Impaired haematopoietic stem cell differentiation and enhanced skewing towards myeloid progenitors in aged caspase-2-deficient mice

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dc.contributor.authorDawar, S.
dc.contributor.authorShahrin, N.
dc.contributor.authorSladojevic, N.
dc.contributor.authorD'Andrea, R.
dc.contributor.authorDorstyn, L.
dc.contributor.authorHiwase, D.
dc.contributor.authorKumar, S.
dc.date.issued2016
dc.description.abstractThe 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.
dc.description.statementofresponsibilitySwati Dawar, Nur Hezrin Shahrin, Nikolina Sladojevic, Richard J D, Andrea, Loretta Dorstyn, Devendra K Hiwase and Sharad Kumar
dc.identifier.citationCell Death and Disease, 2016; 7(12):e2509-1-e2509-9
dc.identifier.doi10.1038/cddis.2016.406
dc.identifier.issn2041-4889
dc.identifier.issn2041-4889
dc.identifier.orcidHiwase, D. [0000-0002-6666-3056]
dc.identifier.orcidKumar, S. [0000-0001-7126-9814]
dc.identifier.urihttp://hdl.handle.net/2440/104465
dc.language.isoen
dc.publisherNature Publishing Group
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1043057
dc.rights©The Author(s) 2016, Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
dc.source.urihttps://doi.org/10.1038/cddis.2016.406
dc.subjectHematopoietic Stem Cells
dc.subjectMyeloid Progenitor Cells
dc.subjectCells, Cultured
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectMice, Knockout
dc.subjectDNA Damage
dc.subjectAneuploidy
dc.subjectCell Differentiation
dc.subjectAging
dc.subjectCaspase 2
dc.titleImpaired haematopoietic stem cell differentiation and enhanced skewing towards myeloid progenitors in aged caspase-2-deficient mice
dc.typeJournal article
pubs.publication-statusPublished

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