Blood vessels from adult versus embryonic stem cells

描述(申请人提供)：拟议实验的目的是比较成人干细胞和胚胎干细胞在人类疾病模型中的治疗潜力：后肢缺血(HI)和心肌梗死(MI)。HI和MI通常是由于大动脉闭塞后血流不足引起的。血流可以通过新生血管和先前存在的血管(血管生成和动脉生成)的生长和重塑来恢复，但通常这些过程不足或受损，导致死亡或截肢。干细胞最近已成为生长新血管的潜在来源。成体干细胞被称为造血干细胞(HSCs)，已经在小鼠和人类的骨髓中被发现，并被用于治疗血液疾病数十年。最近的研究表明，HSCs可以通过分化为血管细胞参与体内的血管生成和动脉生成；然而，HSCs在培养过程中很难或不可能扩增。相反，来自小鼠和人类的胚胎干细胞(ESCs)可以在培养中无限扩增，并在体内形成所有三个生殖层的细胞(多能性)。然而，ESCs可能会受到安全考虑的限制，因为它们在注射到小鼠体内时往往会形成肿瘤。在拟议的实验中，将测试小鼠HSCs在HI和MI后形成血管结构的能力。HSCs形成血管结构以改善HI和MI的不利影响的能力将直接与小鼠ESCs进行比较。小鼠胚胎干细胞将被注射为未分化的多能细胞或经过基因选择和分化的血管细胞。在相同的人类疾病小鼠模型中，将比较HSCs、未分化的ESCs和分化的ESC来源的血管细胞形成功能性血管的能力。其目的是为每种可能与治疗人类血管疾病相关的干细胞的潜在益处和局限性提供新的见解。

DESCRIPTION (provided by applicant): 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.