Cyclic ADP‐Ribose‐Mediated Expansion and Stimulation of Human Mesenchymal Stem Cells by the Plant Hormone Abscisic Acid

Abstract Abscisic acid (ABA) is a phytohormone involved in fundamental processes in higher plants. Endogenous ABA biosynthesis occurs also in lower Metazoa, in which ABA regulates several physiological functions by activating ADP‐ribosyl cyclase (ADPRC) and causing overproduction of the Ca 2+ ‐mobilizing second messenger cyclic ADP‐ribose (cADPR), thereby enhancing intracellular Ca 2+ concentration ([Ca 2+ ] i ). Recently, production and release of ABA have been demonstrated to take place also in human granulocytes, where ABA behaves as a proinflammatory hormone through the same cADPR/[Ca 2+ ] i signaling pathway described in plants and in lower Metazoa. On the basis of the fact that human mesenchymal stem cells (MSC) express ADPRC activity, we investigated the effects of ABA and of its second messenger, cADPR, on purified human MSC. Both ABA and cADPR stimulate the in vitro expansion of MSC without affecting differentiation. The underlying mechanism involves a signaling cascade triggered by ABA binding to a plasma membrane receptor and consequent cyclic AMP‐mediated activation of ADPRC and of the cADPR/[Ca 2+ ] i system. Moreover, ABA stimulates the following functional activities of MSC: cyclooxygenase 2‐catalyzed production of prostaglandin E 2 (PGE 2 ), release of several cytokines known to mediate the trophic and immunomodulatory properties of MSC, and chemokinesis. Remarkably, ABA proved to be produced and released by MSC stimulated by specific growth factors (e.g., bone morphogenetic protein‐7), by inflammatory cytokines, and by lymphocyte‐conditioned medium. These data demonstrate that ABA is an autocrine stimulator of MSC function and suggest that it may participate in the paracrine signaling among MSC, inflammatory/immune cells, and hemopoietic progenitors. Disclosure of potential conflicts of interest is found at the end of this article.