Translational approaches to functional platelet production ex vivo

Platelets, which are released by megakaryocytes, play key roles in haemostasis, angiogenesis, immunity, tissue regeneration and wound healing. The scarcity of clinical cures for life threatening platelet diseases is in a large part due to limited insight into the mechanisms that control the developmental process of megakaryocytes and the mechanisms that govern the production of platelets within the bone marrow. To overcome these limitations, functional human tissue models have been developed and studied to extrapolate ex vivo outcomes for new insight on bone marrow functions in vivo. There are many challenges that these models must overcome, from faithfully mimicking the physiological composition and functions of bone marrow, to the collection of the platelets generated and validation of their viability and function for human use. The overall goal is to identify innovative instruments to study mechanisms of platelet release, diseases related to platelet production and new therapeutic targets starting from human progenitor cells

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 \u3b2-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 \u3bcM 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

A new path to platelet production through matrix sensing Title: A new path to platelet production through matrix sensing

Haematologica 2017 [Epub ahead of print] Citation: Abbonante V, Di Buduo CA, Gruppi C, De Maria C, Spedden E, De Acutis A, Staii C, Raspanti M, Vozzi G, Kaplan D, Moccia F, Ravid K, and Balduini A. A new path to platelet production through matrix sensing. Haematologica. 2017; 102:xxx doi:10.3324/haematol.2016