Most tissues possess tissue-specific stem cells that allow them to maintain tissue integrity. Stem cell niches provide an ideal regulatory microenvironment to support the maintenance and proliferation of adult stem cells. However, adult stem cells and stem cell niches have not been identified for all tissues.
Adult stem cells that give rise to the vascular endothelium are still unknown. In this thesis work, we identified a rare population of vascular endothelial stem cells (VESC) on the vascular wall by the phenotype lin-CD31+CD105+Sca-1+c-kit+. A single c-kit expressing VESC with highly proliferative capacity generated functional blood vessels in vivo. A genetic defect in endothelial c-kit resulted in an abolished colony-forming ability of VESCs and impaired tumor angiogenesis and tumor growth. Angiogenesis, the growth of new blood vessels from pre-existing vessels, is actively involved in many physiological and pathological processes such as wound repair, female reproductive cycling, ischemic disease and tumor development. There are two major groups of cells involved in the adult vascular growth, cells that contribute directly by composing the blood vessels, such as vascular endothelial stem cells, and cells that contribute indirectly in a paracrine manner such as infiltrating hematopoietic cells.
Infiltrating hematopoietic cells from the bone marrow contribute to angiogenesis in a paracrine manner by secreting angiogenic factors or by remodeling the extracellular matrix. In this thesis work, we found that transforming growth factor-β (TGF-β) recruited a massive amount of hematopoietic cells to local microenvironment. TGF-β stimulated vascular endothelial growth factor (VEGF) expression on these hematopoietic effectors and thus induced vascular growth. This stimulation was regulated by p38 and p44/p42 mitogen-activated protein kinase (MAPK) signaling pathways. These results together provided evidence for a dual action mechanism for TGF-β-induced angiogenesis in vivo. In malignant tumors, we found that the tumor expressed osteoblastic and vascular hematopoietic stem cell (HSC) niche molecules and enclosed multipotent hematopoietic progenitors. The proliferating hematopoietic progenitors generated hematopoietic effector cells and supported angiogenesis and tumor growth by secreting matrix metalloprotease 9 (MMP-9) and VEGF. HSPCs were found to be in proximity to tumor vasculature. Tumor microenvironment shared features of HSC niche in the bone marrow. Therapeutic ablation of hematopoietic cells including proliferating hematopoietic cells from tumor using AMD3100 in vivo resulted in inhibited tumor angiogenesis and growth.
In conclusion, we identified and characterized a rare population of c-kit expressing VESCs that give rise to the vascular endothelium in adult. Further purification and detailed characterization of VESCs will provide a better understanding of VESCs and hierarchy of endothelial lineage. Our observations on the in vivo angiogenesis induced by TGF-β elucidated the mechanisms of action of TGF-β in promoting vascular growth. Together with current findings on the ectopic tumor hematopoietic microenvironment, the proliferating hematopoietic progenitors and angiogenic hematopoietic effector cells, these results provided potential therapeutic targets to treat cancer and other diseases.Not Availabl
