The first comprehensive map of human blood stem cell development has been created by researchers.
UCLA scientists and collaborators have developed a first-of-its-kind roadmap that chronicles each step of blood stem cell development in the human embryo, giving scientists with a blueprint for creating fully functional blood stem cells in the lab.
According to Dr. Hanna Mikkola of UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, who led the study, the findings could help broaden therapy choices for blood malignancies like leukaemia and genetic blood abnormalities like sickle cell disease.
Hematopoietic stem cells, commonly known as blood stem cells, have the ability to divide indefinitely and develop into any type of blood cell in the human body. Blood stem cells from donors’ bone marrow and babies’ umbilical cords have been utilized in life-saving transplant therapies for blood and immunological illnesses for decades. However, because of a scarcity of matched donors and the low number of stem cells in cord blood, these treatments are limited.
Researchers have attempted to overcome these constraints by creating blood stem cells in the lab using human pluripotent stem cells, which have the ability to give rise to every cell type in the body. However, success has eluded scientists, in part due to a lack of instructions for converting lab-grown cells into self-renewing blood stem cells rather than short-lived blood progenitor cells that can only create a limited number of blood cell types.
“Nobody has succeeded in making functional blood stem cells from human pluripotent stem cells because we didn’t know enough about the cell we were trying to generate,”aid Mikkola, who is a professor of molecular, cell and developmental biology in the UCLA College and a member of the UCLA Jonsson Comprehensive Cancer Center.
According to UCLA scientist Vincenzo Calvanese, who co-authored the study with UCLA’s Sandra Capellera-Garcia and Feiyang Ma, “the new roadmap will help researchers understand the fundamental differences between the two cell types, which is critical for creating cells that are suitable for use in transplantation therapies.”
“We now have a manual of how hematopoietic stem cells are made in the embryo and how they acquire the unique properties that make them useful for patients,”said Calvanese, who is also a group leader at University College London.
The de-identified data are available to the public on the website The Atlas of Human Hematopoietic Stem Cell Development.
The resource was created using single-cell RNA sequencing and spatial transcriptomics, new technologies that allow scientists to identify the unique genetic networks and functions of thousands of individual cells while also revealing their location in the embryo. The research team included scientists from Germany’s University of Tübingen and Australia’s Murdoch Children’s Research Institute.
The information allows researchers to track blood stem cells as they emerge from the hemogenic endothelium and travel through several regions throughout their development, beginning in the aorta and ending in the bone marrow. The map also reveals particular stages in their maturation process, such as their arrival in the liver, where they acquire blood stem cell-like properties.
Mikkola compares immature blood stem cells to aspiring surgeons to explain the maturation process. Immature blood stem cells must go through several sites to learn how to conduct their work as blood stem cells, just as surgeons must go through different stages of training to learn how to do procedures.
The researchers also discovered the specific precursor that gives rise to blood stem cells in the blood vessel wall. This study resolves a long-standing debate about the stem cells’ biological origins and the conditions required to produce a blood stem cell rather than a blood progenitor cell.
Now that the researchers have identified specific molecular signatures associated with the different phases of human blood stem cell development, scientists can use this resource to see how close they are to making a transplantable blood stem cell in the lab.
“Previously, if we tried to create a blood stem cell from a pluripotent cell and it didn’t transplant, we wouldn’t know where in the process we failed,” Mikkola said. “Now, we can place the cells in our roadmap to see where we’re succeeding, where we’re falling short and fine-tune the differentiation process according to the instructions from the embryo.”
In addition, the map can help scientists understand how blood-forming cells that develop in the embryo contribute to human disease. For example, it provides the foundation for studying why some blood cancers that begin in utero are more aggressive than those that occur after birth.
“Now that we’ve created an online resource that scientists around the world can use to guide their research, the real work is starting,” Mikkola said. “It’s a really exciting time to be in the field because we’re finally going to be seeing the fruits of our labor.”