Scientists at UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research have discovered a unique protein, which is essential for the self-renewal of hematopoietic (blood) stem cells (HSCs) during human development. This discovery lays a foundation for researchers to generate HSCs in the lab that are more similar to those that develop in their natural environment. It could lead to improved treatments for blood-related diseases and cancers by facilitating the creation of patient-specific blood stem cells for transplantation. The study was published online on November 13 in the journal Cell Stem Cell.
The study authors note that for many rears stem cell researchers have attempted to form a method to use pluripotent stem cells for cell-based therapies for blood and immune diseases that are more broadly available. This research has been impeded by the inability to generate and expand human HSCs in culture. HSCs are the blood-forming cells, which serve as an essential link between PSCs and fully-differentiated cells of the blood system. The ability of HSCs to self-renew (reproduce themselves) and differentiate to all blood cell types, is determined in part by the environment that the stem cell came from, known as the niche.
The five-year study involved evaluation of a unique HSC surface protein, GPI-80. The researchers found that it was produced by a specific type of human fetal hematopoietic cells that were the only group that could self-renew and differentiate into different blood cell types. In addition, they found that this subpopulation of hematopoietic cells was the only type able to permanently integrate into and thrive within the blood system of a mouse. Another finding ow the study was that GPI-80 identifies HSCs during multiple phases of human HSC development and migration. These include the early first trimester (first three months) of fetal development when newly generated HSCs can be found in the placenta, and the second trimester when HSCs are actively reproducing in the fetal liver and bone marrow.
“We found that whatever HSC niche we investigated, we could use GPI-80 as the best determinant to find the stem cell as it was being generated or colonized different hematopoietic tissues,” explained study leader Hanna Mikkola, MD, PhD, associate professor of molecular, cell and development biology at UCLA and also a member of the Jonsson Comprehensive Cancer Center. She added, “Moreover, loss of GPI-80 caused the stem cells to differentiate. This essentially tells us that GPI-80 must be present to make HSCs. We now have a very unique marker for investigating how human hematopoietic cells develop, migrate and function.”
Based on the GPI-80 marker, the research team is actively exploring different stages of human HSC development and PSC differentiation, and comparing how blood stem cells are being generated in vitro (in the laboratory) and in vivo (in the natural environment). This paves the way for scientists to redirect PSCs into patient-specific HSCs for transplantation into the patient without the need to find a suitable donor.
“Now that we can use GPI-80 as a marker to isolate the human hematopoietic stem cell at different stages of development, this can serve as a guide for identifying and overcoming the barriers to making human HSCs in vitro, which has never been done successfully,” explained Dr. Mikkola, She added, “We can now better understand the missing molecular elements that in vitro-derived cells don’t have, which is critical to fulfilling the functional and safety criteria for transplantation to patients.”