title: Nonbone marrow-derived circulating progenitor cells contribute to postnatal neovascularization following tissue ischemia.
abstract: Circulating progenitor cells home to sites of postnatal neovascularization and differentiate into endothelial cells but questions remain regarding the source of these cells. Indeed, a recent study suggests that nonbone marrow-derived cells may be even more important than bone marrow-derived cells in the setting of transplant arteriosclerosis. Thus, we aimed to thoroughly investigate the contribution of nonbone marrow-derived progenitor cells for neovascularization. We exclusively identified nonbone marrow-derived progenitor cells by combining a parabiosis model with reverse bone marrow transplantation followed by hindlimb ischemia. In this model, nonbone marrow-derived circulating progenitor cells attributed for 74+/-13% of the circulating progenitor cells that incorporated into the ischemic hindlimb. Increasing evidence suggests that organs such as small intestine and liver contain a considerable number of tissue resident progenitor cells and, thus, represent putative sources for nonbone marrow-derived progenitors. To track organ-derived progenitors, we transplanted sex-mismatched small intestine or liver, respectively, into rats followed by induction of hindlimb ischemia. These experiments show that organ-derived progenitor cells are contributing to postnatal vasculogenesis (intestine: 4.7+/-3.7%; liver: 6.3+/-2.2%). Based on the subsequent observation that liver-derived nonhematopoietic c-kit(+)CD45(-) progenitors are mobilized on induction of hindlimb ischemia, we prospectively isolated and intravenously infused these progenitors from murine livers. The isolated cells demonstrated a marked capacity for enhancing neovascularization and restoring blood flow to the ischemic hindlimb (no cells: 26.4+/-4.8% of normal blood flow; c-kit(+)CD45(-) cells: 67.0+/-8.0% of normal flow; P<0.01). In conclusion, we find that nonbone marrow-derived c-kit(+)CD45(-) progenitors contribute to postnatal neovascularization to an extent that is similar to that of bone marrow-derived progenitor cells. Intestine and liver represent a rich source for mobilized tissue-residing progenitor cells.
authors.affiliation: Department of Molecular Cardiology, J.W. Goethe University, Frankfurt, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Aicher
authors.forename: Markus
authors.initials: M
authors.lastname: Rentsch
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Sasaki
authors.forename: Joachim W
authors.initials: JW
authors.lastname: Ellwart
authors.forename: Fred
authors.initials: F
authors.lastname: Fändrich
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.forename: John P
authors.initials: JP
authors.lastname: Cooke
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
authors.forename: Christopher
authors.initials: C
authors.lastname: Heeschen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017690:Cell Transplantation / Q000379:methods; D005260:Female; D005263:Femoral Artery / Q000601:surgery; D006614:Hindlimb / Q000098:blood supply* / Q000601:surgery; D007421:Intestine, Small / Q000166:cytology / Q000601:surgery / Q000637:transplantation; D007511:Ischemia / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D016031:Liver Transplantation / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D013234:Stem Cells / Q000502:physiology*