Human embryonic stem cell-derived mesenchymal stromal cell transplantation in a rat hind limb injury model.
OBJECTIVE
Mesenchymal stromal cells (MSC) have been used in a wide variety of pre-clinical experiments and in an increasing number of human clinical trials. Although many of these studies have shown different levels of engraftment, the exact fate of MSC after transplantation and the tissue response to their engraftment have not been investigated in detail. In the present work we studied the distribution of human MSC in a rat hind limb ischemic injury model immediately after transplantation and also analyzed the recipient tissue response to transplanted cells.


METHODS
We tracked the in vivo fate of the transplanted MSC utilizing bioluminescence imaging, fluorescence microscopy and gene/protein expression analysis in a rat hind limb ischemia model. We also monitored the viability of transplanted cells by graft versus recipient expression analysis and determined the angiogenic and proliferative effect of transplantation by histologic staining.


RESULTS
According to imaging analysis only a small portion of cells persisted for an extended period of time at the site of injury. Interestingly, recipient versus graft expression studies showed increased synthesis of rat-origin angiogenic factors and no human-origin mRNA or protein synthesis in transplanted tissues. More importantly, despite the lack of robust engraftment or growth factor secretion the transplantation procedure exerted a significant pro-angiogenic and pro-proliferative effect, which was mediated by angiogenic and mitogenic signaling pathways.


CONCLUSIONS
Our results show an immediate temporal tissue effect in response to MSC transplantation that may represent a novel indirect paracrine mechanism for the beneficial effects of cell transplantation observed in injured tissues.
Laurila
Juha P
JP
Medicity Research Laboratory, University of Turku, Turku, Finland.
Laatikainen
Lilja
L
Castellone
Maria D
MD
Trivedi
Parul
P
Heikkila
Jari
J
Hinkkanen
Ari
A
Hematti
Peiman
P
Laukkanen
Mikko O
MO
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D006087:Graft vs Host Reaction / Q000276:immunology; D006789:Host vs Graft Reaction / Q000276:immunology; D006801:Humans; D035002:Lower Extremity / Q000098:blood supply* / Q000473:pathology / Q000601:surgery; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D018919:Neovascularization, Physiologic; D051381:Rats; D012038:Regeneration; D015427:Reperfusion Injury / Q000473:pathology / Q000601:surgery*; D015398:Signal Transduction / Q000502:physiology; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A