Zhang CC, Steele AD, Lindquist S, et al. Prion protein is
expressed on long-term repopulating hematopoietic stem cells and is
important for their self-renewal. PNAS USA 2006;103:2184-9.
Steele AD, Emsley JG, Ozdinler PH, et al. Prion protein (PrPc)
positively regulates neural precursor proliferation during
developmental and adult mammalian neurogenesis. PNAS USA 2006; [Epub
ahead of print].
In this paper, Zhang et al. studied the role of the much maligned
and feared prions in hematopoiesis. Prions are expressed in many
tissues, including hematopoietic cells and neurons. When the authors
examined mouse bone marrow, they found that many marrow cells expressed
prion protein (PrP) and that the erythroid progenitors were
particularly likely to express PrP (more than 80 percent of cells
bearing the erythroid surface antigens were PrP+). They then focused on
the possible function of PrP in hematopoietic stem cells, which are
particularly prevalent in the side population (identified by exclusion of Hoechst Dye 333421).
About half of the hematopoietic stem cells also expressed PrP. The
authors then concentrated on the ability of PrP+ versus PrP null cells
(using PrP knockout mice) to generate hematopoietic progenitors in
clonogenic assays using BFUE, CFU-G, and CFU-GEMM. They found that the
relative proportion of the progenitors and the appearance of the
colonies derived from both PrP+ and PrP null stem cells were normal,
suggesting no difference in the number and proliferating capacity of
PrP+ versus PrP stem cells. Zheng and colleagues then investigated
whether PrP has an effect on self-renewal of pluripotent stem cells.
For this they used a well-described competitive repopulation
transplantation model. In the first four months after transplantation,
they found that PrP null versus PrP+ donor cells exhibited equal
engraftment and reconstitution of peripheral blood. After the first
four months, the PrP+ hematopoietic stem cells clearly out-competed the
PrP null cells - a finding even more striking in secondary and tertiary
transplantation. Further, the long-term repopulating stem cells were
only in PrP+ side population. The conclusion that PrP is augmenting the
yet-to-be fully elucidated self-renewal properties of hematopoietic
stem cells was further confirmed by the superiority of PrP+
hematopoietic stem cells after the stress of 5-FU therapy in
reconstituting the marrow of transplanted recipients, as well as by the
rescue of PrP null cells after retroviral transfection-induced ectopic
PrP expression. In a paper published two weeks later, Steele and
colleagues also examined the function of the PrP in regulation of
neural proliferation and differentiation. In this paper, the authors
showed that, in neuronal tissue, PrP plays an essential role in
neurogenesis and neuron progenitor differentiation.
What are the implications of these findings? First,
that PrP is anchored on the surface of the cells and likely has a
receptor or co-receptor function which affects hematopoietic stem cell
activity. It likely interacts with a yet-to-be-determined ligand. The
elucidation of the function and identity of the postulated ligand would
greatly further our understanding of hematopoietic stem cells and may
be important in the future for in vitro and in vivo stem cell manipulation. Furthermore, PrP is a GPI-linked protein2 and has been shown to be defective in paroxysmal nocturnal hemoglobinuria3 .
Thus, the PrP defect may be the long-sought-after link for
understanding the frequent bone marrow failure and aplasia seen in
patients with somatic PIG-A mutations, resulting in failure of
GPI-linked protein expression, i.e., the pathognomonic lesion of
paroxysmal nocturnal hemoglobinuria. Additionally, since copper is
required for expression of PrP, it may also explain the pancytopenia
described in patients with copper deficiency4 .
