New study findings point to possible stem cell role for normal form of protein
By Charles Choi | January 31, 2006
The normal form of prion protein (PrP) appears necessary for bone marrow stem cells to renew themselves, scientists reported online this week in the Proceedings of the National Academy of Sciences. These findings suggest a potential physiological function in stem cells for the normal form of the widely expressed protein.
"Prior to this work there was no hint that PrP had a function in stem cell biology," co-author Andrew Steele at the Whitehead Institute for Biomedical Research in Cambridge, Mass., told The Scientist. "We are now looking into PrP function in other adult stem cells, particularly neural stem cells."
Prions are infamous for being associated with transmissible spongiform encephalopathies (TSEs) such as mad cow disease, but the function of PrP -- the normal, widespread and highly conserved form of prions -- remains a mystery. In preliminary studies, co-author Cheng Cheng Zhang discovered 40% of adult mouse bone marrow cells expressed PrP on their surfaces. More than 80% of these PrP-marked cells were red blood cells or their developmental precursors, suggesting PrP might be a marker for long-term hematopoietic stem cells, which can give rise to the entire adult blood system.
To determine if PrP was a marker for long-term hematopoietic stem cells, the researchers took bone marrow cells from wild-type mice and purified them into fractions, some of which expressed PrP. Six months after transplantation into lethally irradiated mice, the researchers saw both short- and long-term engraftment in mice that received PrP-containing cells, but only short-term engraftment activity in mice receiving non-PrP cells.
While PrP is a marker for long-term hematopoietic stem cells in wild-type mice, PrP-knockout mice still possess these cells, as well as relatively normal levels of their derived progeny. To determine what function PrP might normally have in hematopoietic stem cells, the researchers carried out several rounds of bone marrow implantations. First they transplanted bone marrow from either wild-type mice or a PrP-null strain into lethally irradiated mice. When the engrafted marrow flourished and generated peripheral blood cells, the researchers implanted the newly reconstituted bone marrow into another lethally irradiated mouse group, then repeated the process a third time.
In each round after the first, bone marrow originating from PrP-null mice experienced a dramatically reduced ability to renew itself, while cells from the wild-type mice did not. Retroviral infections that expressed PrP in recipients of PrP-null bone marrow rescued this defective process, suggesting PrP is necessary for hematopoietic stem cell self-renewal.
Odile Kellerman at the Pasteur Institute in Paris, who did not participate in this study, noted prions often trigger neuron death in TSEs after long incubation periods?similarly, PrP only impacted hematopoietic stem cells over the long term. "In both cases, PrP appears to contribute to the long-lasting adaptation of cells to injury," she told The Scientist. Kellerman suggested that when PrP function is disrupted, cells try to adapt, "but in the long term, this turns out to be detrimental."
The exact mechanism behind how PrP might contribute to hematopoietic stem cell renewal remains unknown. Co-author Harvey Lodish speculated PrP might bond to and concentrate a hormone on the cell surface, or help stem cells adhere to neighboring cells or extracellular matrix. "It should prove fairly straightforward to see if it is adhering to other proteins or any known or unknown hormones,? he told The Scientist.
William Stanford at the University of Toronto, who did not participate in this study, noted that PrP is tethered to cell membranes via a glycosylphosphatidylinositol (GPI) anchor, similar to hematopoietic stem cell marker Sca-1. "This suggests these GPI-anchored proteins, which have similar functions, may operate through a common mechanism," Stanford told The Scientist.
Future experiments could investigate whether overexpressing PrP in hematopoietic stem cells increases self-renewal, and rescues self-renewal defects such as in the Sca-1 deficient mouse, Stanford added -- or if genetically substituting PrP with a different GPI-anchored protein rescues the self-renewal defect seen in PrP-null mice.
Links within this article
C.C. Zhang et al. "Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal." PNAS Early Edition. Published online January 30, 2006.
B.A. Maher. "Prion hypothesis proven?" The Scientist, April 21, 2005.
M. Fogarty. "Prions - The terminators." The Scientist, July 28, 2003.
M. Fogarty. "Researchers further define sources of adult blood stem cells." The Scientist, September 16, 2002.
J.U. Adams. "The tiniest of life's rafts." The Scientist, October 11, 2004