Intrinsic function of the peptidylarginine deiminase PADI4 is dispensable for normal haematopoiesis

Abstract

Peptidylarginine deiminases (PADIs) are strongly associated with the development of autoimmunity, neurodegeneration and cancer but their physiological roles are ill-defined. The nuclear deiminase PADI4 regulates pluripotency in the mammalian pre-implantation embryo but its function in tissue development is unknown. PADI4 is primarily expressed in the bone marrow, as part of a self-renewal-associated gene signature. It has been shown to regulate the proliferation of multipotent haematopoietic progenitors and proposed to impact on the differentiation of haematopoietic stem cells (HSCs), suggesting that it controls haematopoietic development or regeneration. Using conditional in vivo models of steady state and acute Padi4 ablation, we examined the role of PADI4 in the development and function of the haematopoietic system. We found that PADI4 loss does not significantly affect HSC self-renewal or differentiation potential upon injury or serial transplantation, nor does it lead to HSC exhaustion or premature ageing. Thus PADI4 is dispensable for cell-autonomous HSC maintenance, differentiation and haematopoietic regeneration. This work represents the first study of PADI4 in tissue development and indicates that pharmacological PADI4 inhibition is likely to be tolerated without adverse effects.

The Antioxidant TEMPOL Protects Human Hematopoietic Stem Cells From Culture-Mediated Loss of Functions

“…Of note function of PADI4 on HSC maintenance is controversial. 52 Therefore, gene expression modulated by Tempol may be associated with either oxidative stress modulation or with HSC exhaustion/proliferation balance. Our results are in favor of adding antioxidants such as Tempol to the culture medium to improve HSC maintenance in the context of cell/gene therapy protocols.…”

Transcriptomic analysis of PADI4 target genes during multi-lineage differentiation of embryonic stem cells

“…The physiological functions of PADI4 are less well understood, as are its modes of action under physiological conditions (whether through transcriptional, signalling or cell–ECM regulation). In healthy mammals, Padi4 is most highly expressed in the blood and the bone marrow, although it does not have a cell-intrinsic role in mouse haematopoiesis [ 14 , 15 ]. We previously demonstrated that PADI4 is also expressed in embryonic stem (ES) cells and mediates the establishment of pluripotency during the reprogramming of somatic cells to induced pluripotent stem (iPS) cells [ 10 ].…”