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Prion Protein: A Force for Good in Stem Cells
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3 February 2006. The purpose of the prion protein (PrP), other than to beset cows, humans, and other animals with brain-wasting diseases, has been devilishly hard to figure out. In spite of the protein’s widespread expression in many tissues, PrP knockout mice have no dramatic phenotype besides their resistance to infection with pathogenic prions.
Now, work from the labs of Harvey Lodish and Susan Lindquist at the Whitehead Institute and MIT reveals for the first time a positive function of PrP in the long-term maintenance of hematopoietic stem cells (HSCs) in mice. Their study, appearing this week in PNAS Early Edition, shows that PrP is present on the surface of HSCs from adult mice, and marks the cell population that is responsible for successful long-term reconstitution of blood cells after HSC transplantation. The primary role of PrP seems to be to promote the renewal of stem cells—HSCs from PrP-null mice were perfectly functional on a first transplantation, but rapidly lost their ability to repopulate bone marrow after serial transplantation. The results provide a tantalizing glimpse of PrP’s good side, and a way toward a better understanding of why evolution would have saddled us with such a protein.
PrP, the normal form of the pathological prion that causes mad cow disease in bovines and Creutzfeldt-Jakob disease in humans, is a cell surface protein, widely expressed on many cell types. In this study, first author Cheng Cheng Zhang noticed that PrP was abundantly present on adult mouse bone marrow cells. Enrichment for HSCs also enriched for PrP-positive cells, and 85.7 percent of the purified HSC population turned out to bear PrP also.
To directly test the role of PrP in HSC function, the researchers affinity-purified PrP-positive and -negative HSCs and tested which fractions could repopulate the hematopoietic system after transplantation to irradiated mice. Whether they started with whole bone marrow, or more purified stem cells, only the PrP-positive cells gave long-term successful reconstitution.
By these results, PrP appeared to be a bona fide marker for HSCs, but what was the protein’s function? The researchers found that PrP knockout mice had a normal hematopoietic system, with completely adequate levels of progenitors and differentiated cells of all types. Freshly isolated HSCs from PrP knockouts were no less efficient than wild-type cells as donors for bone marrow transplant.
When the investigators pushed stem cells a bit further, however, the lack of PrP began to show up. In serial transplantation experiments, where the bone marrow of reconstituted mice was used as a source of donor cells, the ability of PrP-null stem cells to grow and repopulate the marrow declined dramatically with each successive transplantation. In experiments where normal and PrP-null cell mixtures were transferred, the proportion of blood cells that derived from the PrP-null bone marrow went down with each round. When cells from PrP-null mice were used alone, the result was a dramatic decrease in survival with each iteration. These results were directly attributable to loss of PrP expression, since adding back PrP to null cells isolated after transplantation increased survival in the next round, while the introduction of a mutant PrP did not rescue the mice.
From these experiments, the researchers concluded that while PrP deficiency does not affect HSC activity under normal conditions, it is required for the renewal of stem cells under stress, as in serial transplantation. This idea was backed up by their finding that mice transplanted with PrP-null cells were more sensitive to the bone marrow toxin 5-fluorouracil than mice with hematopoietic systems derived from wild-type stem cells.
The unexpected link between PrP and stem cells provides a first, fascinating look at a physiological role for this infamous protein. The results will no doubt have stem cell mavens from all fields reaching for PrP antibodies to find out how widespread the influence of PrP might be.—Pat McCaffrey.
Reference:
Zhang CC, Steele AD, Lindquist SL, Lodish HF. Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal. Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2184-9. Epub 2006 Feb 7. Abstract
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Comment by: Andrea LeBlanc
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Submitted 3 February 2006
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Posted 3 February 2006
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This is the first time that the prion protein has been shown to be implicated in hematopoietic stem cell survival or proliferation. Such a role for prion protein is unexpected since most prion protein mutations affect the nervous system and not the peripheral systems. However, it is unclear why the prion-null mice do not develop problems with the hematopoietic system with age, since a lack of replenishment in these mice would likely lead to eventual problems with age or when the mice are submitted to certain daily stresses that can happen even in controlled environments (like infections).
The fact that the passage in sequential transplantations decreases the number of cells while the null mice have no problems may indicate that the cells under the stress of isolation initiate mechanisms of cell death. We now have strong evidence for the role of prion protein against Bax-mediated cell death in human neurons and in the breast carcinoma MCF7 cell line (Bounhar et al., 2001; Roucou et al., 2003; Roucou et al., 2005), and PrP has also been shown to prevent TNFα-mediated cell death...
