have a limitless supply of blood stem cells and blood by taking cells from universal donors. This could potentially augment the blood supply for patients who need transfusions,” he added.
So far, the team of researchers were able to produce a mixture of blood stem cells and so-called hematopoietic progenitor cells, which also give rise to blood cells. In the future, they plan to make true blood stem cells in a way that’s practical and safe, without the need for viruses to deliver the transcription factors, and to introduce gene-editing techniques such as CRISPR to correct genetic defects in pluripotent stem cells before blood cells are made.
Senior investigator George Daley, Dean of Harvard Medical School and Head of a research lab at Boston Children’s Hospital’s Stem Cell Program said: “We’re tantalizingly close to generating bona fide human blood stem cells in a dish.”
“We’re now able to model human blood function in so-called humanized mice,” said Daley. “This is a major step forward for our ability to investigate genetic blood disease.”
Source: Harvard Gazette