Switching-on survival and repair response programs in islet transplants by bone marrow-derived vasculogenic cells.
OBJECTIVE
Vascular progenitors of bone marrow origin participate to neovascularization at sites of wound healing and transplantation. We hypothesized that the biological purpose of this bone marrow-derived vascular component is to contribute angiogenic and survival functions distinct from those provided by the local tissue-derived vasculature.


RESULTS
To address this hypothesis, we investigated the functional impact of bone marrow-derived vascular cells on pancreatic islets engraftment using bone marrow-reconstituted Id1(+/-)Id3(-/-) mice, a model of bone marrow-derived vasculogenesis. We show that, in this model, bone marrow-derived vasculogenic cells primarily contribute to the formation of new blood vessels within islet transplants. In contrast, graft revascularization in a wild-type background occurs by tissue-derived blood vessels only. Using these distinct transplant models in which bone marrow-and tissue-derived vasculature are virtually mutually exclusive, we demonstrate that bone marrow-derived vasculogenic cells exhibit enhanced angiogenic functions and support prompt activation of islets survival pathways, which significantly impact on islets engraftment and function. Moreover, gene profiling of vascular and inflammatory cells of the grafts demonstrate that neovascularization by bone marrow-derived cells is accompanied by the activation of a genetic program uniquely tuned to downregulate harmful inflammatory responses and to promote tissue repair.


CONCLUSIONS
These studies uncover the biological significance of bone marrow-derived vasculogenic cells in the response to injury during transplantation. Enhancing the contribution of bone marrow-derived vasculogenic cells to transplantation sites may help to overcome both limited angiogenic responses of the adult tissue-derived vasculature and untoward effects of inflammation on transplant engraftment.
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
Robyn
R
Miller
Vincenzo
V
Cirulli
Giuseppe R
GR
Diaferia
Stefania
S
Ninniri
Gary
G
Hardiman
Bruce E
BE
Torbett
Robert
R
Benezra
Laura
L
Crisa
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002470:Cell Survival / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000503:physiopathology / Q000601:surgery*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology; D006085:Graft Survival / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics; D007515:Islets of Langerhans / Q000098:blood supply* / Q000166:cytology / Q000276:immunology; D016381:Islets of Langerhans Transplantation; D007962:Leukocytes / Q000166:cytology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010195:Pancreatitis / Q000473:pathology / Q000503:physiopathology; D014945:Wound Healing / Q000502:physiology
C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D051796:Inhibitor of Differentiation Proteins; C067679:Idb3 protein, mouse