Cell injury-induced release of FGF2: relevance to intracerebral mesenchymal stromal cell transplantations.

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 posttransplantation 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 ELISAs and bioassays. We found that FGF2 and FGF1, but not VEGF and MCP1 levels were high in extracts despite being low in conditioned media (CM). Extracts induced concentration-dependent proliferation of rat cortical neural progenitor cells (NPC) and human umbilical vein endothelial cells (HUVEC); 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 the tissue regeneration. Page 2 of 33 St em C el ls a nd D ev el op m en t C el l i nj ur yin du ce d re le as e of F G F2 : r el ev an ce to in tr ac er eb ra l m es en ch ym al s tr om al c el l t ra ns pl an ta tio ns . ( do i: 10 .1 08 9/ sc d. 20 15 .0 08 3) T hi s ar tic le h as b ee n pe er -r ev ie w ed a nd a cc ep te d fo r pu bl ic at io n, b ut h as y et to u nd er go c op ye di tin g an d pr oo f co rr ec tio n. T he f in al p ub lis he d ve rs io n m ay d if fe r fr om th is p ro of .