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Old 12-07-2018, 06:45 PM
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rss IGF - Paracrine Factors Released by Osteoblasts Provide Strong Platelet Engraftment P

Related Articles Paracrine Factors Released by Osteoblasts Provide Strong Platelet Engraftment Properties.

Stem Cells. 2018 Dec 05;:

Authors: Abu-Khader A, Law KW, Jahan S, Manesia JK, Pasha R, Hovey O, Pineault N

Abstract
Ex vivo expansion of hematopoietic stem cells (HSC) and progenitors may one day overcome the slow platelet engraftment kinetics associated with umbilical cord blood (UCB) transplantation. Serum-free medium conditioned with osteoblasts (i.e., OCM) derived from mesenchymal stromal cells (MSC) was previously shown to increase cell growth and raise the levels of human platelets (hPLT) 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 (ST) platelet engraftment activities, and to a lesser extent with long term (LT) 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 (SCF). 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 beta-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. SIGNIFICANCE STATEMENT: Osteoblasts are one of many different cell type implicated in the regulation of hematopoiesis through various mechanism including the release of paracrine factors such as growth factors, chemokines and extracellular matrix proteins. We show that these factors strongly modulate the growth of umbilical cord blood stem and progenitor cells through activation of insulin-like growth factor-1 receptor and subsequent activation of the transcriptional activation complex? -catenin/TCF. Osteoblasts also modulated the expression repertoire of cell-surface receptors implicated in the homing of progenitors to the bone marrow. Altogether, these properties significantly enhanced the platelet engrafting activity of progenitors produced in cultures. © AlphaMed Press 2018.


PMID: 30520180 [PubMed - as supplied by publisher]



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