Incorporation of Endothelial Progenitor Cells into Placental Vaculature

内皮祖细胞并入胎盘血管

• 批准号: 8384771
• 负责人: Kayla J Bayless
• 金额: $ 21.53万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384771
• 关键词: Adherens Junction; Adult; Agonist; Anabolism; Anatomy; Angiogenic Factor; Atherosclerosis; Behavior; Blood; Blood Vessels; Bone Marrow; Calculi; Cell Communication; Cell Count; Cell Culture Techniques; Cell Therapy; Cells; Collagen; Communication; Development; Disease; Dose; Economic Burden; Embryo; Endothelial Cells; Endothelium; Equilibrium; Event; Extracellular Matrix; Family suidae; Fetal Growth; Future; Gap Junctions; Gestational Diabetes; Goals; Growth; Health; Human; In Vitro; Insulin; Integrins; Intravenous; Invaded; Ischemia; Knowledge; Label; Modeling; Newborn Infant; Nitric Oxide Synthase; Nutrient; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Physiological; Placenta; Placentation; Population; Pre-Eclampsia; Pregnancy; Process; Protein Isoforms; Pulmonary Hypertension; Recruitment Activity; Research; Signal Transduction; Site; Stem cells; Structure; Surface; Testing; Tight Junctions; Tissues; Umbilical vein; Uterus; Vascularization; Veins; angiogenesis; cardiovascular risk factor; design; diabetic; embryo/fetus; experience; fetal; in vivo; in vivo Model; junctional adhesion molecule; monolayer; neovascularization; novel; osteopontin; peripheral blood; receptor; regenerative; social; socioeconomics; tetrahydrobiopterin; three-dimensional modeling

DESCRIPTION (provided by applicant): Successful placental development has long-term implications for adult health, is necessary for embryo survival and proper fetal growth, and is dependent on vascularization. During pregnancy, placental blood vessels elongate, dilate, and extend new sprouts to facilitate maximal transfer of nutrients from maternal to placental vasculatures for hematotrophic support of the developing embryo/fetus. The long-term research goal is to identify and determine the physiological pathways that promote vessel growth within the placenta. Endothelial Progenitor Cells (EPCs) reside in the bone marrow, migrate, and incorporate into growing blood vessels to form new endothelial cells. A firm relationship has been established between EPCs and pulmonary hypertension, cardiovascular risk, ischemia, atherosclerosis, and pregnancy. EPC numbers decrease in preeclampsia and gestational diabetes, and maternal insulin therapy increases EPC numbers during diabetic pregnancy. We have isolated and characterized EPCs from the peripheral blood of newborn pigs. These EPCs express integrins, and use these transmembrane receptors to adhere and migrate in vitro on osteopontin (OPN) an extracellular matrix molecule with prominent expression in the placenta of both humans and pigs. When EPCs are cultured alone as a monolayer on the surface of 3D collagen matrices supplemented with angiogenic factors, they fail to invade the matrix. However, if cultured with adult human umbilical vein endothelial cells (HUVECs), which invade the matrix and form vascular structures, the EPCs incorporate into these vascular structures. This is similar to their behavior in vivo. Importantly, OPN dose-dependently increases the number of EPCs that incorporate into these vascular structures. The central hypothesis is that OPN recruits EPCs to sites of neovascularization within the placenta. Once there, EPCs communicate directly with adult endothelial cells via junctional adhesion molecules (i.e., gap, tight and adherens junctions) to incorporate into growing vessels. The two objectives are: (1) Determine the intercellular signals that allow EPCs to incorporate into established vasculature; and (2) Determine whether EPCs incorporate into placental vascular networks pigs. Completion of these objectives will aid the rational design and development of novel intravenous EPC-based therapies to normalize placental vasculature, and lessen effects of preeclampsia, gestational diabetes, and other gestational diseases. PUBLIC HEALTH RELEVANCE: Failed pregnancies elicit significant social and economic burdens; therefore, a complete understanding of these events is warranted. This proposal will significantly advance our understanding of how populations of cells found in the blood contribute to new blood vessel growth, which is a required step in pregnancy. Such knowledge will ultimately aid to decrease the socio-economic burdens associated with aberrations or deficiencies in the process.

描述（由申请人提供）：成功的胎盘发育对成人健康具有长期影响，是胚胎存活和胎儿正常生长所必需的，并且依赖于血管形成。在怀孕期间，胎盘血管延长，扩张，并延长新的芽，以促进营养物质从母体到胎盘血管的最大转移，为发育中的胚胎/胎儿提供血液营养支持。长期研究的目标是确定和确定促进胎盘内血管生长的生理途径。内皮祖细胞（Endothelial Progenitor Cells, EPCs）存在于骨髓中，并迁移到生长中的血管中形成新的内皮细胞。EPCs与肺动脉高压、心血管风险、缺血、动脉粥样硬化和妊娠之间存在密切关系。子痫前期和妊娠期糖尿病患者EPC数量减少，糖尿病妊娠期间孕妇胰岛素治疗增加EPC数量。我们从新生猪的外周血中分离并鉴定了EPCs。这些EPCs表达整合素，并利用这些跨膜受体在体外附着和迁移到骨桥蛋白（OPN）上，这是一种细胞外基质分子，在人和猪的胎盘中都有显著表达。当EPCs作为单层细胞单独培养在3D胶原基质表面并补充血管生成因子时，它们不能侵入基质。然而，如果与成人脐静脉内皮细胞（HUVECs）一起培养，EPCs会侵入基质并形成血管结构，EPCs会融入这些血管结构。这与它们在体内的行为相似。重要的是，OPN剂量依赖性地增加了纳入这些血管结构的EPCs的数量。中心假设是，OPN将EPCs招募到胎盘内新生血管的部位。一旦到达，EPCs通过连接粘附分子（即间隙连接、紧密连接和粘附连接）直接与成人内皮细胞交流，并融入生长中的血管。两个目标是：(1)确定允许EPCs并入已建立的脉管系统的细胞间信号；(2)确定EPCs是否融入猪胎盘血管网。这些目标的完成将有助于合理设计和开发基于epc的新型静脉注射疗法，以使胎盘血管正常化，并减轻先兆子痫、妊娠糖尿病和其他妊娠疾病的影响。