Targeted Delivery of Progenitor Cells to the Lung

描述（由申请人提供）：越来越多的证据支持干细胞在损伤或患病人类肺部修复和再生中的潜在应用。虽然胚胎和成体组织来源的干细胞都可以被诱导表达气道或肺泡上皮细胞以及肺血管细胞的表型标记，但植入的大小以及这些祖细胞的扩增和分化的决定因素尚未得到严格确定。祖细胞治疗最容易通过静脉给药，因此，未来肺疾病干细胞治疗的临床试验将需要一种有效的方法来促进系统给药的肺祖细胞的募集、保留、增殖和分化。为此，我们建议研究一种新的纳米聚糖技术用于肺泡内递送和肺泡周围保留生长因子，这些生长因子被认为对人类肺部疾病的啮齿类动物模型中的肺祖细胞的募集、克隆扩增和分化很重要。为实现这一目标，我们提出三个具体目标。我们将首先合成含有特定生长因子（血管内皮生长因子、palifermin和repifermin）或趋化因子（基质细胞衍生因子-1）的纳米聚糖复合物，每种复合物都因其在肺修复和再生中的独特作用而被选择。这些纳米聚糖复合物的合成利用了这些蛋白质中含有的肝素结合位点，以促进它们与复合物的聚阴离子糖胺聚糖组分的结合和稳定。然后我们将监测它们在肺中的滞留和分布的时间过程。接下来，我们将研究这些雾化纳米聚糖复合物在全身（静脉）给药后对人类祖细胞募集和保留在肺部的影响。最后，我们将评估这种纳米聚糖引导的祖细胞治疗对人类肺部疾病、弹性酶诱导的肺气肿和单芥碱诱导的肺动脉高压模型大鼠肺修复和再生的影响。这项评估将包括肺泡血管结构植入和再生的形态学和分子分析，以及肺部结构和功能随时间变化的一系列超极化惰性气体磁共振成像。综上所述，这些研究将用于证明这种独特方法对人类肺部疾病的干细胞治疗的可行性，以及其潜在的有益结构和功能后果。

DESCRIPTION (provided by applicant): Growing evidence supports the potential use of stem cells in the repair and regeneration of injured or diseased human lungs. While both embryonic and adult tissue-derived stem cells can be induced to express phenotypic markers of ainway or alveolar epithelial cells as well as pulmonary vascular cells, the magnitude of engraftment and the determinants of expansion and differentiation of these progenitor cells have yet to be rigorously determined. Progenitor cell therapy is most readily administered intravenously and, thus, future clinical trials of stem cell therapy for pulmonary diseases will require an effective method for promoting the recruitment, retention, proliferation, and differentiation of systemically administered progenitor cells in the lung. To this end, we propose to study the use of a novel nanoglycan technology for the intra-alveolar delivery and peri-alveolar retention of growth factors believed to be important for recruitment, clonal expansion, and differentiation of pulmonary progenitor cells in well-established rodent models of human lung diseases. To achieve this goal, we propose three specific aims. We will first synthesize nanoglycan complexes bearing specific growth factors (vascular endothelial growth factor, palifermin, and repifermin) or a chemokine (stromal cell-derived factor-1) each chosen for its unique effects in lung repair and regeneration. The synthesis of these nanoglycan complexes exploits the heparin-binding sites contained in these proteins to facilitate their association with and stabilization by polyanionic glycosaminoglycan components ofthe complex. We will then monitor the time course of their retention and distribution in the lung. Next, we will study the effects of these aerosolized nanoglycan complexes on human progenitor cell recruitment to and retention in the lung after their systemic (intravenous) administration. Finally, we will assess the consequences of this nanoglycan-guided progenitor cell therapy on lung repair and regeneration in hwo rat models of human pulmonary disease, elastase-induced emphysema and monocrotaline-induced pulmonary hypertension. This assessment will include morphological and molecular analyses of engraftment and regeneration of alveolo-vascular structures, as well as serial hyperpolarized noble gas magnetic resonance imaging of time-dependent changes in lung structure and function. Taken together, these studies will be used to demonstrate the feasibility of this unique approach to stem cell therapy for human pulmonary diseases, as well as its potentially beneficial structural and functional consequences.