Bioengineering a Chimeric Human Lung

描述（由申请人提供）：美国近2500万人患有终末期肺病。肺移植是这些患者唯一的治疗选择，但由于供体器官短缺、长期排斥反应和免疫抑制治疗的需要，肺移植仍然受到阻碍。产生含有患者自身细胞的肺的能力将从根本上改变我们目前治疗终末期肺病的方式。我们建议通过用人多能干细胞（hPSC）衍生的肺祖细胞接种部分脱细胞的供体肺来生物工程化嵌合人肺。我们的目标是（1）获得对hPSC向肺谱系的特化和使用天然肺基质形成肺组织的新见解，以及（2）生物工程化功能肺用于移植。我们设想，可以通过用患者的hPSC衍生的肺细胞部分替代细胞材料来改善被排斥/边缘质量供体肺的功能。我们的假设是接种到肺的脱细胞区域中的hPSC祖细胞将响应于来自组织基质和残余细胞的位点特异性信号而被诱导再生和重塑供体肺。我们的方法将是采用移植排斥的供体肺，并从肺的有限区域去除细胞，同时保留脱细胞基质和周围完整实质的组成，结构和机械性能。通过肺实质同时灌注去细胞化液和门静脉灌注Perfadex溶液，我们将保留完整的肺血管。然后，脱细胞区域将被hPSC衍生的肺祖细胞重新增殖，以产生能够进行某种最低可接受水平的气体交换的肺，这将在重塑时得到改善。目的1是从hPSC中获得并充分表征肺和气道上皮的不同谱系。目的二是通过在脱细胞基质切片上培养人PSC来源的肺细胞来生物工程化人肺组织。目的3是通过用hPSC衍生的肺细胞再填充肺的脱细胞化区域来形成嵌合人肺，并使用临床肺灌注系统研究功能恢复。该提议最终旨在通过组合三个主要创新组分来实现移植排斥的供体肺的功能恢复：（1）从hPSC衍生肺细胞，（2）供体肺的区域性脱细胞化，同时保留脉管系统和实质结构，以及（3）通过用受体细胞再增殖肺来实现功能恢复。

DESCRIPTION (provided by applicant): Nearly 25 million people in the United States suffer from end-stage lung disease. Lung transplantation, the only curative option for these patients, remains hampered by donor organ shortages, long-term rejection, and the need for immunosuppressive therapy. The ability to generate lungs containing a patient's own cells would radically change the way we currently treat end-stage lung disease. We propose to bioengineer chimeric human lungs by seeding partially decellularized donor lungs with human pluripotent stem cell (hPSC) derived pulmonary progenitors. Our goals are to (1) obtain new insights into hPSC specification towards pulmonary lineages and the formation of lung tissue using native lung matrix, and (2) bioengineer functional lungs for transplantation. We envision that the function of rejected/marginal quality donor lungs can be improved by partial replacement of cellular material by a patient's hPSC-derived pulmonary cells. Our hypothesis is that hPSC-progenitors seeded into the decellularized regions of the lung will be induced to regenerate and remodel the donor lung in response to site-specific signals from the tissue matrix and residual cells. Our approach will be to take donor lungs rejected for transplantation and remove cells from limited regions of the lung while preserving the composition, architecture, and mechanical properties of the decellularized matrix and the surrounding intact parenchyma. By simultaneously perfusing decellularization fluids through the lung parenchyma and Perfadex solution through the portal vein, we will preserve intact lung vasculature. The decellularized regions will then be repopulated by hPSC-derived lung progentor cells to produce a lung that is capable of some minimally acceptable level of gas exchange that will improve upon remodeling. Aim 1 is to derive and fully characterize the different lineages of the lung and airway epithelium from hPSCs. Aim 2 is to bioengineer human lung tissue by hPSC-derived pulmonary cells cultured on slices of decellularized matrix. Aim 3 is to form a chimeric human lung by repopulating decellularized regions of the lung with hPSC- derived pulmonary cells and investigate functional recovery using a clinical lung perfusion system. This proposal ultimately aims to achieve functional recovery of donor lungs rejected for transplantation by combining three major innovative components: (1) Derivation of pulmonary cells from the hPSCs, (2) Regional decellularization of the donor lung with the preservation of vasculature and parenchymal architecture, and (3) Functional recovery through repopulation of the lung with the recipient's cells.