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This is the first time that the prion protein has been shown to be implicated in hematopoietic stem cell survival or proliferation. Such a role for prion protein is unexpected since most prion protein mutations affect the nervous system and not the peripheral systems. However, it is unclear why the prion-null mice do not develop problems with the hematopoietic system with age, since a lack of replenishment in these mice would likely lead to eventual problems with age or when the mice are submitted to certain daily stresses that can happen even in controlled environments (like infections).
The fact that the passage in sequential transplantations decreases the number of cells while the null mice have no problems may indicate that the cells under the stress of isolation initiate mechanisms of cell death. We now have strong evidence for the role of prion protein against Bax-mediated cell death in human neurons and in the breast carcinoma MCF7 cell line (Bounhar et al., 2001; Roucou et al., 2003; Roucou et al., 2005), and PrP has also been shown to prevent TNFα-mediated cell death in MCF7 cells (Diarra-Mehrpour et al., 2004). Therefore, one possible explanation of the results is that the stem cells undergo Bax activation during the isolation and transplantation procedure and the presence of PrP prevents Bax-mediated cell death.
PrP has been shown to play a role in stimulated lymphocyte proliferation (Cashman et al., 1990; Mabbott et al., 1997), so the idea of PrP acting as a receptor for certain molecules is not entirely novel. Nevertheless, this is an interesting manuscript that brings forth the often ignored normal function of prion protein, a protein that is expressed in many tissues, often at fairly high levels.
References:
Bounhar Y, Zhang Y, Goodyer C, LeBlanc A (2001) Prion protein protects against Bax-mediated cell death. J Biol Chem 276:39145-39149. Abstract
Cashman N, Loertscher R, Nalbantoglu J, Shaw I, Kascsak R, Bolton D, Bendheim P (1990) Cellular isoform of the scrapie agent protein participates in lymphocyte activation. Cell 61:185-192. Abstract
Diarra-Mehrpour M, Arrabal S, Jalil A, Pinson X, Gaudin C, Pietu G, Pitaval A, Ripoche H, Eloit M, Dormont D, Chouaib S (2004) Prion Protein Prevents Human Breast Carcinoma Cell Line from Tumor Necrosis Factor alpha-Induced Cell Death. Cancer Res 64:719-727. Abstract
Mabbott NA, Brown KL, Manson J, Bruce ME (1997) T-lymphocyte activation and the cellular form of the prion protein. Immunology 92:161-165. Abstract
Roucou X, Guo Q, Zhang Y, Goodyer CG, LeBlanc AC (2003) Cytosolic prion protein is not toxic and protects against Bax-mediated cell death in human primary neurons. J Biol Chem 278:40877-40881. Abstract
Roucou X, Giannopoulos PN, Zhang Y, Jodoin J, Goodyer CG, LeBlanc A (2005) Cellular prion protein inhibits proapoptotic Bax conformational change in human neurons and in breast carcinoma MCF-7 cells. Cell Death Differ. 2005 Jul;12(7):783-95.
Abstract
 View all comments by Andrea LeBlanc |
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Comment by: Markus Glatzel
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Submitted 6 February 2006
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Posted 6 February 2006
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Zhang et al. show that the physiological form of the prion protein, PrPC, is expressed on hematopoietic stem cells, and may play a role in hematopoietic stem cell renewal. The authors speculate that PrPC might be a (co)receptor, protecting hematopoietic stem cells from apoptosis. This study represents one of many showing a putative function for PrPC. It differs from many other studies in that the relevance of this putative function is demonstrated in vivo.
A number of points come to mind:
There is no shortage of putative functions of PrPC. As a matter of fact, PrPC has been shown to bind copper (Brown et al., 1997); have antiapoptotic properties (Zanata et al., 2002); possess superoxide dismutase activity (Brown and Besinger, 1998); activate intracellular tyrosine kinases (Mouillet-Richard et al., 2000); and interact with Hsp60 (Watarai et al., 2003), among other things. If that seems confusing, it only gets worse if one looks at PrPC/PrPSc binding proteins. PrPC/PrPSc has been shown to bind to Bcl-2 (Kurschner et al., 1995), caveolin (Gorodinsky and Harris, 1995), the...
