Endothelial cells in the bone marrow help generate various types of blood cells such as red cells, white cells, and platelets. During normal blood stem cell production, several neighboring endothelial cells from peripheral blood vessels extend and envelope the stem cells. The process resembles constructing a nurturing home, a niche, in which stem cells can divide and give birth to new ones.
Genetic mutations in bone marrow cells, however, can cause blood disorders. While bone marrow transplantation can restore blood production, the procedure carries risk, including immune system suppression related infections, graft vs. host disease, or engraftment failure of the transplanted bone marrow cells.
In a new study led by hematologist Leonard Zon from Boston Children’s Hospital, researchers presented a way to make a blood stem cell niche anywhere in the body with the goal of eliminating the need for bone marrow donors and revolutionizing blood disorder treatment (1).
To figure out how a stem cell niche emerged, Zon and his team used RNA tomography (tomo-seq) on tissues in the zebrafish tail, which houses the site of new blood stem cell production as human bone marrow does. Tomo-seq allowed the researchers to map gene activity in different cells, and by using this approach, the researchers identified 29 genes exclusively expressed in the fish endothelial cells.
After isolating these endothelial cells, the researchers found that a combination of members from three transcription factor families, Ets, SoxF, and Nuclear Hormone Receptor (NHR), were necessary to form a stem cell niche. By next injecting different combinations of these factors into zebrafish embryos, they demonstrated that these three factors were sufficient to lead to a new niche. The transcription factors increased the expression of niche endothelial cell genes across multiple cell types, including ectodermal lineages such as skin cells and neurons, muscle, and arterial endothelial cells. The researchers also discovered several genes that were not previously linked to niche building.
“I was hoping to find what genes control the program to create a niche,” Zon said. “I wasn’t prepared when my research member came to me and said this is the best day he’s ever had.”
This finding is exciting. They didn’t use a stem cell intermediate but directly reprogrammed various cell types into endothelial cells.
- Tomer Itkin, Weill Cornell Medicine
The interaction between stem cells and the niche microenvironment is complex and challenging to control even within the natural bone marrow (2). So, Zon and his team were surprised when they discovered that these newly created endothelial cells attracted a large influx of blood stem cells, confirming their functionality as a stem cell niche. The stem cells remained within the new niche for several hours and divided multiple times in six of ten zebrafish embryos studied. In contrast, without the factors injected, stem cells only lingered briefly in tissues outside of the niche regions and underwent a single division.
“This finding is exciting,” said Tomer Itkin, a stem cell and regenerative biologist at Weill Cornell Medicine who was not involved in the study. “They didn’t use a stem cell intermediate but directly reprogrammed various cell types into endothelial cells.”
This discovery could help change the treatment of blood disorders such as myelofibrosis, which involves the abnormal growth of tissues within the bone marrow. These disruptions displace stem cells, making it difficult for the body to regenerate and repair itself. The liver and spleen could be potential sites for establishing niches and supporting stem cell production because of their similar ability to develop cells involved in the immune system (3).
According to Itkin, one of the challenges of translating these findings from zebrafish to humans is determining whether the identified transcription factors can induce niche formation in humans. If successful, this study would provide the proof of principle needed to move toward human trials.
References
- Hagedorn, E. J. et al. Transcription factor induction of vascular blood stem cell niches in vivo. Dev Cell 58, 1–15 (2023).
- Asada, N. et al. Complexity of bone marrow hematopoietic stem cell niche. Int J Hematol 106, 45–54 (2017).
- Asakura, A. et al. Hematopoietic potential cells in skeletal muscle. Cell Res 17, 836–838 (2007).
