The purpose of the proposed experiments is to compare the therapeutic potential of adult versus embryonic stem cells in mouse models of human disease: hind limb ischemia (HI) and myocardial infarction (MI). HI and MI are often caused by insufficient blood flow after occlusion of a large artery. Blood flow may recover through the growth and remodeling of new and pre-existent blood vessels (angiogenesis and arteriogenesis, respectively), but often these processes are insufficient or impaired, leading to death or amputation of limbs. Stem cells have recently emerged as a potential source for growing new vessels. Adult stem cells known as hematopoietic stem cells (HSCs) have been identified in the bone marrow of mice and humans, and used for decades in the treatment of hematological disorders. Recent findings suggest HSCs can participate in angiogenesis and arteriogenesis in vivo by differentiating into vascular cells; however, HSCs are difficult or impossible to expand in culture. Embryonic stem cells (ESCs) from both mice and humans, conversely, can be expanded indefinitely in culture, and form cells of all three germ layers in vivo (pluripotent). ESCs may be limited by safety concerns, though, since they often form tumors when injected into mice. In the proposed experiments, the ability of mouse HSCs to form vascular structures after HI and MI will be tested. The ability of HSCs to form vascular structures to ameliorate the detrimental effects of HI and MI of will be directly compared with mouse ESCs. Mouse ESCs will be injected as undifferentiated pluripotent cells or genetically selected and differentiated vascular cells. HSCs, undifferentiated ESCs and differentiated ESC-derived vascular cells will be compared in their ability to form functional blood vessels in the same mouse models of human disease. The objective is to provide novel insights into the potential benefits and limitations of each type of stem cell that may be relevant in treating human vascular diseases.
| Manka, David; Spicer, Zachary; Millhorn, David E (2005) Bcl-2/adenovirus E1B 19 kDa interacting protein-3 knockdown enables growth of breast cancer metastases in the lung, liver, and bone. Cancer Res 65:11689-93 |