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Zhang et al. show that the physiological form of the prion protein, PrPC, is expressed on hematopoietic stem cells, and may play a role in hematopoietic stem cell renewal. The authors speculate that PrPC might be a (co)receptor, protecting hematopoietic stem cells from apoptosis. This study represents one of many showing a putative function for PrPC. It differs from many other studies in that the relevance of this putative function is demonstrated in vivo.
A number of points come to mind:
There is no shortage of putative functions of PrPC. As a matter of fact, PrPC has been shown to bind copper (Brown et al., 1997); have antiapoptotic properties (Zanata et al., 2002); possess superoxide dismutase activity (Brown and Besinger, 1998); activate intracellular tyrosine kinases (Mouillet-Richard et al., 2000); and interact with Hsp60 (Watarai et al., 2003), among other things. If that seems confusing, it only gets worse if one looks at PrPC/PrPSc binding proteins. PrPC/PrPSc has been shown to bind to Bcl-2 (Kurschner et al., 1995), caveolin (Gorodinsky and Harris, 1995), the laminin receptor precursor (Rieger et al., 1997), plasminogen (Fischer et al., 2000), and N-CAM (Schmitt-Ulms et al., 2001).
Will the proposed, hematopoietic stem cell-related function of PrPC stand the test of time? The answer to date is uncertain. If the sole purpose of PrPC would relate to the hematopoietic system, then why is its expression orders of magnitude higher in the central nervous system?
Looking at all of these studies, and also taking into account that PrPC is extremely conserved throughout evolution and highly expressed in several tissue compartments including the central nervous system, the hematopoietic system, and the musculoskeletal system, one may consider that “the” PrPC function might not exist. Perhaps PrPC executes a multitude of functions. The challenge will be to find out how these different pieces of the puzzle fit together.
References:
Brown DR, Besinger A (1998) Prion protein expression and superoxide dismutase activity. Biochem J 334:423-429. Abstract
Brown DR, Qin K, Herms JW, Madlung A, Manson J, Strome R, Fraser PE, Kruck T, von Bohlen A, Schulz-Schaeffer W, Giese A, Westaway D, Kretzschmar H (1997) The cellular prion protein binds copper in vivo. Nature 390:684-687. Abstract
Fischer MB, Roeckl C, Parizek P, Schwarz HP, Aguzzi A (2000) Binding of disease-associated prion protein to plasminogen. Nature 408:479-483. Abstract
Gorodinsky A, Harris DA (1995) Glycolipid-anchored proteins in neuroblastoma cells form detergent-resistant complexes without caveolin. J Cell Biol 129:619-627. Abstract
Kurschner C, Morgan JI. (1995) The cellular prion protein (PrP) selectively binds to Bcl-2 in the yeast two-hybrid system: identification of candidate proteins binding to prion protein. Brain Res Mol Brain Res 30:165-168. Abstract
Mouillet-Richard S, Ermonval M, Chebassier C, Laplanche JL, Lehmann S, Launay JM, Kellermann O (2000) Signal transduction through prion protein. Science 289:1925-1928. Abstract
Rieger R, Edenhofer F, Lasmezas CI, Weiss S (1997) The human 37-kDa laminin receptor precursor interacts with the prion protein in eukaryotic cells. Nat Med 3:1383-1388. Abstract
Schmitt-Ulms G, Legname G, Baldwin MA, Ball HL, Bradon N, Bosque PJ, Crossin KL, Edelman GM, DeArmond SJ, Cohen FE, Prusiner SB (2001) Binding of neural cell adhesion molecules (N-CAMs) to the cellular prion protein. J Mol Biol 314:1209-1225. Abstract
Watarai M, Kim S, Erdenebaatar J, Makino S, Horiuchi M, Shirahata T, Sakaguchi S, Katamine S (2003) Cellular prion protein promotes Brucella infection into macrophages. J Exp Med 198:5-17. Abstract
Zanata SM, Lopes MH, Mercadante AF, Hajj GN, Chiarini LB, Nomizo R, Freitas AR, Cabral AL, Lee KS, Juliano MA, De Oliveira E, Jachieri SG, Burlingame A, Huang L, Linden R, Brentani RR, Martins VR (2002) Stress-inducible protein 1 is a cell surface ligand for cellular prion that triggers neuroprotection. Embo J 21:3307-3316. Abstract
View all comments by Markus Glatzel |
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