Prion protein deficiency impairs hematopoietic stem cell determination and sensitizes myeloid progenitors to irradiation
Capucine Siberchicot,
Nathalie Gault,
Nathalie Déchamps,
Vilma Barroca,
Adriano Aguzzi,
Paul-Henri Roméo,
J. Pablo Radicella,
Anne Bravard,
Jacqueline Bernardino-Sgherri
Affiliations
Capucine Siberchicot
French Alternative Energies and Atomic Energy Commission (CEA)/Direction of Fundamental Research (DRF)/Institute of Biology François Jacob (IBFJ)/Institute of Cellular and Molecular Radiobiology (iRCM), 92265 Fontenay-aux-Roses Cedex, France;Laboratory of Research in Genetic Instability (LRIG), 92265 Fontenay-aux-Roses Cedex, France;Université Paris-Diderot, Sorbonne Paris Cité, Paris, France;Université Paris-Sud, Paris, France
Nathalie Gault
French Alternative Energies and Atomic Energy Commission (CEA)/Direction of Fundamental Research (DRF)/Institute of Biology François Jacob (IBFJ)/Institute of Cellular and Molecular Radiobiology (iRCM), 92265 Fontenay-aux-Roses Cedex, France;Université Paris-Diderot, Sorbonne Paris Cité, Paris, France;Université Paris-Sud, Paris, France;Laboratory of Repair and Transcription in Hematopoietic Stem Cells (LRTS), 92265 Fontenay-aux-Roses Cedex, France;Inserm U967, 92265 Fontenay-aux-Roses Cedex, France
Nathalie Déchamps
French Alternative Energies and Atomic Energy Commission (CEA)/Direction of Fundamental Research (DRF)/Institute of Biology François Jacob (IBFJ)/Institute of Cellular and Molecular Radiobiology (iRCM), 92265 Fontenay-aux-Roses Cedex, France;Université Paris-Diderot, Sorbonne Paris Cité, Paris, France;Université Paris-Sud, Paris, France;Inserm U967, 92265 Fontenay-aux-Roses Cedex, France
Vilma Barroca
French Alternative Energies and Atomic Energy Commission (CEA)/Direction of Fundamental Research (DRF)/Institute of Biology François Jacob (IBFJ)/Institute of Cellular and Molecular Radiobiology (iRCM), 92265 Fontenay-aux-Roses Cedex, France;Université Paris-Diderot, Sorbonne Paris Cité, Paris, France;Université Paris-Sud, Paris, France;Laboratory of Repair and Transcription in Hematopoietic Stem Cells (LRTS), 92265 Fontenay-aux-Roses Cedex, France;Inserm U967, 92265 Fontenay-aux-Roses Cedex, France
Adriano Aguzzi
Institute of Neuropathology, University of Zurich, Zurich, Switzerland
Paul-Henri Roméo
French Alternative Energies and Atomic Energy Commission (CEA)/Direction of Fundamental Research (DRF)/Institute of Biology François Jacob (IBFJ)/Institute of Cellular and Molecular Radiobiology (iRCM), 92265 Fontenay-aux-Roses Cedex, France;Université Paris-Diderot, Sorbonne Paris Cité, Paris, France;Université Paris-Sud, Paris, France;Laboratory of Repair and Transcription in Hematopoietic Stem Cells (LRTS), 92265 Fontenay-aux-Roses Cedex, France;Inserm U967, 92265 Fontenay-aux-Roses Cedex, France
J. Pablo Radicella
French Alternative Energies and Atomic Energy Commission (CEA)/Direction of Fundamental Research (DRF)/Institute of Biology François Jacob (IBFJ)/Institute of Cellular and Molecular Radiobiology (iRCM), 92265 Fontenay-aux-Roses Cedex, France;Laboratory of Research in Genetic Instability (LRIG), 92265 Fontenay-aux-Roses Cedex, France;Université Paris-Diderot, Sorbonne Paris Cité, Paris, France;Université Paris-Sud, Paris, France
Anne Bravard
French Alternative Energies and Atomic Energy Commission (CEA)/Direction of Fundamental Research (DRF)/Institute of Biology François Jacob (IBFJ)/Institute of Cellular and Molecular Radiobiology (iRCM), 92265 Fontenay-aux-Roses Cedex, France;Laboratory of Research in Genetic Instability (LRIG), 92265 Fontenay-aux-Roses Cedex, France;Université Paris-Diderot, Sorbonne Paris Cité, Paris, France;Université Paris-Sud, Paris, France;Laboratory of Repair and Transcription in Hematopoietic Stem Cells (LRTS), 92265 Fontenay-aux-Roses Cedex, France;Inserm U967, 92265 Fontenay-aux-Roses Cedex, France
Jacqueline Bernardino-Sgherri
French Alternative Energies and Atomic Energy Commission (CEA)/Direction of Fundamental Research (DRF)/Institute of Biology François Jacob (IBFJ)/Institute of Cellular and Molecular Radiobiology (iRCM), 92265 Fontenay-aux-Roses Cedex, France;Laboratory of Research in Genetic Instability (LRIG), 92265 Fontenay-aux-Roses Cedex, France;Université Paris-Diderot, Sorbonne Paris Cité, Paris, France;Université Paris-Sud, Paris, France;Laboratory of Repair and Transcription in Hematopoietic Stem Cells (LRTS), 92265 Fontenay-aux-Roses Cedex, France;Inserm U967, 92265 Fontenay-aux-Roses Cedex, France
Highly conserved among species and expressed in various types of cells, numerous roles have been attributed to the cellular prion protein (PrPC). In hematopoiesis, PrPC regulates hematopoietic stem cell self-renewal but the mechanisms involved in this regulation are unknown. Here we show that PrPC regulates hematopoietic stem cell number during aging and their determination towards myeloid progenitors. Furthermore, PrPC protects myeloid progenitors against the cytotoxic effects of total body irradiation. This radioprotective effect was associated with increased cellular prion mRNA level and with stimulation of the DNA repair activity of the Apurinic/pyrimidinic endonuclease 1, a key enzyme of the base excision repair pathway. Altogether, these results show a previously unappreciated role of PrPC in adult hematopoiesis, and indicate that PrPC-mediated stimulation of BER activity might protect hematopoietic progenitors from the cytotoxic effects of total body irradiation.
