Abstract
Low molecular weight heparin (LMWH)/protamine (P) nano/micro particles (N/MPs) (LMWH/P N/MPs) were applied as carriers for heparin-binding growth factors (GFs) and for adhesive cells including adipose-derived stromal cells (ADSCs) and bone marrow-derived mesenchymal stem cells (BMSCs). A mixture of LMWH and P yields a dispersion of N/MPs (100 nm–3 μm in diameter). LMWH/P N/MPs can be immobilized onto cell surfaces or extracellular matrix, control the release, activate GFs and protect various GFs. Furthermore, LMWH/P N/MPs can also bind to adhesive cell surfaces, inducing cells and LMWH/P N/MPs-aggregate formation. Those aggregates substantially promoted cellular viability, and induced vascularization and fibrous tissue formation in vivo. The LMWH/P N/MPs, in combination with ADSCs or BMSCs, are effective cell-carriers and are potential promising novel therapeutic agents for inducing vascularization and fibrous tissue formation in ischemic disease by transplantation of the ADSCs and LMWH/P N/MPs-aggregates. LMWH/P N/MPs can also bind to tissue culture plates and adsorb exogenous GFs or GFs from those cells. The LMWH/P N/MPs-coated matrix in the presence of GFs may provide novel biomaterials that can control cellular activity such as growth and differentiation. Furthermore, three-dimensional (3D) cultures of cells including ADSCs and BMSCs using plasma-medium gel with LMWH/P N/MPs exhibited efficient cell proliferation. Thus, LMWH/P N/MPs are an adequate carrier both for GFs and for stromal cells such as ADSCs and BMSCs, and are a functional coating matrix for their cultures.
Highlights
Drug repositioning is recognized as an effective strategy against the laborious and expensive de novo drug discovery as well as the difficult approval system of new drugs [1]
adipose-derived stromal cells (ADSCs) and bone marrow-derived mesenchymal stem cells (BMSCs) proliferated in DMEM using low-concentration serum (2% human serum (HS) or fetal bovine serum (FBS)) on fibroblast growth factor (FGF)-2 immobilized Low molecular weight heparin (LMWH)/P nano/micro particles (N/MPs)-coated plates (Figure 6) [7]
It should be noted that the cell growth of cultured BMSCs and ADSCs on LMWH/P N/MPs-coated plates in low FBS (1%–2%) medium with FGF-2 was significantly stimulated, and similar stimulation was observed in those cultured cells on LMWH/P
Summary
Drug repositioning is recognized as an effective strategy against the laborious and expensive de novo drug discovery as well as the difficult approval system of new drugs [1]. The in vivo effects of GFs from PRP and LMWH/P N/MPs have been demonstrated in neovascularization and formation of granulation tissue using enhanced filtration of inflammatory cells in nude mice [6]. LMWH/P N/MPs-coating matrix provides an excellent biomaterial to immobilize and retain GFs and cytokines for superior growth of various types of cells with low (1%–2%) serum (either fetal bovine serum (FBS) or human serum (HS)) medium. ADSCs and BMSCs proliferated in DMEM using low-concentration serum (2% HS or FBS) on FGF-2 immobilized LMWH/P N/MPs-coated plates (Figure 6) [7]. The much lower concentrations of the cytokines than those recommended by the manufacturer (Lonza Japan Corp.) were required for maximal expansion of CD34+ HCs on the LMWH/P N/MPs-coated plates [8,50] Those findings may have important implications for the use of heparinoid as an artificial matrix for ex vivo expansion of CD34+ HCs with adequate cytokines. LMWH/P N/MPs-coating matrix in the presence of much lower concentrations of SCF, Tpo and Flt-3 is a convenient and safe material for superior expansion of CD34+ HCs using HPGM without any animal serum [8,50]
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