Bone marrow stem and progenitor cell contribution to neovasculogenesis is dependent on model system with SDF-1 as a permissive trigger

Abstract

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-1␣ (SDF-1␣) and its mobilizing effects on BM. Blocking SDF-1␣ activity with neutralizing antibodies abrogated BMderived neovascularization in lung cancer and retinopathy. IntroductionThe mechanisms governing bone marrow (BM)-derived contribution to tissue neovascularization and the origin of marrow cells participating in this process are undefined, and remain a root of controversy in the field. Although initially thought to arise from local angiogenic events, recent studies purport that BM-derived cells including endothelial progenitor cells, hemangiocytes, and hemangioblasts contribute directly to vessel formation in different models of neovascularization. [1][2][3][4][5][6][7][8][9][10] However, contradictory results relegate BM involvement to paracrine mechanisms rather than direct vessel contribution through the action of cells such as tie-2 expressing monocytes (TEMs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and recruited blood circulating cells (RBCCs). [11][12][13][14][15][16][17][18][19] Moreover, it was recently reported that BM-derived endothelial progenitor cells expressing vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2 ϩ ) are not mobilized from BM in a mouse model of cancer. 14 Several reports indicate the importance of timing and environment on BM-derived neovascularization in cancer. 2,5,20,21 These results coupled with different model systems and experimental techniques may explain confounding results.Therefore, we reasoned that we could test various situations of neovessel formation using a novel technique in which multiple neovascularization models were established in individual mice. This technique reduced experimental variations and allowed direct comparative analyses among models.Our data suggest that neovascularization can occur through multiple redundant mechanisms dictated by the local microenvironment. BM-derived cells can participate in neovascularization in some but not all settings. BM contribution is dependent on site-specific expression of stromal cell derived factor-1␣ (SDF-1␣), its mobilizing effects on BM, and its capacity to promote homing of those mobilized cells to specific tissues. Furthermore, we show that SDF-1␣ activity can be significantly inhibited by therapeutic intervention, thereby reducing BM contribution to neovascularization. We also confirm the adult hematopoietic stem cell (HSC) as a long-t...

Reversing Resistance to Vascular-Disrupting Agents by Blocking Late Mobilization of Circulating Endothelial Progenitor Cells

“…In our hands, however, disruption of this immediate VDA-induced CEP peak using DC101 or another antiangiogenic agent (sunitinib) was not observed. The variations in CEP levels reported herein were synchronized with changes in levels of G-CSF, MMP-9, and SDF-1, 3 key proteins known to orchestrate CEP mobilization (21,31,43,48,49). Interestingly, although antiangiogenic strategies had no effect on the initial CEP peak, their administration after CA-4-P completely abrogated the late CEP burst and showed the most potent antitumor activity with concomitant disruption of GFP + bone marrow-derived cell tumor infiltration.…”

“…Although in some preclinical studies authors have shown the incorporation of CEPs in tumor neovessels (24)(25)(26)(27), the contribution and general relevance of CEPs to tumor angiogenesis and progression have been controversial and the subject of intense scrutiny as the result of several studies in which investigators reported contradictory data (28)(29)(30)(31)(32). Alternatively, in other preclinical studies, authors have suggested that CEPs are not only key contributors to tumor neoangiogenesis and tumor growth (24)(25)(26) but are also critical regulators of the angiogenic switch promoting metastatic progression (33).…”

SDF-1:CXCR4 Axis Is Fundamental for Tissue Preservation and Repair

“…These investigators quantified the levels of vascular endothelial growth factor and SDF-1 in the vitreous of patients with retinal detachment (RD) and proliferative diabetic retinopathy as well as other pathologies. Vascular endothelial growth factor and SDF-1 levels are increased in proliferative diabetic retinopathy; 16,17 however, only SDF-1 levels were increased in RD. Interestingly, the up-regulation of SDF-1 in RD did not lead to proliferation of the vasculature of the retina.…”

Potential Use of CXCR4 Antagonists to Mobilize Endothelial and Mesenchymal Stem Cells

“…Recent elegant experiments using multiple model systems to evaluate angiogenesis in mice confi rm that bone marrow stem cells make a signifi cant contribution to neovascularization and that this is dependent on the nature of the extent of the disease. Thus, there is evidence that the more the severe the ischemia the greater the contribution of bone marrow stem cells to the vasculogenesis [ 67 ] .…”