The Plant Hormone Abscisic Acid is a Pro-Survival Factor in Human and Murine Megakaryocytes

Abscisic acid (ABA) is a phytohormone involved in pivotal physiological functions in higher plants. Recently, ABA proved to be secreted and active also in mammals, where it stimulates the activity of innate immune cells, of mesenchymal and hematopoietic stem cells and of insulin-releasing pancreatic β-cells through a signaling pathway involving the second messenger cyclic ADP-ribose (cADPR). In addition to behaving as an animal hormone, ABA holds promise also as nutraceutical plant-derived compound in humans. Many biological functions of ABA in mammals are mediated by its binding to the LANCL-2 receptor protein. A putative binding of ABA to GRP78, a key regulator of endoplasmic reticulum (ER) stress, has been also proposed. Here we investigated the role of exogenous ABA in modulating thrombopoiesis, the process of platelet generation. Our results demonstrate that expression of both LANCL-2 and GRP78 is up-regulated during hematopoietic stem cell differentiation into mature megakaryocytes (Mks). Functional ABA receptors exist in mature Mks, because ABA induces intracellular Ca2+ increase ([Ca2+]i) through protein kinase A (PKA) activation and subsequent cADPR generation. In vitro exposure of human or murine hematopoietic progenitor cells to 10 μM ABA does not increase recombinant thrombopoietin (rTpo)-dependent Mk differentiation or platelet release. However, in conditions of cell stress induced by rTpo and serum deprivation, ABA stimulates, in a PKA- and cADPR-dependent fashion, the Mitogen Activated Kinase ERK 1/2, resulting in the modulation of lymphoma 2 (Bcl-2) family members, increased Mk survival and higher rates of platelets production. In conclusion, we demonstrate that ABA is a pro-survival factor for Mks in a Tpo independent manner.