Kyle Loh, PhD

Where do blood stem cells come from?

By Christopher Vaughan

April 26, 2024

Hematopoietic stem cells (HSCs) are the source of a large number of vastly important blood and immune cells, but the source of HSCs themselves has been a longstanding question in biology. Now, a group of researchers from the Institute for Stem Cell Biology and Regenerative medicine have found an answer to this question in mice. Furthermore, they used what they discovered to generate cells that act very much like HSC from human pluripotent stem cells in a Petri dish. These discoveries will likely set the stage for other important HSC research and may eventually help lead to new therapies for a wide range of devastating diseases, the researchers said.

“If we are eventually able to produce true HSC in the lab, we will have a limitless source of blood and immune cells,” said Kyle Loh, PhD.  “We will be able to produce blood for transfusions, as well as immune cells to fight cancer and disease.”

The paper was published in April in the journal Developmental Cell. Loh and Siebel Investigator Lay Teng Ang, PhD, were senior co-authors on the paper. Former graduate student Jonas Fowler, PhD and graduate student Sherry Li Zheng were co-first authors. Other institute members who took part in the researcher included Irv Weissman, MD; Kristy Red-Horse, PhD; Matthew Porteus, MD, PhD; Hiro Nakauchi, MD, PhD; and Ravi Majeti, MD, PhD. 

Since the 19th century, it had been proposed that newly created HSC during this embryonic period were created out of endothelial tissue (the cells that make up the inner lining) of early arteries. Over the years, there have been many experiments, some done by Institute researchers, adding evidence to this theory. 

“In all the previous experiments there were various complexities that muddied the picture of exactly what cells HSCs come from and the path they take to become HSCs,” Loh said. There have been some spectacular studies tracing the lineage of individual cells in living mice and turning pluripotent stem cells into cells that look and act in some ways like HSCs, he said. “But efforts to convert pluripotent stem cells led to cells that have always been missing markers that should exist on real HSCs,” Loh said. 

Furthermore, when researchers used the knowledge gained from these studies to create their own HSCs from pluripotent stem cells, the resulting HSCs could only create mixed populations of blood and non-blood cells, indicating that there were still unaddressed differences between what could do in the lab and what was occurring naturally in living animals. 

The institute researchers decided to more lineage tracing studies of mouse development, but in this case they worked to very precisely mark the embryonic endothelial cells of developing mice during very specific windows in the developmental timeline. “We confirmed that endothelial cells in the early mouse embryo could indeed generate functional HSCs,” Loh said. Interestingly, though, HSCs were only generated during a very short, 2.5-day period, from day 8.5 through day 10 of development. After this, any new HSCs are generated from other HSCs. “It’s pretty amazing  that during this 2.5 day period in the embryo, we create the all future blood cells that can perpetuate themselves for the rest of the adult lifespan,” Loh said.

Using information that they gleaned by following the cells at specific stages of development in the mice—from endothelial cells to functional blood and immune cells—the researchers came up with a protocol for applying certain cell signals that would coax cell endothelial cells’ development in one direction and block the cells’ development in others. Loh, An and their colleagues then used this protocol guide the differentiation of human pluripotent stem cells through the various stages of embryonic development to become arterial endothelial cells and then to become HSCs with all the right cellular markers and the potential to differentiate into all the products of normal HSC. “We were able to create a very pure population of HSCs from just the pluripotent stem cells, which no one had been able to do before,” Loh said.

Loh, An and their colleagues are not quite ready to say the HSC-like cells they produced are true HSC cells, however. “The HSCs we made are just like normal HSCs, except they don’t engraft into bone marrow when injected into mice,” Low said. “That’s a mystery we want to solve in the future.”