Newly discovered cells could help treat blood and immune system disorders: Experiments reveal first line of daughter cells formed from HSCs is already unique, favoring development of various specialized cell lines.

Scientists at the University of California, San Francisco have discovered characteristics of a family of daughter cells, known as multipotent progenitors (MPPs), which are among the first to develop from stem cells within the bone marrow and create the entire blood system.

Researchers claim that by manipulating the fate of MPPs, or parent stem cells, medical scientists could eventually overcome discrepancies and imbalances within the blood system that are caused by aging or certain types of leukemia (blood cancer). The study was published online recently in Cell Stem Cell.

“Similar imbalances can render patients vulnerable immediately following bone-marrow transplants, especially following transplants of umbilical cord blood stem cells,” explained senior scientist Emmanuelle Passegué, PhD, Professor of Medicine and a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF. “Such patients often need red-blood-cell and platelet transfusions, as well as antibiotics to fight infections, until their grafted stem cells kick in and they produce an adequate balance of different types of blood cells.”

Passegué’s group established that the beginning of production of all type and forms of specialized blood cells required by the body begins with the hematopoietic stem cells (HSCs).

“What we show is that the stem cell is making very educated decisions,” stated Passegué. “Previously, researchers thought that the developmental paths of daughter cells were randomly specified by the HSC, but we conclude that the HSC normally responds appropriately to signals in the environment, making the different MPPs in parallel, but at different speeds and in different amounts to meet the body’s needs.”

The research team used mice to investigate the patterns of cell signaling and gene expression. These were studied to identify which developmental paths are preferred when a relatively novel HSC produces daughter cells, resulting in the development of billions of new red blood cells, white blood cells and platelets every day. The researchers also explored the responses of HSCs at the time of transplantation. HSCs are the only known cells that can engraft with bone marrow and regenerate the whole blood system – they are immortal. They can self-renew, or divide to produce progenitor cells that cannot self-renew or engraft within the bone marrow, but can produce lines of specialized cells.   

These experiments revealed that the first line of daughter cells formed from HSCs is already unique, favoring the development of various specialized cell lines. Two rare types of daughter cells were identified – MPP2 and MPP3 – which work together with other common daughter cells – MPP4 – to generate new cells in the blood system. MPP2 were found to favour the development of red blood cells and platelets, whereas MPP3 favored the development of inflammatory cells.

Moreover, the study revealed that MPP4 cells, known to produce lymphocytes, can easily be manipulated to produce inflammatory cells if the body is in dire need of them, as is the case during transplantation. Researchers found that during transplantation, HSCs minimize their own self-renewal and also begin to overproduce MPP2 and MPP3 cells, which fulfill the need of generating excess amounts of red blood cells, inflammatory cells and platelets. MPP4 production ultimately returns to normal, allowing the immune system to replenish its stores of lymphocytes.

“In humans it’s clear that imbalances often arise during aging, with production of disease-fighting immune cells lagging far behind youthful levels,” Passegué stated. “It will be compelling to test whether the developmental pathways leading to cell specialization can be manipulated to favour production of specific lineage-biased MPPs in order to optimize blood recovery following hematopoietic injury or to rebalance the output of various cell lineages in an aging or deregulated blood & immune system disorder.”