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Story of discovery: getting a Notch up on cord blood cell transplantation

Blood stem cell transplants can be life-saving for people with a number of conditions. However, it can be challenging to find blood stem cells in needed quantities from a donor whose cells are similar enough to a patient’s cells to be a sufficient “match” for transplantation. Cells from bone marrow and from circulating blood have been used in treatments for many years, and blood from the umbilical cord, collected after a baby is born, has been another source of blood stem cells used more recently. Cord blood from donors is available in public cord blood “banks,” and the match between donor and recipient may not need to be quite as close as is needed for transplants of other types of blood cells. However, cord blood from each donor exists in only limited quantities. Researchers supported by NIDDK have discovered key factors that promote blood stem cell growth and maturation, and, with these insights, have developed ways to expand the numbers of cells from cord blood for use in transplants. This research may increase the availability of such treatments to benefit many more people.

Cord Blood Cell Transplantation

Cord blood is found in blood vessels of the placenta and the umbilical cord—tissue that is normally discarded. It is collected after a baby is born and after the umbilical cord is cut between the mother and the baby. Approved by the U.S. Food and Drug Administration only for use in blood (hematopoietic) stem cell transplantation procedures, cord blood has been transplanted into thousands of patients who have serious medical conditions such as bone marrow failure syndromes, blood disorders, immunodeficiencies, certain metabolic disorders, and cancers. Cord blood stem cells (which are different from embryonic stem cells) facilitate healing and repair of damaged cells and tissue—that is, they are early stage blood cells that, like other blood stem cells, provide a source for the regrowth of all the types of specialized blood cells. Cord blood transplantation, therefore, is an example of regenerative medicine.

A critical advantage of cord blood is that cord blood stem cells can be easily transplanted; the transplanted cells do not have to be an exact match with the recipient’s tissues. However, the main disadvantage is that a single umbilical cord is insufficient; a single umbilical cord contains a limited number of stem cells that do not mature into a sufficient number of specialized types of blood cells needed for adults. Cord blood cell transplants (from a single umbilical cord) could thus place an adult patient at increased risk of life-threatening infections due to the inadequate number of infection-fighting types of blood cells. Such patients may need two or more units of cord blood. Yet, they may still be at risk because, compared with conventional bone marrow transplantation, it may take longer for transplanted cord blood stem cells to engraft—that is, to start working properly in a patient’s body—and give rise to other types of blood cells. For this reason, cord blood cell treatment is used more often in children, who have a small body size and thus require fewer cells. Basic research on blood cells has sparked ideas for expanding the numbers of cells in a unit of cord blood.

Notch: The Story Begins

In 1994, while investigating the cellular and molecular mechanisms underlying the production and function of blood cells—NIDDK-supported researchers discovered for the first time that in human early stage blood cells, a gene encoding a protein called Notch is “turned on.” NIDDK-supported researchers then set out to determine whether Notch influences the function of blood stem cells. Notch, which sits in the cell membrane, transmits signals originating from the outside of the cell to direct the turning on or turning off of genes. Using laboratory mice, they demonstrated, in 2002, that activated Notch had two distinct activities—1) the inhibition of stem cell maturation into different blood cell types and 2) the stimulation of stem cell self-renewal (i.e., an increase in stem cell number). In 2003, with support from NIDDK and other sources, researchers reported that they could induce early stage mouse blood cells to proliferate by exposing the cells to an engineered protein that binds to Notch; this protein was a modified version of a protein called Delta1. Interestingly, the researchers did not see this effect if they simply mixed the modified Delta1 protein into the liquid in which the cells were growing; through their experiments, they realized they had to immobilize this protein on the dish in which the cells were growing for it to have the desired effect of increasing the numbers of cells.

Notch-driven Engraftment of Cord Blood Cells in Human Pilot Study

Taking advantage of their knowledge of the Notch-signaling pathway and blood stem cells and the modified Delta1 protein, investigators supported by NIDDK and others were able to significantly increase, by greater than 100-fold, the number of early stage blood cells from a unit of cord blood. The researchers then conducted, and reported in 2010, a pilot clinical study of 10 participants with leukemia to begin to assess the safety of infusing patients with cord blood stem cells that had been expanded to greater numbers using the modified Delta1 protein/Notch procedure, and to begin evaluating the engraftment properties of the expanded stem cells. In the course of their treatment for leukemia, the participants were given radiation therapy and chemotherapy to destroy the blood cancer cells; these treatments also destroyed the stem cells in their bone marrow. Cord blood cell transplantation was subsequently used to repopulate the bone marrow. Each participant received two units of cord blood—one unit of non-expanded blood and one containing expanded numbers of blood cells, or two units of non-expanded blood. In this small group of participants, no safety issues were encountered. In addition, the time for engraftment, measured in terms of white blood cell recovery, was significantly shorter for participants who received Delta1/Notch-expanded cells than for those who received only non-expanded cord blood.

Manipulating Blood Stem Cells into Mature Blood Cells

Blood stem cells mature along two tracks—1) the myeloid lineage, which produces white blood cells (e.g., macrophages and neutrophils), red blood cells, and other cells, and 2) the lymphoid lineage, which produces T cells, B cells, and other cells. The immune system consists of two major pillars: the innate (general defense) and the adaptive (specialized defense). Both systems work closely together and take on different tasks. Researchers have sought to identify a minimum cocktail of factors necessary to enable the reconstitution of both myeloid and lymphoid lineages from blood stem cells. Previous NIH-supported research found that experimentally increasing production of a factor called HoxB4 in mouse early stage blood stem cells could reconstitute the myeloid lineage but only minimally reconstituted the lymphoid lineage. In further experiments to try to reconstitute both lineages, in 2016, investigators supported by NIDDK and others discovered that Delta1/Notch activation of mouse early stage blood stem cells, in combination with increased HoxB4 in these cells, enabled the cells to fully reconstitute the myeloid and lymphoid lineages when transplanted into mice lacking their own blood cells.

Clinical Trial Assessments of Notch-Activated Cord Blood Cell Transplantation

The NIDDK-supported research to increase numbers of blood stem cells led one of the investigators to start a clinical cell therapy company. The company is investigating (in two Phase 2 clinical trials) whether Delta1/Notch-expanded cord blood cells could reduce the time to white blood cell recovery and reduce the rate of infections in individuals with blood cell cancers.

NIDDK-supported Research

The translation of scientific knowledge and technology into improvements in the practice of medicine is central to the missions of the NIH and the NIDDK. As this story illustrates, the initial investment in basic science research has led to the development of a laboratory-based methodology to expand the stem cell population in cord blood for potential beneficial transplantation treatment of people with a myriad of blood disorders and diseases.

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