Paracrine Factors Released by Osteoblasts Provide Strong Platelet Engraftment Properties. (24th December 2018)

• Record Type: Journal Article
• Authors: Abu‐Khader, Ahmad; Law, Kyle W.; Jahan, Suria; Manesia, Javed K.; Pasha, Roya; Hovey, Owen; Pineault, Nicolas
• Is Part Of: Stem cells. Volume 37:Number 3(2019)
• Page Start: 345
• Page End: 356
• Publication Date: 2018-12-24
• Subjects: Osteoblasts -- Platelet engraftment -- Progenitor expansion -- Hematopoietic reconstitution -- IGF‐2 -- Cellular therapy; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2956
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: Ex vivo expansion of hematopoietic stem cell (HSCs) and progenitors may one day overcome the slow platelet engraftment kinetics associated with umbilical cord blood transplantation. Serum‐free medium conditioned with osteoblasts (i.e., osteoblast‐conditioned medium [OCM]) derived from mesenchymal stromal cells (MSC) was previously shown to increase cell growth and raise the levels of human platelets in mice transplanted with OCM‐expanded progenitors. Herein, we characterized the cellular and molecular mechanisms responsible for these osteoblast‐derived properties. Limiting dilution transplantation assays revealed that osteoblasts secrete soluble factors that synergize with exogenously added cytokines to promote the production of progenitors with short‐term platelet engraftment activities, and to a lesser extent with long‐term platelet engraftment activities. OCM also modulated the expression repertoire of cell‐surface receptors implicated in the trafficking of HSC and progenitors to the bone marrow. Furthermore, OCM contains growth factors with prosurvival and proliferation activities that synergized with stem cell factor. Insulin‐like growth factor (IGF)‐2 was found to be present at higher levels in OCM than in control medium conditioned with MSC. Inhibition of the IGF‐1 receptor, which conveys IGF‐2′ intracellular signaling, largely abolished the growth‐promoting activity of OCM on immature CD34 + subsets and progenitors in OCM cultures. Finally, IGF‐1R effects appear to be mediated in part by the coactivator β‐catenin. In summary, these results provide new insights into the paracrine regulatory activities of osteoblasts on HSC, and how these can be used to modulate the engraftment properties of human HSC and progenitors expanded in culture. Stem Cells 2019;37:345–356 Abstract : Platelet engraftment is a significant issue with cord blood transplantation. Here, we show that that the production of platelet engrafting stem and progenitor is significantly enhanced in culture when medium is conditioned with osteoblasts (i.e., osteoblast‐conditioned medium). This activity correlated with increases in cell growth, and expression of cell surface receptors implicated in the adhesion and migration of stem and progenitors to the bone marrow. These results provide new insights into the paracrine regulatory activities of osteoblasts, and how those can modulate the engraftment properties of stem and progenitor cells.