Self-Renewing Hematopoietic Stem Cells May Benefit Leukemia Patients

Researchers at Weill Cornell Medicine are reporting that they have successfully converted cells from blood vessels in mice into blood-forming stem cells.

In a paper published in Nature, they report for the first time on the independent conversion of adult endothelial cells to functional multi-potent cells that meet the criteria of normal hematopoietic stem cells (HSCs). These discoveries have significant clinical implications and suggest a novel way of developing personalized leukemia therapies in which HSCs derived from a patient’s own cells could treat their leukemia. 

“Our approach could be used for generation of autologous hematopoietic stem and progenitor cells for a marrow graft after the patients have been treated with high doses of chemotherapy and irradiation. This is important since endothelial cells isolated from the patient for programming do not harbor the mutations that might lead to leukemia relapse,” senior study author Shahin Rafii, MD, told OncoTherapy Network. Rafii is the Director of the Ansary Stem Cell Institute at Weill Cornell Medicine in New York.

The findings could lead to a new way of correcting genetic defects that cause blood diseases like sickle cell anemia as well as many other blood disorders. The team writes that it has developed a stepwise spatially and temporally controlled in vitro model that reveals the signaling pathways driving endothelial to hemogenic endothelial cell and HSC transition (EHT).

Rafii and his colleagues in this current paper demonstrate a tractable approach for fully reprogramming adult mouse endothelial cells to HSCs through transient expression of the transcription-factor-encoding genes Fosb, Gfi1, Runx1, and Spi1. The researchers report that during the first 8 days (induction phase) a conversion is initiated by these four specific genes in mature endothelial cells. Subsequently, this cascade of events results in endogenous Runx1 expression.

Between days 8 through 20 (specification phase), the researchers report that RUNX1 and FGRS-transduced endothelial cells transition to a hematopoietic state and produced HSCs that no longer required FGRS expression.

Since endothelial cells are readily amenable to gene editing, the clonally expanded endothelial cells with this stepwise approach could generate HSCs with customized functions, according to the researchers. One function could involve adaptive T-cell subsets. Rafii said this could translate into a new approach for combating leukemia.

“Autologous patient-derived endothelial cells are readily amenable to genetic editing by Talens and CRISPR/Cas9 genetic editing,” Rafii told OncoTherapy Network. “These genetically repaired endothelial cells could be readily switched to normal hematopoietic stem cells for transplantation.”

Rafii said these new findings not only suggest a new way to cure some forms of leukemia, but also help decipher the complex biology of stem cell self-renewal machinery. The discovery that vascular niche cells help choreograph this stepwise process could be a game-changer that has significant clinical implications in oncology and in regenerative and reproductive medicine, according to the authors.