title: Impaired haematopoietic stem cell differentiation and enhanced skewing towards myeloid progenitors in aged caspase-2-deficient mice.
abstract: The apoptotic cysteine protease caspase-2 has been shown to suppress tumourigenesis in mice and its reduced expression correlates with poor prognosis in some human malignancies. Caspase-2-deficient mice develop normally but show ageing-related traits and, when challenged by oncogenic stimuli or certain stress, show enhanced tumour development, often accompanied by extensive aneuploidy. As stem cells are susceptible to acquiring age-related functional defects because of their self-renewal and proliferative capacity, we examined whether loss of caspase-2 promotes such defects with age. Using young and aged Casp2-/-mice, we demonstrate that deficiency of caspase-2 results in enhanced aneuploidy and DNA damage in bone marrow (BM) cells with ageing. Furthermore, we demonstrate for the first time that caspase-2 loss results in significant increase in immunophenotypically defined short-term haematopoietic stem cells (HSCs) and multipotent progenitors fractions in BM with a skewed differentiation towards myeloid progenitors with ageing. Caspase-2 deficiency leads to enhanced granulocyte macrophage and erythroid progenitors in aged mice. Colony-forming assays and long-term culture-initiating assay further recapitulated these results. Our results provide the first evidence of caspase-2 in regulating HSC and progenitor differentiation, as well as aneuploidy, in vivo.
authors.affiliation: Centre for Cancer Biology, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Swati
authors.initials: S
authors.lastname: Dawar
authors.affiliation: Centre for Cancer Biology, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Nur Hezrin
authors.initials: NH
authors.lastname: Shahrin
authors.affiliation: Centre for Cancer Biology, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Nikolina
authors.initials: N
authors.lastname: Sladojevic
authors.affiliation: Centre for Cancer Biology, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: D'Andrea
authors.affiliation: Centre for Cancer Biology, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Loretta
authors.initials: L
authors.lastname: Dorstyn
authors.affiliation: Centre for Cancer Biology, University of South Australia, Adelaide, South Australia 5001, Australia.|Department of Haematology, SA Pathology, Adelaide, South Australia 5000, Australia.
authors.forename: Devendra K
authors.initials: DK
authors.lastname: Hiwase
authors.affiliation: Centre for Cancer Biology, University of South Australia, Adelaide, South Australia 5001, Australia.
authors.forename: Sharad
authors.initials: S
authors.lastname: Kumar
mesh_terms: D000375:Aging / Q000378:metabolism*; D000782:Aneuploidy; D000818:Animals; D053143:Caspase 2 / Q000172:deficiency* / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D004249:DNA Damage; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000473:pathology*
chemical_list: D053143:Caspase 2