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修复和再生受伤或患病的人肺中的潜在用途。虽然胚胎和成人组织来源的干细胞都可以被诱导表达肺泡上皮细胞和肺血管细胞的表型标记，但这些祖细胞的植入数量和扩增和分化的决定因素尚未得到严格的确定。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全身给药的祖细胞在肺内的招募、保留、增殖和分化。为此，我们建议研究使用一种新的纳米多聚糖技术来在肺泡内传递和在肺泡周围保留生长因子，这些生长因子被认为是在已建立的人类肺部疾病的啮齿动物模型中招募、克隆扩增和分化肺前体细胞的重要因素。为了实现这一目标，我们提出了三个具体目标。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)的纳米多聚糖复合体，每种因子都因其在肺修复和再生中的独特作用而被选择。这些纳米多聚糖复合体的合成利用了这些蛋白质中包含的肝素结合部位，以促进它们与复合体的多阴离子糖胺多聚糖组分的结合和稳定。然后，我们将监测它们在肺部的滞留和分布的时间进程。接下来，我们将研究这些雾化纳米多聚糖复合体在全身(静脉)给药后对人类祖细胞在肺内募集和滞留的影响。最后，我们将评估这种纳米多糖引导的祖细胞疗法对人类肺部疾病、弹性酶诱导的肺气肿和野百合碱诱导的肺动脉高压这两种大鼠模型的肺修复和再生的影响。这项评估将包括对肺泡血管结构植入和再生的形态和分子分析，以及对肺结构和功能随时间变化的一系列超极化稀有气体磁共振成像。总之，这些研究将被用来证明这种独特的方法用于人类肺部疾病干细胞治疗的可行性，以及其潜在的有益的结构和功能后果。

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.