Role of Adult Angioblasts in Vascular Maintenance

描述(由申请人提供)：骨髓源干细胞作为治疗多种病理疾病的潜在治疗剂正在紧张的研究中。外源性骨髓细胞治疗可改善啮齿动物梗死后的心肌功能和卒中后的脑功能。尽管在骨髓干细胞的潜在临床应用方面取得了巨大的进展，但人们对其在体内的正常功能或控制其生长和分化的因素知之甚少。此外，人们对这些细胞从骨髓转移到血液中后发生的变化一无所知，但人们认为这些细胞必须通过血液才能到达组织损伤的位置。此外，目前还没有确定循环细胞是否等同于多能骨髓干细胞，但来自我们和其他实验室的初步数据表明，至少有多种细胞类型的祖细胞存在于血液中。为了开始了解循环干细胞生物学，我们专注于一种类型，即循环内皮祖细胞(CEP)，即可分化为内皮细胞的循环细胞。我们的第一个目标是通过更好地描述它们的表型(S)和确定控制它们生长和分化的因素来进一步了解CEP生物学。这一认识可能使我们能够在体内调节CEP的功能，从而对临床有利。干细胞生物学的另一个鲜为人知的组成部分是，系统性疾病可能如何改变它们的功能。我们尤其感兴趣的是糖尿病如何影响CEP功能。我们实验室的证据表明，CEP功能障碍可能与糖尿病相关的血管疾病有关，CEP治疗可以改善糖尿病小鼠的血管形成。我们的第二个目标是确定糖尿病环境如何改变CEP功能。为了实现我们的目标，我们将1)确定血源性CD34+和CD14+富含细胞在体内新生血管中的作用；2)确定CEP生长和分化的分子和细胞调节因子，以及体内糖尿病引起的这些调节因子的潜在变化；3)描述外源性CEP调节剂在糖尿病和非糖尿病小鼠新生血管中CEP功能的潜在作用。

DESCRIPTION (provided by applicant): Bone marrow derived stem cells are under intense study as potential therapeutic agents for a wide variety of pathologies. Treatment with exogenous bone marrow cells can improve myocardial function after infarct and brain function after stroke in rodents. Despite tremendous progress in the development of potential clinical uses of bone marrow stem cells, little is known about their normal in vivo functions or factors controlling their growth and differentiation. Further, nothing is known about the changes that occur in these cells once they move from the bone marrow to the blood, yet it is thought that the cells must travel through the blood to reach the site of tissue damage. Also, it has not been determined if circulating cells are equivalent to the multi-potent bone marrow stem cells, but preliminary data from our and other laboratories suggest that at a minimum, progenitors for many cell types reside in the blood. To begin to understand circulating stem cell biology we have focused on one type, namely circulating endothelial cell progenitors (CEPs), i.e, circulating cells that can differentiate into endothelial cells. Our first goal is to further the understanding of CEP biology by better delineating their phenotype(s) and identifying factors that control their growth and differentiation. This understanding may allow us to modulate CEP function in vivo to clinical advantage. Another component of stem cell biology about which little is known is how systemic disorders might alter their function. Our interest in particular is in how diabetes may affect CEP function. Evidence from our laboratory indicates that CEP dysfunction may be involved in diabetes associated vascular disease and that CEP therapy can improve vascularization in diabetic mice. Our second goal is to determine how the diabetic environment alters CEP function. To accomplish our goals we will 1) define the role of blood-derived CD34+ and CD14+ enriched cells in neovascularization in vivo; 2) identify molecular and cellular regulators of CEP growth and differentiation, and potential diabetes induced changes in these regulators in vivo; and 3) delineate potential roles of exogenous CEP modulators on CEP function in neovascularization in diabetic and non-diabetic mice.