The Plant Hormone Abscisic Acid Stimulates the Proliferation of Human Hemopoietic Progenitors through the Second Messenger Cyclic ADP-Ribose

Abstract

Abscisic acid (ABA) is a hormone involved in pivotal physiological functions in higher plants, such as response to abiotic stress and control of seed dormancy and germination. Recently, ABA was demonstrated to be autocrinally produced by human granulocytes, b pancreatic cells, and mesenchymal stem cells (MSC) and to stimulate cell-specific functions through a signaling pathway involving the second messenger cyclic ADP-ribose (cADPR). Here we show that ABA expands human uncommitted hemopoietic progenitors (HP) in vitro, through a cADPR-mediated increase of the intracellular calcium concentration ([Ca 21 ] i ). Incubation of CD34 1 cells with micromolar ABA also induces transcriptional effects, which include NF-jB nuclear translocation and transcription of genes encoding for several cytokines. Human MSC stimulated with a lymphocyte-conditioned medium produce and release ABA at concentrations sufficient to exert growth-stimulatory effects on co-cultured CD34 1 cells, as demonstrated by the inhibition of colony growth in the presence of an anti-ABA monoclonal antibody. These results provide a remarkable example of conservation of a stress hormone and of its second messenger from plants to humans and identify ABA as a new hemopoietic growth factor involved in the cross-talk between HP and MSC.

Microgram amounts of abscisic acid in fruit extracts improve glucose tolerance and reduce insulinemia in rats and in humans

“…Activated platelets or quartz particles stimulate ABA release from monocytes/macrophages and ABA, in an autocrine manner, stimulates release of cytokines and prostaglandin E2 (4,5). IL-8 induces human mesenchymal stem cells to release ABA, which stimulates the release of growth factors from these cells and colony growth from human hemopoietic progenitors (6,7). An intriguing clue to the conserved role of ABA as a stress hormone in plants and animals comes from the observation that UV light stimulates NO release in both Arabidopsis and human keratinocytes via ABA production (8,9).…”

Abscisic Acid Transport in Human Erythrocytes

“…RBC represent a convenient model system for the study of ABA transport in mammalian cells, for two reasons: (i) RBC plasma membranes (ghosts) can be easily isolated and resealed, yielding transportcompetent vesicles (47), and (ii) RBC express the ABA receptor LANCL2, which upon ABA binding stimulates AC in several animal cell types (12)(13)(14)(15)(16)(17)(18)48), thus triggering the first step of the intracellular ABA signaling pathway after ABA influx. The first member of the LANCL family, LANCL1, was indeed isolated from human erythrocyte membranes, where it is present as a peripheral membrane protein (49).…”

“…In human granulocytes and other cells of the innate immune response, ABA stimulates cell-specific functions, such as phagocytosis, chemotaxis, reactive oxygen species, and nitric oxide production (12)(13)(14). ABA also expands human mesenchymal stem cells (15) and human hemopoietic progenitors (16). In cells involved in the control of systemic glucose homeostasis, ABA is an endogenous stimulator of insulin release from pancreatic ␤ cells and an enhancer of glucose uptake by adipocytes and myoblasts (17).…”

Cycling Assay for Determining Intracellular Cyclic ADP-Ribose Levels

“…Moreover, PCA extraction itself is quite tedious and a modification has been proposed in which PCA is substituted with an organic solvent (Young and Kirkland 2006). This assay has been used (together with other studies) to demonstrate a role for cADPR in the differentiation of HL60 cells (Munshi et al 2002), the lipopolysaccharide-stimulated proliferation of peripheral blood mononuclear cells (Bruzzone et al 2003) and microglia activation (Franco et al 2006), the mammalian cell responses to abscisic acid (Bruzzone et al 2007(Bruzzone et al , 2008(Bruzzone et al , 2012Bodrato et al 2009;Magnone et al 2009;Scarfì et al 2009), the Arabidopsis circadian clock (Dodd et al 2007), and renin production and release in As4.1 cells (Yi et al 2007 …”