Bone marrow stem and progenitor cell contribution to neovasculogenesis is dependent on model system with SDF-1 as a permissive trigger.
Adult bone marrow (BM) contributes to neovascularization in some but not all settings, and reasons for these discordant results have remained unexplored. We conducted novel comparative studies in which multiple neovascularization models were established in single mice to reduce variations in experimental methodology. In different combinations, BM contribution was detected in ischemic retinas and, to a lesser extent, Lewis lung carcinoma cells, whereas B16 melanomas showed little to no BM contribution. Using this spectrum of BM contribution, we demonstrate the necessity for site-specific expression of stromal-derived factor-1alpha (SDF-1alpha) and its mobilizing effects on BM. Blocking SDF-1alpha activity with neutralizing antibodies abrogated BM-derived neovascularization in lung cancer and retinopathy. Furthermore, secondary transplantation of single hematopoietic stem cells (HSCs) showed that HSCs are a long-term source of neovasculogenesis and that CD133(+)CXCR4(+) myeloid progenitor cells directly participate in new blood vessel formation in response to SDF-1alpha. The varied BM contribution seen in different model systems is suggestive of redundant mechanisms governing postnatal neovasculogenesis and provides an explanation for contradictory results observed in the field.
Madlambayan
Gerard J
GJ
Program in Stem Cell Biology and Regenerative Medicine, University of Florida, Gainesville, Florida, USA.
Butler
Jason M
JM
Hosaka
Koji
K
Jorgensen
Marda
M
Fu
Dongtao
D
Guthrie
Steven M
SM
Shenoy
Anitha K
AK
Brank
Adam
A
Russell
Kathryn J
KJ
Otero
Jaclyn
J
Siemann
Dietmar W
DW
Scott
Edward W
EW
Cogle
Christopher R
CR
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000503:physiopathology; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology; D008546:Melanoma, Experimental / Q000098:blood supply / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000502:physiology; D012171:Retinal Vessels / Q000473:pathology
C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4