title: Cell Injury-Induced Release of Fibroblast Growth Factor 2: Relevance to Intracerebral Mesenchymal Stromal Cell Transplantations.
abstract: Beneficial effects of intracerebral transplantation of mesenchymal stromal cells (MSC) and their derivatives are believed to be mediated mostly by factors produced by engrafted cells. However, the mesenchymal cell engraftment rate is low, and the majority of grafted cells disappear within a short post-transplantation period. Here, we hypothesize that dying transplanted cells can affect surrounding tissues by releasing their active intracellular components. To elucidate the type, amounts, and potency of these putative intracellular factors, freeze/thaw extracts of MSC or their derivatives were tested in enzyme-linked immunosorbent assays and bioassays. We found that fibroblast growth factor (FGF)2 and FGF1, but not vascular endothelial growth factor and monocyte chemoattractant protein 1 levels were high in extracts despite being low in conditioned media. Extracts induced concentration-dependent proliferation of rat cortical neural progenitor cells and human umbilical vein endothelial cells; these proliferative responses were specifically blocked by FGF2-neutralizing antibody. In the neuropoiesis assay with rat cortical cells, both MSC extracts and killed cells induced expression of nestin, but not astrocyte differentiation. However, suspensions of killed cells strongly potentiated the astrogenic effects of live MSC. In transplantation-relevant MSC injury models (peripheral blood cell-mediated cytotoxicity and high cell density plating), MSC death coincided with the release of intracellular FGF2. The data showed that MSC contain a major depot of active FGF2 that is released upon cell injury and is capable of acutely stimulating neuropoiesis and angiogenesis. We therefore propose that both dying and surviving grafted MSC contribute to tissue regeneration.
authors: 1 Department of Research, SanBio, Inc. , Mountain View, California.
authors: Irina
authors: I
authors: Aizman
authors: 1 Department of Research, SanBio, Inc. , Mountain View, California.
authors: Deepti
authors: D
authors: Vinodkumar
authors: 2 Department of Production Development, SanBio, Inc. , Mountain View, California.
authors: Michael
authors: M
authors: McGrogan
authors: 1 Department of Research, SanBio, Inc. , Mountain View, California.
authors: Damien
authors: D
authors: Bates
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology; D002454:Cell Differentiation; D002457:Cell Extracts / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006085:Graft Survival / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D058953:Neural Stem Cells / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; D002457:Cell Extracts; D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1