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2 results on '"Haigh OL"'

1. DROSHA but not DICER is required for human haematopoietic stem cell function

Author

Gu, K, Walpole, C, Gooneratne, S, Liu, X, Haigh, OL, Radford, KJ, Chong, MM, Gu, K, Walpole, C, Gooneratne, S, Liu, X, Haigh, OL, Radford, KJ, and Chong, MM

Abstract

OBJECTIVES: DROSHA and DICER have central roles in the biogenesis of microRNAs (miRNAs). However, we previously showed that in the murine system, DROSHA has an alternate function where it directly recognises and cleaves protein-coding messenger (m)RNAs and this is critical for safeguarding the pluripotency of haematopoietic stem cells (HSCs). Maintenance of murine HSC function is dependent on DROSHA-mediated cleavage of two mRNAs, Myl9 and Todr1. The goal of this study is to determine whether this pathway is conserved in human HSCs. METHODS: DROSHA and DICER were knocked down in human cord blood CD34+ HSCs with short hairpin RNAs. The function of HSCs was analysed in vitro and in humanised mice. Analysis of mRNA cleavage was performed by capture of 5' phosphorylated RNAs. RESULTS: Consistent with murine HSCs, DROSHA knockdown impaired the differentiation of human HSCs in vitro and engraftment into humanised mice, whereas DICER knockdown had no impact. DROSHA cleaves the MYL9 mRNA in human HSCs and DROSHA deficiency resulted in the accumulation of the mRNA. However, ectopic expression of MYL9 did not impair human HSC function. We were unable to identify a human homolog of Todr1. CONCLUSION: A miRNA-independent function of DROSHA is critical for the function of human HSCs. DROSHA directly recognises and degrades mRNAs in humans HSCs. However, unlike in murine HSCs, the degradation of the MYL9 mRNA alone is not critical for human HSC function. Therefore, DROSHA must be inhibiting other targets and/or has another miRNA-independent function that is essential for safeguarding the pluripotency of human HSCs.

Published
2022

2. Activation of human CD141 + and CD1c + dendritic cells in vivo with combined TLR3 and TLR7/8 ligation.

Author

Pearson FE, Chang K, Minoda Y, Rojas IML, Haigh OL, Daraj G, Tullett KM, and Radford KJ

Subjects
Animals, Cell Differentiation drug effects, Cytokines blood, Dendritic Cells drug effects, Humans, Imidazoles pharmacology, Liver drug effects, Liver metabolism, Lung drug effects, Lung metabolism, Lymphoid Tissue drug effects, Lymphoid Tissue metabolism, Mice, Poly I-C pharmacology, Toll-Like Receptors agonists, Up-Regulation drug effects, Antigens, CD1 metabolism, Antigens, Surface metabolism, Dendritic Cells immunology, Toll-Like Receptors metabolism
Abstract

Mice reconstituted with human hematopoietic stem cells are valuable models to study aspects of the human immune system in vivo. We describe a humanized mouse model (hu mice) in which fully functional human CD141 + and CD1c + myeloid and CD123 + plasmacytoid dendritic cells (DC) develop from human cord blood CD34 + cells in immunodeficient mice. CD141 + DC are the human equivalents of murine CD8 + /CD103 + DC which are essential for the induction of tumor-inhibitory cytotoxic T lymphocyte responses, making them attractive targets to exploit for the development of new cancer immunotherapies. We used CD34 + -engrafted NSG-A2 mice to investigate activation of DC subsets by synthetic dsRNA or ssRNA analogs polyinosinic-polycytidylic acid/poly I:C and Resiquimod/R848, agonists for TLR3 and TLR8, respectively, both of which are expressed by CD141 + DC. Injection of hu mice with these agonists resulted in upregulation of costimulatory molecules CD80, CD83 and CD86 by CD141 + and CD1c + DC alike, and their combination further enhanced expression of these molecules by both subsets. When combined, poly I:C and R848 enhanced serum levels of key cytokines associated with cross-presentation and the induction of cytotoxic T lymphocyte responses including IFN-α, IFN-β, IL-12 and CXCL10. These data advocate a combination of poly I:C and R848 TLR agonists as means of activating human DC for immunotherapy., (© 2018 Australasian Society for Immunology Inc.)

Published
2018
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