Effect of heparin on the biological properties and molecular signature of human mesenchymal stem cells

Abstract

Chronic use of heparin as an anti-coagulant for the treatment of thrombosis or embolism invokes many adverse systemic events including thrombocytopenia, vascular reactions and osteoporosis. Here, we addressed whether adverse effects might also be directed to mesenchymal stem cells that reside in the bone marrow compartment. Harvested human bone marrow-derived mesenchymal stem cells (hMSCs) were exposed to varying doses of heparin and their responses profiled. At low doses (<200 ng/ml), serial passaging with heparin exerted a variable effect on hMSC proliferation and multipotentiality across multiple donors, while at higher doses (≥100 µg/ml), heparin supplementation inhibited cell growth and increased both senescence and cell size. Gene expression profiling using cDNA arrays and RNA-seq analysis revealed pleiotropic effects of low-dose heparin on signaling pathways essential to hMSC growth and differentiation (including the TGFβ/BMP superfamily, FGFs, and Wnts). Cells serially passaged in low-dose heparin possess a donor-dependent gene signature that reflects their altered phenotype. Our data indicate that heparin supplementation during the culturing of hMSCs can alter their biological properties, even at low doses. This warrants caution in the application of heparin as a culture supplement for the ex vivo expansion of hMSCs. It also highlights the need for careful evaluation of the bone marrow compartment in patients receiving chronic heparin treatment.

Fabrication and Characterization of Heparin/Collagen Sponge for in Vitro Differentiation of Wharton’s Jelly-Derived Mesenchymal Stem Cells into Hepatocytes

“…Heparin has been previously shown to influence the MSC proliferation, phenotype, and biological properties (33). Modification in biological properties may affect the differentiation capability of MSCs.…”

Sulfated hyaluronan alters fibronectin matrix assembly and promotes osteogenic differentiation of human bone marrow stromal cells

“…5C). sGAG, in particular Hep and heparan sulfate, have been reported to promote osteogenesis of BMSC63553. Effects have been strongly dependent on cellular systems, detailed sGAG properties (doses, molecular weight, number of sulfate residues per disaccharide unit (degree of sulfation D.S.…”

Microfluidic Screening Reveals Heparan Sulfate Enhances Human Mesenchymal Stem Cell Growth by Modulating Fibroblast Growth Factor-2 Transport

“…We have previously shown that supplementation of hMSC cultures with the generic hyper‐sulfated glycosaminoglycan (GAG) heparin, results in adverse changes in the biological properties of the cells . However, HS preparations can selectively bind FGF‐2 and potentiate its signaling , improving growth and potency of hMSCs .…”