UCLA Researchers Identify Unique Protein Key to the Development of Blood Stem Cells

This discovery lays the groundwork for researchers to generate HSCs in the lab (in vitro) that better mirror those that develop in their natural environment (in vivo). This could lead to improved therapies for blood-related diseases and cancers by enabling the creation of patient-specific blood stem cells for transplantation.

The findings are reported online November 13, 2014, ahead of print in the journal Cell Stem Cell.

The research community has long sought to harness the promise of pluripotent stem cells (PSCs) to overcome a significant roadblock in making cell-based therapies blood and immune diseases more broadly available, which has been hampered by the inability to generate and expand human HSCs in culture. HSCs are the blood forming cells that serve as the critical link between PSCs and fully differentiated cells of the blood system. The ability of HSCs to self-renew (replicate themselves) and differentiate to all blood cell types, is determined in part by the environment that the stem cell came from, called the niche.

In the five-year study, Mikkola and Drs. Sacha Prashad and Vincenzo Calvanese, members of Mikkola’s lab and lead authors of the study, investigated a unique HSC surface protein called GPI-80. They found that it was produced by a specific subpopulation of human fetal hematopoietic cells that were the only group that could self-renew and differentiate into various blood cell types. They also found that this subpopulation of hematopoietic cells was the sole population able to permanently integrate into and thrive within the blood system of a recipient mouse.

Mikkola and colleagues further discovered that GPI-80 identifies HSCs during multiple phases of human HSC development and migration. These include the early first trimester of fetal development when newly generated HSCs can be found in the placenta, and the second trimester when HSCs are actively replicating in the fetal liver and the fetal 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,” said Mikkola, associate professor of molecular, cell and development biology at UCLA and also a member of the Jonsson Comprehensive Cancer Center. “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.”

Mikkola’s team is actively exploring different stages of human HSC development and PSC differentiation based on the GPI-80 marker, and comparing how blood stem cells are being generated in vitro and in vivo. 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,” said Mikkola. “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.”

The research was supported by the California Institute of Regenerative Medicine and National Institutes of Health. Additional UCLA funding is provided by philanthropy to the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and Jonsson Comprehensive Cancer Center.

About Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research

The stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA's Jonsson Comprehensive Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.

To learn more about the center, visit our website at http://www.stemcell.ucla.edu